research on cancer immunotherapy

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Cancer Immunotherapy Research

Immunotherapies are revolutionizing the way we treat cancer. These promising and potent drugs aim to harness the body’s immune system, directing it to attack tumors. From basic science to clinical trials, Comprehensive Cancer Center researchers are conducting innovative studies to optimize the use of current immunotherapies, such as checkpoint inhibitors, predict who will respond, and identify new immune targets for therapy by dissecting the underlying mechanisms of antitumor immunity and immune tolerance.

The University of Chicago Medicine was among the first sites in the Midwest certified to offer breakthrough CAR T-cell therapy for select cancers in adults and children. Used to supplement forms of cancer treatment like chemotherapy, radiation and stem cell transplants, CAR T-cell therapy works by using modified versions of a patient’s own blood cells to target and destroy cancer cells.

Meet Sam Tinaglia and his mom, Suzie, and learn how CAR T-cell therapy works

Read Sam Tinaglia's story

Predicting Immunotherapy Response

Understanding how to overrule a signaling pathway that can cause treatments to fail in metastatic melanoma patients should help physicians extend the benefits of recently approved immunity-boosting drugs known as checkpoint inhibitors to more patients. Thomas Gajewski, MD, PhD , and colleagues showed how these tumors shield themselves from T cells—the immune system’s front-line anti-cancer weapon—by producing high levels of beta-catenin, an intracellular messenger (Spranger et al., Nature 523:231-5, 2015; Luke et al., Clin Cancer Res Epub ahead of print, 2019).

Justin Kline, MD , and colleagues have identified a subset of diffuse large B-cell lymphoma (DLBCL) with alterations in the PD-L1 gene and high levels of infiltration with T cells. Patients with these gene alterations generally had inferior outcomes following frontline chemo-immunotherapy but for those in which the cancer relapsed or did not respond to this therapy, these alterations were actually associated with better anti-PD1 immunotherapy response (Godfrey et al., Blood Epub ahead of print, 2019). These studies suggest that the more we know about the molecular events in tumors, the better we can predict how patients will respond to immunotherapy.

Optimizing Immunotherapy

Thomas Gajewski, MD, PhD , and colleagues have explored how our microbiome (i.e., the bacterial flora in our gastrointestinal tract) influences responses to immunotherapy. In pioneering preclinical animal studies, they boosted the ability of the immune systems of mice with melanoma to attack tumor cells by introducing a particular strain of bacteria into their digestive tracts. These gains were comparable to treatment with anticancer drugs known as checkpoint inhibitors, such as anti-PD-L1 antibodies. The combination of oral doses of the bacteria and anti-PD-L1 antibody nearly abolished tumor outgrowth (Sivan et al., Science 350: 1084-9, 2015). Subsequent work demonstrated that the commensal microbiome is associated with anti-PD-1 responsiveness in metastatic melanoma patients (Matson et al., Science 359: 104-8, 2018). These results have set the stage for clinical trials and provide important insights into why some people do or do not respond to immunotherapy and help identify mechanisms of drug resistance.

Wenbin Lin, PhD , Ralph Weichselbaum, MD , and collaborators are developing ways to spur checkpoint blockade immunotherapy into more potent action with drug cocktails contained in nanoparticles. For example, combination of anti-PD-L1 immunotherapy with nanoparticles containing oxaliplatin and other anti-cancer agents were effective in stimulating the immune system and eradicating colorectal tumors in animal models (Duan et al., Nat Commun 10:1899, 2019). Other studies by the team are combining radiotherapy with nanotechnology to overcome some limitations of checkpoint inhibitors (Lu et al., Nat Biomed Eng 2:600-10, 2018). These strategies may eventually help physicians make better use of checkpoint inhibitors to treat many types of cancer.

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Our researchers are leading immunotherapy clinical trials in multiple types of cancer, including melanoma and bladder cancer .

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Cancer Immunology and Immunotherapy at CCR

The Center for Cancer Research (CCR) is a world leader in cancer immunology and immunotherapy research. Our researchers have pioneered many of the seminal advances in these rapidly growing fields and are conducting clinical trials aimed at creating immune-based treatments for cancer.

Our Immunology and Immunotherapy Clinical Trials

Physician-scientists at the CCR are actively testing new immunotherapeutics in clinical trials aimed at improving outcomes for patients with cancer, HIV, or immunodeficiency disorders. Patients are seen at the NIH Clinical Center, the Nation’s largest hospital dedicated entirely to clinical research.

Our Immunology and Immunotherapy Research

Scientists at the CCR have long been pioneers in the fields of basic, translational, and clinical immunology. Research carried out at CCR has led to the development of several novel and effective therapeutics that harness the power of the immune system to fight cancer. This includes critical advances in developing adoptive cell therapy, immune checkpoint inhibitors, vaccines, cytokines and immunotoxins as cancer treatments. Ongoing basic research at CCR is deciphering the complex mechanisms that regulate development and activation of the innate and adaptive immune response, and how these processes become dysregulated in cancer and other diseases. CCR is also translating these advances in basic research into the next generation of cancer therapeutics.

Our Immunology and Immunotherapy Related Fellowships and Jobs

CCR has opportunities for those interested in pursuing a career in immunology and immunotherapy research, including the  NCI Immunotherapy Fellowship , and laboratory-based fellowships for postbaccalaureate, predoctoral and postdoctoral trainees. CCR fellows and faculty have access to unique resources, including cutting-edge technologies and cores, a highly collaborative environment of top researchers, awards for outstanding post docs and scientific symposia and lectures featuring world renowned experts.

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Abstract 7380: Predicting immunotherapy outcomes from H&E images in lung cancer

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Jessica Loo , Yang Wang , Pok Fai Wong , Ellery Wulczyn , Jeremy Lai , Peter Cimermancic , David F. Steiner , Shamira S. Weaver; Abstract 7380: Predicting immunotherapy outcomes from H&E images in lung cancer. Cancer Res 15 March 2024; 84 (6_Supplement): 7380. https://doi.org/10.1158/1538-7445.AM2024-7380

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Checkpoint blockade immunotherapy is a cornerstone of lung cancer treatment, but there is a need to improve the identification of patients who will respond favorably. Here, we explored a deep learning approach to predict immunotherapy outcomes from hematoxylin and eosin (H&E) images in non-small cell lung cancer (NSCLC). We included 150 unique cases with metastatic NSCLC (113 adenocarcinoma, 29 squamous cell, 8 other) treated with anti-PD-1/PD-L1 immunotherapy (56 nivolumab, 49 atezolizumab, 44 pembrolizumab, 1 durvalumab) as mono or combination (14 with chemotherapy, 1 with ipilimumab) therapy in a single institution. Each case consisted of a representative H&E whole slide image (53 biopsies, 50 needle core biopsies, 47 resections) obtained prior to immunotherapy, and the outcome reported as the 1-year overall survival (OS). PD-L1 status (tumor proportion score ≥ 1%) was known for 70 cases. We preprocessed the H&E images using two deep learning models previously developed using The Cancer Genome Atlas dataset. First, we used a classification model to identify tumor regions and randomly sampled a fixed number of tumor patches for each case. Then, we used a self-supervised pathology foundation model to obtain a compressed visual representation of each patch, known as an embedding. Next, using our dataset, we trained a deep multiple instance learning (DeepMIL) model with a gated attention mechanism to predict the binary 1-year OS status (0=deceased, 1=alive) for each case. As a baseline, we also trained a linear-probe (logistic regression) model using the averaged embeddings. Given the small dataset size, 5-fold cross-validation was used to train and evaluate both the DeepMIL and linear-probe models, with cases randomly split across folds. For evaluation, we used survival analysis to compare the 0/1 case groups. Overall, across all 150 cases, univariable Cox regression showed that 1-year OS was more strongly associated with the DeepMIL status (46/104, HR=0.55, p=0.03) than the linear-probe status (55/95, HR=0.81, p=0.44). Results were consistent on the subset of 70 cases with known PD-L1 status, whereby OS was most strongly associated with the DeepMIL status (19/51, HR=0.40, p=0.04) compared to the linear-probe status (31/39, HR=0.46, p=0.09) and PD-L1 status (30/40, HR=0.65, p=0.32). In multivariable Cox regression adjusting for age group and smoking status, OS remained more strongly associated with the DeepMIL status (HR=0.45, p=0.08) than PD-L1 status (HR=0.72, p=0.47). In conclusion, the DeepMIL status predicted from H&E images showed a stronger association with outcomes compared to PD-L1 status, a standard biomarker for immunotherapy in NSCLC. These exploratory results demonstrate the potential of deep learning using pathology foundation models to improve immunotherapy outcomes prediction, even with small datasets. Such approaches may even enable the discovery of novel biomarkers from H&E images to advance precision medicine.

Citation Format: Jessica Loo, Yang Wang, Pok Fai Wong, Ellery Wulczyn, Jeremy Lai, Peter Cimermancic, David F. Steiner, Shamira S. Weaver. Predicting immunotherapy outcomes from H&E images in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7380.

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Cancer immunotherapies: advances and bottlenecks

Affiliations.

• 1 Department of Urology, Peking University First Hospital, Beijing, China.
• 2 The Institution of Urology, Peking University, Beijing, China.
• 3 Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, China.
• 4 National Urological Cancer Center, Beijing, China.
• PMID: 37691932
• PMCID: PMC10484345
• DOI: 10.3389/fimmu.2023.1212476

Immunotherapy has ushered in a new era in cancer treatment, and cancer immunotherapy continues to be rejuvenated. The clinical goal of cancer immunotherapy is to prime host immune system to provide passive or active immunity against malignant tumors. Tumor infiltrating leukocytes (TILs) play an immunomodulatory role in tumor microenvironment (TME) which is closely related to immune escape of tumor cells, thus influence tumor progress. Several cancer immunotherapies, include immune checkpoint inhibitors (ICIs), cancer vaccine, adoptive cell transfer (ACT), have shown great efficacy and promise. In this review, we will summarize the recent research advances in tumor immunotherapy, including the molecular mechanisms and clinical effects as well as limitations of immunotherapy.

Keywords: cancer immunotherapy; immune checkpoint blockade; neoadjuvant immunotherapy; tumor microenvironment.

Copyright © 2023 Rui, Zhou and He.

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• Immunotherapy, Adoptive
• Neoplasms* / therapy

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March 21, 2024

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Research points to an immunotherapy to overcome resistant leukemia

by University of Zurich

Researchers at the University of Zurich and the University Hospital Zurich have discovered that a specific mutation in the cancer cells of an aggressive type of blood cancer can prevent novel immunotherapies such as CAR T-cell therapy from working. Their study also explains why the cancer cells are resistant and how this resistance can be overcome: through concomitant pharmacotherapy or genetically improved CAR T-cells.

Acute myeloid leukemia (AML) is an aggressive form of blood cancer. It is caused by mutations in a large number of genes that are acquired in the course of a person's life. One of these genes—the tumor suppressor gene TP53—plays a key role.

Normally, TP53 helps to prevent the development of tumors. Blood cancer patients in whom this gene is mutated, however, face an extremely poor prognosis, as their genes are resistant to conventional chemotherapeutic agents. Intensive research is therefore being carried out into new therapeutic approaches, such as CAR ( chimeric antigen receptor ) T-cells, which are already being used successfully for other cancers of the blood.

Mutation in blood cancer cells weakens immunotherapy defense cells

An international research team led by Professors Markus Manz and Steffen Boettcher from the University of Zurich (UZH) and the Department of Medical Oncology and Hematology at the University Hospital Zurich (USZ) has now shown that TP53-mutant AML cells are also significantly more resistant to a new type of immunotherapy—CAR T-cell therapy—than AML cells without the mutated gene . The paper is published in the journal EMBO Molecular Medicine .

"The reason for the poorer effect of CAR T-cells with mutated TP53 is that these immune cells are exhausted more quickly and are therefore less active against the cancer cells," says Steffen Boettcher, chief of service at USZ.

In CAR T-cell therapy, certain immune cells—the T-cells—are extracted from a patient's blood. These immune cells are then genetically modified in the lab so that they form numerous new contact points (CARs) on their surface. Reintroduced into the patient, these CAR T-cells are able to recognize certain surface structures on the tumor cells, which enables the CAR T-cells to identify the cancer cells and destroy them in a targeted manner. Various CAR T-cell products are currently being tested against AML in early clinical trials.

Concomitant pharmacotherapies or advanced CAR T-cells are effective against resistant cancer cells

In their study, the researchers not only examined the mechanism underlying the resistance of mutated AML cells to CAR T-cell immunotherapy; they also found out how the endurance of CAR T-cells can be increased and a weak point of TP53-mutant AML cells can be exploited to overcome this resistance.

Through additional pharmacological concomitant therapies or further genetic improvement of the CAR T-cells, they were able to drastically increase the effectiveness of CAR T-cells against TP53-mutant AML cells to the point where there was no longer any therapeutic difference compared to non-mutated AML cells.

"This proof-of-principle study shows that concurrent pharmacological therapies and genetically engineered CAR T-cells are promising strategies to develop more effective and tolerable immunotherapies for patients with TP53-mutant AML," says head of clinic Markus Manz.

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What is immunotherapy?

• Go to the cancer types section for information about treatment for your type of cancer

Immunotherapy uses our immune system to fight cancer. It works by helping the immune system recognise and attack cancer cells.

You might have immunotherapy on its own or with other cancer treatments. Immunotherapy is a standard treatment for some types of cancer. And it is in trials for other types of cancer.

There are different types of immunotherapy. These include monoclonal antibodies, checkpoint inhibitors, and vaccines. Some types of immunotherapy are also called targeted treatments or biological therapies. 

The immune system and immunotherapy

Our immune system works to protect the body against infection, illness and disease. It can also protect us from the development of cancer. 

The immune system includes the lymph glands, spleen and white blood cells. Normally, it can spot and destroy faulty cells in the body, stopping cancer developing. But a cancer might develop when:

• the immune system recognises cancer cells but it is not strong enough to kill the cancer cells
• the cancer cells produce signals that stop the immune system from attacking it
• the cancer cells hide or escape from the immune system

Immunotherapy helps our immune system to fight cancer. There are different types of immunotherapy treatments. These work in different ways to help our immune system recognise and attack cancer cells.

• Find out more about the immune system

Why might you have immunotherapy?

Immunotherapy is not suitable for all types of cancers. But it is one of the main treatments for a few types. 

Researchers are also looking at immunotherapy in clinical trials for some types of cancer.

You can have immunotherapy on its own or in combination with other treatments such as surgery, chemotherapy or radiotherapy.

Whether you have immunotherapy depends on:

• the type of cancer you have
• how far your cancer has spread (the stage) 
• other cancer treatments you’ve had

Before you have some types of immunotherapy you might need to have tests using some of your cancer cells or a blood sample. This is to find out whether the treatment is likely to work. These tests look for changes in certain proteins or genes. 

Your cancer specialist can tell you if this applies to your treatment. This is not the case for all immunotherapies and you don’t always need this test.

To test your cancer cells, your specialist needs a sample (biopsy) of your cancer. They might be able to use some tissue from a biopsy or operation you have already had.  

Types of immunotherapy

Immunotherapy treatments do not always fit easily into a certain type or group of treatments. This is because some drugs or treatments work in more than one way and belong to more than one group. So you might hear the same drug or treatment called different things.

For example, a type of immunotherapy called checkpoint inhibitors are also described as a monoclonal antibody or targeted treatment.

We have pages about the following immunotherapies:

• monoclonal antibodies
• checkpoint inhibitors
• CAR-T cell therapy.

Ask your specialist about immunotherapy. They can explain:

• whether this treatment is suitable for you
• what the aim of treatment would be
• what it would involve and the side effects
• Read about the different types of immunotherapy

Monoclonal antibodies (MABs)

Antibodies are found naturally in our blood and help us to fight infection. MAB therapies mimic natural antibodies but are made in a laboratory. Monoclonal means all one type. So each MAB therapy is a lot of copies of one type of antibody.

MABs recognise and attach to specific proteins on the surface of cancer cells. Many different MABs are available to treat cancer. They work in different ways and some work in more than one way. 

MABs work as an immunotherapy in different ways. They might do one of the following:

• trigger the immune system
• help the immune system to attack cancer
• Read more about MABs that have an effect on the immune system

Checkpoint inhibitors

Checkpoint inhibitors are MABs that work by helping the immune system attack cancer cells. Cancer can sometimes push a stop button on the immune cells, so the immune system won’t attack them. Checkpoint inhibitors block cancers from pushing the stop button.

• Read about checkpoint inhibitors

Vaccines to treat cancer

Researchers are looking at whether vaccines can help the immune system to recognise and attack cancer cells.

In the same way that vaccines work against diseases, the vaccines are made to recognise proteins that are on particular cancer cells. This helps the immune system to recognise and mount an attack against those particular cancer cells.

• Read more about vaccines to treat cancer

Cytokines are a group of proteins in the body that play an important part in boosting the immune system.

Interferon and interleukin are types of cytokines found in the body. Scientists have developed man made versions of these to treat some types of cancer.

• More about cytokines

CAR T-cell therapy

This treatment changes the genes in a person’s white blood cells (T cells) to help them recognise and kill cancer cells. Changing the T cell in this way is called genetically engineering the T cell.

It is available as a possible treatment for some children with leukaemia and some adults with lymphoma. People with other types of cancer might have it as part of a clinical trial. 

• Read more about CAR T-cell therapy

This page is due for review. We will update this as soon as possible.

Related links

Cancer treatment.

Cancer treatments include surgery, radiotherapy and drug treatments (such as chemotherapy, hormone therapy or targeted cancer drugs). Find out about treatments and side effects.

Immunotherapy treatments include monoclonal antibodies, checkpoint inhibitors, cytokines, vaccines and CAR T-cell therapy. Find out how they work and about the side effects.

Targeted cancer drugs

Targeted cancer drugs work by ‘targeting’ those differences that help a cancer cell to survive and grow. Find out more about what they are and the different types.

Immunisations and cancer treatment

Your resistance to infection can sometimes be low if you have or have recently had some cancer treatments. There are some vaccinations you shouldn't have when you have low immunity because they could make you feel very ill. 

Flu vaccine and cancer treatment

Cancer or its treatment can lower your resistance to infection and make you more likely to catch flu. The flu vaccination makes it less likely that you will catch flu. 

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DNA origami-based vaccines toward safe and highly-effective precision cancer immunotherapy

Broadly applicable vaccine platform enables enhanced anti-tumor responses through nanometer-precise spacing of adjuvant molecules and a variety of antigens.

Therapeutic cancer vaccines are a form of immunotherapy in the making that could not only destroy cancer cells in patients, but keep a cancer from coming back and spreading. Multiple therapeutic cancer vaccines are being studied in clinical trials, but despite their promise, they are not routinely used yet by clinical oncologists to treat their patients.

The central ingredient of therapeutic cancer vaccines is antigens, which are preferentially produced or newly produced (neoantigens) by tumor cells and enable a patient's immune system to search and destroy the cancerous cells. In most cases, those antigens cannot act alone and need the help of adjuvant molecules that trigger a general alarm signal in immune cells known as antigen-presenting cells (APCs). APCs internalize both antigen and adjuvant molecules and present the antigens to different types of T cells. Those T cells then launch an immediate attack against the tumor, or preserve a longer-lasting memory of the tumor for future defense.

A cancer vaccine's effectiveness depends on the level and duration of the "alarm" its adjuvants can ring in APCs. Previously, researchers found that delivering adjuvant and antigen molecules to APCs simultaneously using nanostructures like DNA origami can increase APC activation. However, none of these approaches systematically investigated how the number and nanoscale arrangement of adjuvant molecules affect downstream tumor-directed immunity.

Now, a research team at the Wyss Institute at Harvard University, Dana-Farber Cancer Institute (DFCI), Harvard Medical School (HMS), and Korea Institute of Science and Technology (KIST) has created a DNA origami platform called DoriVac, whose core component is a self-assembling square block-shaped nanostructure. To one face of the square block, defined numbers of adjuvant molecules can be attached in highly tunable, nanoprecise patterns, while the opposite face can bind tumor antigens. The study found that molecules of an adjuvant known as CpG spaced exactly 3.5 nanometers apart from each other resulted in the most beneficial stimulation of APCs that induced a highly-desirable profile of T cells, including those that kill cancer cells (cytotoxic T cells), those that cause beneficial inflammation (Th-1 polarized T cells), and those that provide a long-term immune memory of the tumor (memory T cells). DoriVac vaccines enabled tumor-bearing mice to better control the growth of tumors and to survive significantly longer than control mice. Importantly, the effects of DoriVac also synergized with those of immune checkpoint inhibitors, which are a highly successful immunotherapy that is already widely used in the clinic. The findings are published in Nature Nanotechnology .

"DoriVac's DNA origami vaccine technology merges different nanotechnological capabilities that we have developed over the years with an ever-deepening knowledge about cancer-suppressing immune processes," said Wyss Core Faculty member William Shih, Ph.D., who led the Wyss Institute team together with first-author Yang (Claire) Zeng, M.D., Ph.D.. "We envision that in the future, antigens identified in patients with different types of tumors could be quickly loaded onto prefabricated, adjuvant-containing DNA origami to enable highly effective personalized cancer vaccines that can be paired with FDA-approved checkpoint inhibitors in combination therapies." Shih is also a Professor at HMS and DFCI's Department of Cancer Biology and, as some of the other authors, a member of the NIH-funded cross-institutional "Immuno-engineering to Improve Immunotherapy" ( i3 ) Center based at the Wyss.

DNA origami rationale

The CpG adjuvant is a synthetic strand of DNA made up of repeated CpG nucleotide motifs that mimic the genetic material from immune cell-invading bacterial and viral pathogens. Like its natural counterparts, CpG adjuvants bind to a "danger receptor" called TLR9 in immune cells, which in turn induces an inflammatory (innate) immune response that works in concert with the antigen-induced (adaptive) immune response.

"We knew from previous work that to trigger strong inflammatory responses, TLR9 receptors need to dimerize and aggregate into multimeric complexes binding to multiple CpG molecules. The nanoscale distances between the CpG-binding domains in effective TLR9 assemblies revealed by structural analysis fell right into the range of what we hypothesized we could mirror with DNA origami structures presenting precisely spaced CpG molecules," explained Zeng, who was an Instructor in Medicine at the time of the study and now is a senior scientist at DFCI and Harvard Medical School (HMS). In addition to Shih, Zeng was also mentored on the project by senior authors Ju Hee Ryu, Ph.D., a Principal Researcher at KIST, and Wyss Founding Core Faculty member David Mooney, Ph.D., who also is Professor at Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), and one of the i3 Center's Principal Investigators.

Zeng and the team fabricated DoriVac vaccines in which different numbers of CpG strands were spaced at 2.5, 3.5, 5, or 7 nanometers apart from each other on one face of the square block, and a model antigen was attached to the opposite face. They protected their structures from being degraded in the body using a chemical modification method that Shih's group had developed earlier. When internalized by different types of APCs, including dendritic cells (DCs), which orchestrate tumor-directed T cell responses, the DoriVac vaccines improved the uptake of antigens compared to controls consisting of free antigen molecules. A CpG spacing of 3.5 nanometers produced the strongest and most beneficial responses in APCs, and significantly outperformed a control vaccine containing only free CpG molecules. "We were excited to find that the DoriVac vaccine preferentially induced an immune activation state that supports anti-tumor immunity, which is what researchers generally want to see in a good vaccine," said Zeng.

Besides spacing, the numbers of CpG molecules in DoriVac vaccines also mattered. The team tested vaccines containing between 12 to 63 optimally spaced CpG molecules and found that 18 CpG molecules provided the best APC activation. This meant that their approach can also help limit the dosage of CpG molecules and thus minimize commonly observed toxic side effects observed with adjuvants.

Gained in (tumor) translation

Importantly, these in vitro trends translated to in vivo mouse tumor models. When prophylactically injected under the skin of mice, DoriVac vaccines accumulated in the closest lymph nodes where they stimulated DCs. A vaccine loaded with a melanoma antigen prevented the growth of subsequently injected aggressive melanoma cells. While all control animals had succumbed to the cancer by day 42 of the experiment, DoriVac-protected animals all were alive. DoriVac vaccines also inhibited tumor growth in mice in which the formation of melanoma tumors was already underway, with a 3.5 nanometer spacing of 18 CpG molecules again providing maximum effects on DC and T cells, and the strongest reduction in tumor growth.

Next, the team asked whether DoriVac vaccines could also boost immune responses produced by small "neoantigens" emerging in melanoma tumors. Neoantigens are ideal targets because they are exclusively made by tumor cells. However, they often are not very immunogenic themselves, which make highly effective adjuvants an important component in neoantigen vaccines. A DoriVac vaccine customized with four neoantigens enabled the researchers to significantly suppress growth of the tumor in mice that produced the neoantigens.

Finally, the researchers asked whether DoriVac could synergize with immune checkpoint therapy, which reactivates T cells that have been silenced in tumors. In mice, the two therapies combined resulted in the total regression of melanoma tumors, and prevented them from growing back when the animals were exposed to the same tumor cells again four months later. The animals had built up an immune memory of the tumor. The team obtained a similar vaccination efficiency in a mouse lymphoma model.

"We think that DoriVac's value for determining a sweet spot in adjuvant delivery and enhancing the delivery and effects of coupled antigens can pave the way to more effective clinical cancer vaccines for use in patients with a variety of cancers," said Zeng. The team is currently translating the DoriVac platform toward its clinical application, which is supported by the study's assessment of vaccine distribution and vaccine-directed antibodies in mice, as well as cytokines produced by immune cells in response to the vaccines in vivo .

"The DoriVac platform is our first example of how our pursuit of what we call Molecular Robotics -- synthetic bioinspired molecules that have programmable shape and function -- can lead to entirely new and powerful therapeutics. This technology opens an entirely new path for development of designer vaccines with properties tailored to meet specific clinical challenges. We hope to see its rapid translation into the clinic," said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Children's Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at SEAS.

Other authors on the study are Olivia Young, Christopher Wintersinger, Frances Anastassacos, James MacDonald, Giorgia Isinelli, Maxence Dellacherie, Miguel Sobral, Haiqing Bai, Amanda Graveline, Andyna Vernet, Melinda Sanchez, Kathleen Mulligan, Youngjin Choi, Thomas Ferrante, Derin Keskin, Geoffrey Fell, Donna Neuberg, Cathrine Wu, and Ick Chan Kwon. The study was funded by the Wyss Institute's Validation Project and Institute Project programs, Claudia Adams Barr Program at DFCI, Korean Fund for Regenerative Medicine (award #21A0504L1), Intramural Research Program of KIST (award #2E30840), and National Institutes of Health (under the i3 Center supporting U54 grant (award #CA244726-01).

• Skin Cancer
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Story Source:

Materials provided by Wyss Institute for Biologically Inspired Engineering at Harvard . Original written by Benjamin Boettner. Note: Content may be edited for style and length.

Journal Reference :

• Yang C. Zeng, Olivia J. Young, Christopher M. Wintersinger, Frances M. Anastassacos, James I. MacDonald, Giorgia Isinelli, Maxence O. Dellacherie, Miguel Sobral, Haiqing Bai, Amanda R. Graveline, Andyna Vernet, Melinda Sanchez, Kathleen Mulligan, Youngjin Choi, Thomas C. Ferrante, Derin B. Keskin, Geoffrey G. Fell, Donna Neuberg, Catherine J. Wu, David J. Mooney, Ick Chan Kwon, Ju Hee Ryu, William M. Shih. Fine tuning of CpG spatial distribution with DNA origami for improved cancer vaccination . Nature Nanotechnology , 2024; DOI: 10.1038/s41565-024-01615-3

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Immunotherapy In-Depth

Gain in-depth knowledge about immunotherapy and the unique role your immune system plays in preventing, controlling, and eliminating a variety of cancers.

What is immunotherapy?

Cancer immunotherapy, also known as immuno-oncology, is a form of cancer treatment that uses the power of the body’s own immune system to prevent, control, and eliminate cancer.

Cancer immunotherapy comes in a variety of forms , including targeted antibodies, cancer vaccines, adoptive cell transfer, tumor-infecting viruses, checkpoint inhibitors, cytokines, and adjuvants. Immunotherapies are a form of biotherapy (also called biologic therapy or biological response modifier (BRM) therapy) because they use materials from living organisms to fight disease. Some immunotherapy treatments use genetic engineering to enhance immune cells’ cancer-fighting capabilities and may be referred to as gene therapies. Many immunotherapy treatments for preventing, managing, or treating different cancers can also be used in combination with surgery, chemotherapy, radiation, or targeted therapies to improve their effectiveness.

Immunotherapy can:

Educate the immune system to recognize and attack specific cancer cells, provide the body with additional components to enhance the immune response, boost immune cells to help them eliminate cancer, unleashing the power of the immune system is a smart way to fight cancer., it’s precise.

The immune system is precise, so it is possible for it to target cancer cells exclusively while sparing healthy cells.

It’s Dynamic

The immune system can adapt continuously and dynamically, just like cancer does, so if a tumor manages to escape detection, the immune system can re-evaluate and launch a new attack.

It Remembers

The immune system’s “memory” allows it to remember what cancer cells look like, so it can target and eliminate the cancer if it returns.

Why Immunotherapy

Immunotherapies have been approved in the United States and elsewhere to treat a variety of cancers and are prescribed to patients by oncologists. These approvals are the result of years of research and testing designed to demonstrate the effectiveness of these treatments. Immunotherapies are also available through clinical trials , which are carefully controlled and monitored studies involving patient volunteers.

Immunotherapy doesn’t always work for every patient, and certain types of immunotherapy are associated with potentially severe but manageable side effects. Scientists are developing ways to determine which patients are likely to respond to treatment and which aren’t. This research is leading to new strategies to expand the number of patients who may potentially benefit from treatment with immunotherapy.

Although scientists haven’t yet mastered all the immune system’s cancer-fighting capabilities, immunotherapy is already helping to extend and save the lives of many cancer patients. Immunotherapy holds the potential to become more precise, more personalized, and more effective than current cancer treatments—and potentially with fewer side effects. Learn more about how you can support new breakthroughs in cancer immunotherapy research .

Many cancer patients and caregivers may be familiar with traditional treatments, such as chemotherapy and radiation . Several important features of immunotherapy , a form of cancer treatment that uses the power of the body’s immune system to prevent, control and eliminate cancer, make for a more specific answer to cancer.

• Immunotherapy enables the  immune system  to recognize and target cancer cells, making it a universal answer to cancer.
• The list of cancers that are currently treated using immunotherapy is extensive.  See the full list of immunotherapies by cancer type .
• Immunotherapy has been an effective treatment for patients with certain types of cancer that have been resistant to chemotherapy and radiation treatment (e.g., melanoma).
• Immunotherapy can train the immune system to remember cancer cells. This “immunomemory” may result in longer-lasting remissions.
• Clinical studies on long-term  overall survival  have shown that the beneficial responses to cancer immunotherapy treatment are durable—that is, they may be maintained even after treatment is completed.
• Cancer immunotherapy is focused on the immune system and may be more targeted than conventional cancer treatments such as chemotherapy or radiation.
• Side effects vary according to each therapy and how it interacts with the body. Conventional cancer treatments have a direct effect of a chemical or radiological therapy on cancer and healthy tissues, which may result in common side effects such as hair loss and nausea.
• Side effects of cancer immunotherapy may vary depending on which type of immunotherapy is used. Potential side effects relate to overstimulation or misdirection of the immune system and may range from minor symptoms of inflammation (e.g., fever) to major conditions similar to autoimmune disorders.
• There are pros and cons to every cancer treatment. Speak with your oncology care team about immunotherapy and what is the best treatment plan for you.

Get more information

Resources, answers, and support.

Organizations that provide support and reliable answers for cancer patients and their loved ones

ImmunoGlossary

A comprehensive glossary that will help explain some of the terms you’ll come across on our website

Frequently Asked Immunotherapy Questions

What types of cancers can immunotherapy treat.

Immunotherapy has the potential to treat all cancers.

Immunotherapy enhances the immune system’s ability to recognize, target, and eliminate cancer cells, wherever they are in the body, making it a potential universal answer to cancer.

Immunotherapy has been approved in the U.S. and elsewhere as a first-line of treatment for several cancers, and may also be an effective treatment for patients with certain cancers that are resistant to prior treatment. Immunotherapy may be given alone or in combination with other cancer treatments. As of December 2019, the FDA has approved immunotherapies as treatments for nearly 20 cancers as well as cancers with a specific genetic mutation

Does immunotherapy have any side effects?

Immunotherapy may be accompanied by side effects that differ from those associated with conventional cancer treatments, and side effects may vary depending on the specific immunotherapy used. In most cases, potential immunotherapy-related side effects can be managed safely as long as the potential side effects are recognized and addressed early.

• Cancer immunotherapy treats the patient—by empowering their immune system—rather than the disease itself like chemotherapy and radiation. Patients may be tested for biomarkers that may indicate whether cancer immunotherapy would be an effective treatment.
• Side effects of immunotherapy may results from stimulation of the immune system and may range from minor inflammation and flu-like symptoms, to major, potentially life-threatening conditions similar to autoimmune disorders.
• Common side effects may include but are not limited to skin reactions, mouth sores, fatigue, nausea, body aches, headaches, and changes in blood pressure.

Conventional cancer treatments also have a range of side effects with a wide range of severity.

• Chemotherapy is intended to target fast-growing cancer cells, so it may damage other fast-growing normal cells in your body. Common side effects may include but are not limited to hair loss, nausea, diarrhea, skin rash, and fatigue.
• Radiation uses radioactive particles to destroy cancer cells in a localized area, so it may damage other healthy cells in that area. Side effects may be associated with the area of treatment, such as difficulty breathing when aimed at the chest, or nausea when aimed at the stomach. Skin problems and fatigue are common.
• The goal of surgery is to remove the cancerous tumor or tissue and varies according to the type of surgery performed. Common side effects may include but are not limited to pain, fatigue, swelling, numbness, and risk of infection.

How long does immunotherapy last?

Cancer immunotherapy offers the possibility for long-term control of cancer.

Immunotherapy can “train” the immune system to remember cancer cells. This “immunomemory” may result in longer-lasting and potentially permanent protection against cancer recurrence.

Clinical studies on long-term overall survival have shown that the beneficial responses to cancer immunotherapy treatment can be durable—that is, they continue even after treatment is completed.

How long has immunotherapy been used as a cancer treatment?

Cancer immunotherapy originated in the late 1890s with a cancer surgeon named Dr. William B. Coley (1862–1936) . He discovered that infecting cancer patients with certain bacteria sometimes resulted in tumor regression and even some complete remissions. Advances in cancer immunology since Coley’s time have revealed that, in patients that responded to his treatment, his bacterial toxin therapy stimulated their immune systems to attack the tumors.

While Coley’s approach was largely dismissed during his lifetime, his daughter, Helen Coley Nauts , discovered his old notebooks and founded the Cancer Research Institute in 1953 to support research into his theory. In 1990, the FDA approved the first cancer immunotherapy, a bacteria-based tuberculosis vaccine called Bacillus Calmette-Guérin (BCG), which was shown to be effective for patients with bladder cancer .

What is the relationship between cancer and the immune system?

While many of our cells grow and divide naturally, this behavior is tightly controlled by a variety of factors, including the genes within cells. When no more growth is needed, cells are told to stop growing.

Unfortunately, cancer cells acquire defects that cause them to ignore these stop signals, and they grow out of control. Because cancer cells grow and behave in abnormal ways, this can make them stand out to the immune system, which can recognize and eliminate cancer cells through a process called immunosurveillance .

However, this process isn’t always successful. Sometimes cancer cells develop ways to evade and escape the immune system, which allows them to continue to grow and metastasize, or spread to other organs. Therefore, immunotherapies are designed to boost or enhance the cancer-fighting capabilities of immune cells and tip the scales in the immune system’s favor.

What types of immunotherapy treatments are there?

Immunotherapy treatments can be broken down into five types:

• Targeted antibodies are proteins produced by the immune system that can be customized to target specific markers (known as antigens) on cancer cells, in order to disrupt cancerous activity, especially unrestrained growth. Some targeted antibody-based immunotherapies, known as antibody-drug conjugates (ADCs), are equipped with anti-cancer drugs that they can deliver to tumors. Others, called bi-specific T cell-engaging antibodies (BiTEs), bind both cancer cells and T cells in order to help the immune system respond more quickly and effectively. All targeted antibody therapies are currently based on monoclonal antibodies (clones of a parent bonding to the same marker(s)).
• Adoptive cell therapy takes a patient’s own immune cells, expands or otherwise modifies them, and then reintroduces them to the patient, where they can seek out and eliminate cancer cells. In CAR T cell therapy, cancer-fighting T cells are modified and equipped with specialized cancer-targeting receptors known as CARs (chimeric antigen receptors) that enable superior anti-cancer activity. Natural killer cells (NKs) and tumor-infiltrating lymphocytes (TILs) can also be enhanced and reinfused in patients.
• Oncolytic virus therapy uses viruses that are often, but not always, modified in order to infect tumor cells and cause them to self-destruct. This can attract the attention of immune cells to eliminate the main tumor and potentially other tumors throughout the body.
• Cancer vaccines are designed to elicit an immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens. Cancer vaccines can be made from a variety of components, including cells, proteins, DNA, viruses, bacteria, and small molecules. Some versions are engineered to produce immune-stimulating molecules. Preventive cancer vaccines inoculate individuals against cancer-causing viruses and bacteria, such as HPV or hepatitis B.
• Immunomodulators govern the activity of other elements of the immune system to unleash new or enhance existing immune responses against cancer. Some, known as antagonists, work by blocking pathways that suppress immune cells. Others, known as agonists, work by stimulating pathways that activate immune cells. Checkpoint inhibitors target the molecules on either immune or cancer cells, telling them when to start or stop attacking a cancer cell. Cytokines are messenger molecules that regulate maturation, growth, and responsiveness. Interferons (IFN) are a type of cytokine that disrupts the division of cancer cells and slows tumor growth. Interleukins (IL) are cytokines that help immune cells grow and divide more quickly. Adjuvants are immune system agents that can stimulate pathways to provide longer protection or produce more antibodies (they are often used in vaccines, but may also be used alone).

What is the difference between immunotherapy and chemotherapy?

Chemotherapy is a direct form of attack on rapidly-dividing cancer cells, but this can affect other rapidly dividing cells including normal cells. When patients respond, the treatment’s effects happen immediately. These direct effects of chemotherapy, however, last only as long as treatment continues.

Immunotherapy treats the patient’s immune system, activating a stronger immune response or teaching the immune system how to recognize and destroy cancer cells. Immunotherapy may take more time to have an effect, but those effects can persist long after treatment ceases.

Who can receive immunotherapy? What immunotherapies are approved for standard care?

As of March 2022, the U.S. Food and Drug Administration had approved over 60 immunotherapies that together cover almost every major cancer type:

• Aldesleukin (immunomodulator) for kidney cancer and melanoma
• Alemtuzumab (targeted antibody) for leukemia
• Amivantamab (bispecific antibody) for lung cancer
• Atezolizumab (checkpoint inhibitor) for bladder, liver, and lung cancer, and melanoma
• Avelumab (checkpoint inhibitor) for bladder, kidney, and skin cancer (Merkel cell carcinoma)
• Axicabtagene ciloleucel (CAR T cell therapy) for lymphoma
• Bacillus Calmette-Guérin [BCG] (vaccine) for bladder cancer
• Belantamab mafodotin-blmf (antibody-drug conjugate) for multiple myeloma
• Bevacizumab (targeted antibody) for brain, cervical, colorectal, kidney, liver, lung, and ovarian cancer
• Blinatumomab (bi-specific T cell-engaging antibody) for leukemia
• Brentuximab vedotin (antibody-drug conjugate) for lymphoma
• Brexucabtagene autoleucel (CAR T cell therapy) for leukemia and lymphoma
• Cemiplimab (checkpoint inhibitor) for lung cancer and skin cancer (basal cell carcinoma and cutaneous squamous cell carcinoma)
• Cetuximab (targeted antibody) for colorectal and head and neck cancer
• Ciltacabtagene autoleucel (CAR T cell therapy) for multiple myeloma
• Daratumumab (targeted antibody) for multiple myeloma
• Denosumab (targeted antibody) for sarcoma
• Dinutuximab (targeted antibody) for pediatric neuroblastoma
• Dostarlimab (checkpoint inhibitor) for uterine (endometrial) cancer
• Durvalumab (checkpoint inhibitor) for lung cancer
• Elotuzumab (targeted antibody) for multiple myeloma
• Enfortumab vedotin-ejfv (antibody-drug conjugate) for bladder cancer
• Gemtuzumab ozogamicin (antibody-drug conjugate) for leukemia
• Granulocyte-macrophage colony-stimulating factor, or GM-CSF (immunomodulator) for neuroblastoma
• Hepatitis B Vaccine (Recombinant) (preventive vaccine) for liver cancer
• Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant (preventive vaccine) for cervical, vulvar, vaginal, and anal cancer
• Human Papillomavirus 9-valent Vaccine, Recombinant (preventive vaccine) for cervical, vulvar, vaginal, anal, and throat cancer
• Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant (preventive vaccine) for cervical cancer
• Ibritumomab tiuxetan (antibody-drug conjugate) for lymphoma
• Idecabtagene vicleucel (CAR T cell therapy) for multiple myeloma
• Imiquimod (immunomodulator) for skin cancer (basal cell carcinoma)
• Inotuzumab ozogamicin (antibody-drug conjugate) for leukemia
• Interferon alfa-2a (immunomodulator) for leukemia and sarcoma
• Interferon alfa-2b (immunomodulator) for leukemia, lymphoma, and melanoma
• Ipilimumab (checkpoint inhibitor) for colorectal, liver, and lung cancer, and melanoma and mesothelioma
• Isatuximab (targeted antibody) for multiple myeloma
• Lisocabtagene maraleucel (CAR T cell therapy) for lymphoma
• Loncastuximab tesirine​ (antibody-drug conjugate) for lymphoma
• Margetuximab (targeted antibody) for breast cancer
• Mogamulizumab (targeted antibody) for lymphoma
• Naxitamab-gqgk (targeted antibody) for neuroblastoma
• Necitumumab (targeted antibody) for lung cancer
• Nivolumab (checkpoint inhibitor) for bladder, colorectal, esophageal, GEJ, head and neck, kidney, liver, lung, and stomach cancer, lymphoma, melanoma, and mesothelioma
• Obinutuzumab (targeted antibody) for leukemia and lymphoma
• Ofatumumab (targeted antibody) for leukemia
• Panitumumab (targeted antibody) for colorectal cancer
• Peginterferon alfa-2b (immunomodulator) for melanoma
• Pembrolizumab (checkpoint inhibitor) for bladder, breast, cervical, colorectal, esophageal, head and neck, kidney, liver, stomach, lung, and uterine cancer as well as lymphoma, melanoma, and any MSI-H or TMB-H solid cancer regardless of origin
• Pertuzumab (targeted antibody) for breast cancer
• Pexidartinib (immunomodulator) for tenosynovial giant cell tumor
• Polatuzumab vedotin (antibody-drug conjugate) for lymphoma
• Poly ICLC (immunomodulator) for skin cancer (squamous cell carcinoma)
• Ramucirumab (targeted antibody) for colorectal, esophageal, liver, lung, and stomach cancer
• Relatlimab (checkpoint inhibitor) for melanoma
• Rituximab (targeted antibody) for leukemia and lymphoma
• Sacituzumab govitecan-hziy (antibody-drug conjugate) for bladder and breast cancer
• Sipuleucel-T (vaccine) for prostate cancer
• Tafasitamab (targeted antibody) for lymphoma
• Tebentafusp-tebn (bispecific antibody) for melanoma
• Tisagenlecleucel (CAR T cell therapy) for leukemia (including pediatric) and lymphoma
• Tisotumab vedotin (antibody-drug conjugate) for cervical cancer
• Trastuzumab (targeted antibody) for breast, esophageal, and stomach cancer
• Trastuzumab deruxtecan (antibody-drug conjugate) for breast, esophageal, and stomach cancer
• Trastuzumab emtansine (antibody-drug conjugate) for breast cancer
• T-VEC (oncolytic virus) for melanoma

New immunotherapies are being developed and immunotherapy clinical trials are under way in nearly all forms of cancer.

Can people with autoimmune diseases and cancer be treated with immunotherapy?

People with mild autoimmune diseases are able to receive most immunotherapies . Typically, autoimmune treatment is adjusted and a checkpoint immunotherapy, such as those targeting the PD-1/PD-L1 pathway, is used. However, each patient should speak with his or her doctor regarding the options that are most appropriate.

Can people with HIV be treated with immunotherapy?

People with HIV who are receiving effective anti-viral treatment and whose immune systems are functioning normally may respond to cancer immunotherapy and are therefore eligible to receive immunotherapy, both as a standard of care and as part of a clinical trial.

How can I receive immunotherapy treatment?

The administration and frequency of immunotherapy regimens vary according to the cancer, drug, and treatment plan. Clinical trials can offer many valuable treatment opportunities for patients. Discuss your clinical trial options with your doctor.

How can I tell whether immunotherapy is working?

Immunotherapy treatments may take longer to produce detectable signs of tumor shrinkage compared to traditional therapies. Sometimes tumors may appear to grow on scans before getting smaller, but this apparent swelling may be caused by immune cells infiltrating and attacking the cancer. Many patients who experience this phenomenon, known as pseudoprogression, often report feeling better overall.

In certain cancer types, immune-related side effects may be linked with treatment success—specifically, melanoma patients who develop vitiligo (blotched loss of skin color)—but for the vast majority of patients, no definitive link has been established between side effects and immunotherapy’s effectiveness.

How is the Cancer Research Institute involved in the development of immunotherapy?

For more than 65 years , the Cancer Research Institute (CRI) has been the pioneer in advancing immune-based treatment strategies against cancer. It is the world’s leading nonprofit organization dedicated exclusively to saving more lives by fueling the discovery and development of powerful immunotherapies for all types of cancer.

CRI provides financial support to scientists at all stages of their careers along the entire spectrum of immunotherapy research and development: from basic discoveries in the lab that shed light on the fundamental components and mechanisms of the immune system and its relationship to cancer, to efforts focused on translating those discoveries into lifesaving treatments that are then tested in clinical trials for cancer patients.

What is cancer immunology?

Cancer immunology studies the relationship between cancer and the body’s immune system, including its innate ability to prevent or eliminate cancer cells, called immunosurveillance. Research shows that the body’s natural defense mechanisms can recognize and target cancer cells. Cancer immunologists focus on developing immunotherapies to boost those natural defenses.

What are immunotherapies?

Cancer immunotherapies also are known as biologic therapy, biotherapy, or biological response modifier therapy, and include checkpoint blockade, cancer vaccines, monoclonal antibodies, oncolytic virus therapy, T cell transfer, and other immune-modulating drugs such as cytokines and other adjuvant therapies. These effective ways for preventing, managing, or treating different cancers can be used in conjunction with surgery, chemotherapy, or radiation.

Is cancer immunology a new field of research?

The earliest forms of what would later be considered the start of cancer immunotherapy originated with research done by Dr. William B. Coley (1862-1936), a cancer surgeon and father of CRI founder Helen Coley Nauts . He discovered that “killed” bacteria stimulated the immune system to attack cancer cells. Modern cancer immunology is based on more recent advances in scientific understanding of the immune system’s various components, their function, and their role in cancer control. Cancer immunology is a relatively young field, but advances in treatment are aided by donor support.

Where can I get more information about immunology?

• Read our timeline of milestones in the field.
• Learn what immunotherapy is .
• Discover which immunotherapies are available for different cancers .
• Find out how different types of immunotherapy work .
• Get to know the scientists and patients behind the progress .
• Search for patient-specific resources .

Boosting the Body’s Immune System to Fight Cancer

Immunotherapy treatment harnesses the body’s natural strength to fight cancer—empowering the immune system to conquer more types of cancer and save more lives.

bind to antigens on threats in the body (e.g., bacteria, viruses, cancer cells) and mark cells for attack and destruction by other immune cells

release antibodies to defend against threats in the body

CD4+ Helper T Cells

send “help” signals to the other immune cells (e.g., B cells and CD8+ killer T cells) to make them more efficient at destroying harmful invaders

CD8+ Killer T Cells

destroy thousands of virus-infected cells each day, and are also able to seek out and destroy cancer cells

help immune cells communicate with each other to coordinate the right immune response

Dendritic Cells

digest foreign and cancerous cells and present their proteins to immune cells that can destroy them

Macrophages

engulf and destroy bacteria, virus-infected cells, and cancer as well as present antigens to other immune cells

Natural Killer Cells

recognize and destroy virus-infected and tumor cells quickly without the help of antibodies and “remember” these threats

Regulatory T Cells

provide the checks and balances to ensure that the immune system does not overreact

How the Immune System Works

Organs, tissues, and glands around your body coordinate the creation, education, and storage of key elements in your immune systems.

Thin tube about 4 to 6 inches long in the lower right abdomen. The exact function is unknown; one theory is that it acts as a storage site for “good” digestive bacteria

Bone marrow

Soft, sponge-like material found inside bones. Contains immature cells that divide to form more blood-forming stem cells, or mature into red blood cells, white blood cells (B cells and T cells), and platelets

Cells lining this set of organs and glands, as well as the bacteria throughout it, influence the balance of the immune system.

Lymph nodes

Small glands located throughout the body that filter bacteria, viruses, and cancer cells, which are then destroyed by special white blood cells. Also, the site where T cells are “educated” to destroy harmful invaders in your body

This organ’s receptors detect bacteria and viruses. Nasal mucus catches these pathogens so the immune system can learn to defend against them.

This organ is not only a physical barrier against infection but also contains dendritic cells for teaching the rest of the body about new threats. The skin microbiome is also an important influence the balance of the immune system.

An organ located to the left of the stomach. Filters blood and provides storage for platelets and white blood cells. Also serves as a site where key immune cells (B cells) multiply in order to fight harmful invaders

A set of organs that can stop germs from entering the body through the mouth or the nose. They also contain a lot of white blood cells.

Thymus gland

Small gland situated in the upper chest beneath the breastbone. Functions as the site where key immune cells (T cells) mature into cells that can fight infection and cancer

Immunotherapy Matters, For One and All

As a science-first organization dedicated to supporting cancer immunotherapy research, we’re funding a future that fights back against cancer—all with your help.

of every dollar spent goes to programs

All cancers

can potentially be treated with immunotherapy

clinical trials funded

$28.5 Million

awarded in 2021

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• Published: 28 June 2022

The expanding palette of immunotherapy research

Nature Cancer volume  3 ,  page 651 ( 2022 ) Cite this article

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The advent of immunotherapy has revolutionized the cancer field, but it is not without its challenges. In this issue, we launch our Series on Cancer Immunotherapy presenting commissioned Reviews and opinion pieces on the latest advances and efforts to expand the palette of immunotherapies and their clinical translation.

Despite the explosion of the cancer immunotherapy field over the past decade, the idea of harnessing the power of the immune system against cancer is far from new. The origins of immunotherapy can be traced to the end of the nineteenth century and the work of William Coley, who, starting in 1891, used first live and later attenuated bacteria to treat patients with sarcoma. Despite reporting some striking results, his work was received with skepticism by the nascent cancer research field that more readily embraced radio- and chemotherapy. Paul Ehrlich’s theory of immune surveillance to suppress tumor growth was met with similar skepticism when it was first proposed in 1909. Half a century would pass before the theory was revisited by Macfarlane Burnet and Lewis Thomas, as improved technology and an increasing understanding of biology gave traction to the tumor immunology field. In subsequent decades, painstaking fundamental and translational research would lead to milestones in clinical immunotherapy, such as the approval, by the US Food and Drug Administration, of interferon-α in 1986, followed by that of interleukin-2 and the monoclonal antibody rituximab in the 1990s and of the first therapeutic vaccine against cancer in 2010, to culminate in approval of the first immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cell therapy in the past decade.

The growth of the field in recent years is astonishing: there are currently dozens of approved immunotherapies and thousands of ongoing clinical trials. This expanded immunotherapy palette includes immune checkpoint inhibitors, adoptive cell therapies, vaccines, cytokines and oncolytic virus therapies that have been proven effective against a number of cancers, alone or in combination with other treatments. However, longstanding hurdles remain to be overcome if immunotherapies are to reach a wider population of patients. Among these hurdles are potentially serious immune-related adverse effects and the variable and/or limited efficacy and response rates that are influenced not only by cancer type, tumor heterogeneity, microenvironment, immunogenicity, and strength of the immune system of individual patients, but also by the development of resistance to immunotherapy. Added to these limitations is the difficulty in predicting efficacy and response and thus the pressing need for more and better biomarkers and clinical trial designs.

Part of the massive growth of the immunotherapy field over the past decade reflects the concerted drive by researchers across disciplines to address these challenges and break new scientific ground. As a result, the spectrum of immunotherapy research today spans preclinical discovery science, translational and clinical work. Among the areas that meet at the immunotherapy nexus are cancer immunology and biology, tumor and immune multi-omics profiling, technology development and computational science, chemical and cell engineering, drug development and testing. Some of the key priorities for this interdisciplinary community are to gain a deeper understanding of the immunotherapeutic response and resistance, to identify new immunotherapeutic targets and modalities, to expand efficacy to more tumor types, including hard-to-treat cancers, to improve the means of identifying and predicting response, resistance and toxicities, and to achieve a more effective exploration of treatment synergies.

To provide expert insights into this fast-moving field, we are pleased to launch in this issue our Series on Cancer Immunotherapy , consisting of specially commissioned Review, Perspective, News and Comment articles, and accompanied by a collection of relevant primary research articles published in Nature Cancer . Readers can access the series through its dedicated website, which will be updated as new content is published.

We launch the Series with a Review and a Viewpoint that touch on distinct but crucial topics. In their Review, Ignacio Melero and colleagues discuss immunotherapy combinations by presenting the current status of this area of translational and clinical research and outlining a roadmap for the effective prioritization and testing of promising combinations 1 . Separately, in a Viewpoint, Valsamo Anagnostou, Alberto Bardelli, Timothy Chan and Samra Turajlic engage in a thoughtful discussion on the tumor mutational burden as a biomarker for tumor immunotherapy and share their distinct views on its advantages, limitations, technical challenges and potential broad utility across more patient populations 2 . Accompanying these newly published pieces is a Perspective by Daniel Wells and colleagues on the roles of bystander T cells in tumors and their potential to be targeted therapeutically 3 . In a separate Review, Eugene Hwang et al. delve into the current landscape of cancer immunotherapies for the hard-to-treat setting of pediatric brain tumors 4 . Finally, in their Review, J. Joseph Melenhorst and colleagues provide a deep dive into the current status of CAR T cell therapies, the challenges that remain to be surmounted and strategies for improving CAR T cell engineering to achieve efficacy beyond hematological malignancies 5 . Upcoming pieces will focus on cancer vaccines and ways to improve their clinical development, and the latest knowledge on T cell antigens and strategies for their therapeutic utilization, with further foundational research and clinical topics covered in future articles.

Through our selection of commissioned and primary research articles, we aim to provide an up-to-date and unique view of the evolving palette of cancer immunotherapy and the ways its salient areas are interconnected through the underlying biology and immunology, mechanistic and therapeutic synergies, technological and clinical advances and challenges. We hope our readers enjoy this Series, and we are deeply thankful to our authors and referees for their efforts and contributions.

Sanmamed, M. F., Berraondo, P., Rodriguez-Ruiz, M. E. & Melero, I. Nat. Cancer https://doi.org/10.1038/s43018-022-00401-1 (2022).

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The expanding palette of immunotherapy research. Nat Cancer 3 , 651 (2022). https://doi.org/10.1038/s43018-022-00410-0

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Stealing Strategies from Cancerous T Cells May Boost Immunotherapy

March 20, 2024 , by Sharon Reynolds

CAR T cells (yellow) may get a boost in cancer-killing abilities from the addition of mutations found in blood-cancer cells.

For some people with blood cancers like leukemia and lymphoma, CAR T-cell therapies have proven to be a transformative treatment. But for solid tumors like breast, colorectal, or pancreatic cancer, which make up about 90% of cancer cases, success with T-cell therapies has been harder to come by.

One big reason for these failures is that T cells , the immune system’s primary defense against infected and diseased cells, often become weakened and incapacitated in the toxic environment found within and around solid tumors. Researchers have been exploring many ways to help CAR T cells and other experimental T-cell therapies survive within these hostile surroundings, known as the tumor microenvironment .

In a new study, an NCI-funded research team showed the promise of one such tactic: looking to the genetic changes that cancerous T cells themselves use to stay alive and grow. Incorporating those genetic changes into T-cell therapies, the team found, may make them better cancer killers .

When tested in mice, T cells engineered to have one specific genetic alteration the team discovered in cancerous T cells gave the engineered cells “superpowers,” said Jaehyuk Choi, M.D., Ph.D., of Northwestern University, who co-led the study.

Adding the genetic change, a fusion of parts of two genes, helped the engineered T cells divide faster, kill more tumor cells, and survive for more than a year in the treated mice. And, importantly, it didn’t make the T cells behave like cancer cells, the researchers reported February 7 in Nature .

“When we added [this] single mutation, we didn’t see the sort of unrestrained [T-cell] growth [you see in cancer], but it gave [the engineered] T cells capabilities that they don’t naturally have,” explained the study’s other leader, Kole Roybal, Ph.D., of the University of California San Francisco.

The first two decades of T-cell therapy research focused on the basics, explained Rosa Nguyen, M.D., Ph.D., who studies cellular therapies in NCI’s Center for Cancer Research but was not involved in this study. That work included figuring out what molecules on cancer cells can be targeted by T cells and how to change T cells to better identify such targets, as is done in CAR T-cell therapies .

“Now people are getting super creative in coming up with different things [to add] to these cells to make them work better,” Dr. Nguyen said. “That’s what the field is moving toward now.”

Harnessing nature’s survival strategies

Any type of cell in the body has the potential to turn cancerous, even immune cells. As its name implies, the blood cancer called T-cell lymphoma starts in T cells.

These cancerous T cells have something many normal T cells often lack: the ability to thrive in the hostile environment of a tumor. That environment can include other immune cells that actually work to slow down or disable T cells, as well as other cells and molecules that make it hard for T cells to function.

First Cancer TIL Therapy Gets FDA Approval for Advanced Melanoma

The new treatment, lifileucel, was originally developed by NCI researchers and is the first cell therapy approved for a solid tumor.

Dr. Choi’s lab has been studying the survival traits of T-cell lymphomas for over a decade. “It’s … amazing how these T-cell cancers have developed ways to protect themselves,” he explained.

From the perspective of developing a T cell – based therapy, many of the mutations found in cancerous T cells provide an additional advantage, Dr. Choi explained: Any one of them, on its own, is not likely to direct a cell to become cancerous.

Their years of research clearly showed that “nature has already done this massive experiment to make [cancerous] T cells stronger,” he explained. So “we thought maybe [nature] can show us the way” to improve T-cell therapies.

Better, faster-acting, and safe T cells

Joining forces with Dr. Roybal’s lab, which specializes in T-cell engineering, the researchers first carefully analyzed a wide range of cancerous T cells from T-cell lymphomas, looking for genetic alterations that appeared to help them survive in that tumor microenvironment.

They initially found 71 candidate alterations. In further laboratory experiments, they engineered CAR T cells to have some of the most promising candidate alterations, and this achieved what the researchers had hoped: They increased the CAR T cells’ ability to kill cancer cells and keep creating more CAR T cells.

Additional work revealed what appeared to be the most promising alteration: a fusion of parts of two genes, CARD11 and PIK3R3.

“This single [fusion] activated many things that people have predicted would help [improve] T-cell therapies,” Dr. Choi explained. In experiments in mice, treating them with CAR T cells engineered to express this fusion gene increased the production of molecules that T cells need to survive and function.

And these improvements only occurred when the specific protein recognized by the T cells’ specialized receptor, their chimeric antigen receptor , was present. That is, these extra-engineered CAR T cells would only become supercharged where and when needed inside a tumor.

Improved T cell survival and persistence in solid tumors

The team tested the CAR T cells engineered to express the gene fusion in mouse models of different cancers, including solid tumors like mesothelioma and melanoma. Across those experiments, they found that the treatment was much more effective at shrinking tumors—and keeping them under control for longer—than CAR T cells without the fusion.

“Persistence, the ability to stick around in the tumor microenvironment, is the biggest problem [these cells] solved,” Dr. Choi said. While T cells without the fusion died within a few days, the ones with the fusion “seem to stick around for as long as needed,” he said.

The treatment was very effective even though the mice didn’t also get chemotherapy, Dr. Choi pointed out. That is important because currently, “almost everyone who gets treated with [T-cell therapies] needs to have what’s called conditioning chemotherapy beforehand,” Dr. Choi explained. But this chemotherapy can cause side effects, often severe enough that patients have to wait longer to get the T-cell treatment or possibly preventing them from doing so at all.

“If we ever want these sorts of therapies to be given in less specialized centers, or even in the outpatient setting, we need to get rid of these cumbersome techniques [like conditioning chemotherapy] that are toxic to patients,” added Dr. Roybal.

The researchers also engineered the fusion into a different type of T cell – based immunotherapy, called TCRs, and saw similar results.

One CAR T-Cell Therapy for Blood Cancers?

Using CRISPR, researchers have developed a potential “universal” immunotherapy for blood cancers like leukemia and lymphoma.

In a mouse model of melanoma, for example, TCR T cells with the fusion gene flowed into tumors in much greater numbers and killed tumor cells much more effectively than TCR T cells without the fusion gene. The TCR T cells with the fusion even showed this advantage at starting doses 20 to 100 times lower than TCR T cells without the fusion.

Being able to give a lower dose of a T-cell therapy would provide another safety advantage for patients, Dr. Roybal explained. Current CAR T-cell therapies, which are given in large doses, have the potential to cause a dangerous—or even fatal—immune system overreaction called cytokine release syndrome . That risk would likely be lower with a smaller dose that ramps up its activity over time, he added.

The researchers also tracked the T cells in the mice for more than 400 days after treatment. Though they initially multiplied rapidly to kill the tumors, their numbers then shrank back down and showed no signs of becoming cancerous themselves.

Testing supercharged T cells in people

The researchers have launched a biotechnology startup to move their CAR T-cell therapy with this gene fusion into human trials, although they are likely 2 to 3 years away from launching these studies, Dr. Roybal explained.

Eventually, researchers may want to try mixing and matching different ways to soup up T cells, Dr. Nguyen said. But these approaches first need to be tested one at a time to better understand how each one works. “We have to use a stepwise approach,” she said.

Drs. Roybal and Choi also want to keep exploring the dozens of other promising mutations their screen initially uncovered.

“We found a lot of different mutations … that could [potentially] be used” in T-cell therapies to treat “a variety of different types of cancer,” said Dr. Roybal.

“Maybe the [CARD11–PIK3R3] fusion protein will be good for [fighting] some subset of solid cancers. And one of the other [mutations] we found will be important for another subset,” he said. “This is the beginning [of this research], not the end.”

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Immunotherapy: The future of cancer treatment

Manisha sahu.

Department of Oral Pathology and Microbiology, Chhattisgarh Dental College and Research Institute, Rajnandgaon, Chhattisgarh, India

Hemakumari Suryawanshi

Head and neck squamous cell carcinomas (HNSCCs) are one of the most common cancers worldwide. A large number of patients are diagnosed with locally advanced disease and require multimodal treatment approaches. Standard treatment modalities ranging from surgery to chemotherapy and radiation are yielding mixed results. To overcome this hurdle, newer innovative approaches are required to reduce the morbidity and mortality of the patients. In the last few decades, immunotherapy has become an important part of treating some types of cancer. The immune system plays a key role in the development, establishment and progression of HNSCC. A greater understanding of the dysregulation and evasion of the immune system in the evolution and progression of HNSCC provides the basis for improved therapies and outcomes for patients. Newer types of immune treatments are now being studied, and they will impact how we treat cancer in the future. This article provides a brief overview of the current immunotherapeutic strategies for cancer with emphasis on HNSCC.

INTRODUCTION

Head-and-neck squamous cell cancers (HNSCCs) are one of the most common cancers worldwide.[ 1 ] The treatment of HNSCC varies by tumor site and stage, however the standard treatment include surgery, radiation and cytotoxic chemotherapy.[ 2 ] Despite advances in treatment, more than half of all cancers recur locoregionally or distantly.[ 3 ] Cancer immunotherapy is emerging as a beneficial tool for cancer treatment by activating the immune system to produce antitumor effects. In 1891, Dr. William Coley, the father of immunotherapy, made the first attempt to stimulate the immune system for improving a cancer patient's condition by intratumoral injections of inactivated bacterial toxin.[ 4 ]

All cancers arise as a result of somatic genomic alterations. These alterations arise sequentially and give rise to the progressively more aggressive and invasive phenotypes during tumorigenesis. Such genomic variations could give rise to tumor antigens, which could be recognized by the immune system as nonself and elicit cellular immunwponses.[ 5 ] However, avoiding immune destruction is one of the hallmarks of cancer. HNSCCs are highly immunosuppressive malignancy with high mutational burden. Cancer cells have evolved multiple mechanisms, such as defects in antigen presentation machinery, the upregulation of negative regulatory pathways and the recruitment of immunosuppressive cell populations to escape immune surveillance. There has been extensive research on the complex and dynamic interaction between tumor cells and host immune cells which has led to the development of currently approved immunotherapies. Immunotherapy is designed to either actively target a specific antigen on the tumor or enhance the host's immune system.[ 1 , 5 ]

Cancer immunotherapy was voted “breakthrough of the year” by Science in 2013 and has revolutionized the field of oncology.[ 6 ] The cancer immunotherapy aims at harnessing the specificity and killing mechanisms of the immune system to target and eradicate malignant cells. The Society for Immunotherapy of Cancer established the Cancer Immunotherapy Guideline-Head and Neck Cancer subcommittee to provide evidence-based recommendations on how best to incorporate immunotherapies into practice for the treatment of patients with HNSCC.[ 7 ] The present article provides a brief overview of the current immunotherapeutic strategies for cancer with emphasis on HNSCC.

TUMOR IMMUNOLOGY

Immune system.

The immune system is comprised of the innate and adaptive immune system. The innate immune system includes dendritic cells (DCs), natural killer cells (NK), macrophages, neutrophils, eosinophils, basophils and mast cells. Innate immune cells do not require prior stimulation by antigens and act as a first line of defense against foreign antigens. The adaptive immune system includes B lymphocytes, CD4+ helper T lymphocytes and CD8+ cytotoxic T lymphocytes, and requires formal presentation by antigen-presenting cells (APCs) for its activation. The adaptive immune system generates antigen-specific T- and B-cell lymphocytes.[ 8 ]

Immunoediting

Each cell is estimated to experience over 20,000 DNA damaging events each day which are normally repaired. Cells which are not repaired and which acquire malignant or potentially malignant changes are then usually recognized and killed by the tumor immunosurveillance system. However, tumor cells develop mechanisms to thwart immune recognition and response, a dynamic process termed immunoediting that leads to immune escape.[ 8 ]

There is now an improved understanding of the complex interaction between immune system and tumor cells. The theory of Immune Editing was put forth by Schreiber et al . where they hypothesize that the body's immune system interacts with the tumor in three distinct phases namely elimination, equilibrium and escape.[ 9 , 10 ] The cancer immunosurveillance hypothesis developed by Burnet and Thomas is now considered a component of cancer immunoediting.

The elimination phase refers to the initial damage and possible destruction of tumor cells by the innate immune system, followed by presentation of the tumor antigens in the cellular debris to DCs which then present them to T-cells and thereby create tumor-specific CD4+ and CD8+ T-cells. These help destroy the remaining tumor cells if elimination is complete. The equilibrium phase occurs when any tumor cells survive the initial elimination attempt but are not able to progress, being maintained in a state of equilibrium with the immune cells. In the escape phase, cancer cells grow and metastasize due to loss of control by the immune system.[ 8 ]

Escape mechanisms of HNSCC

HNSCC is one of the most immunosuppressive human tumors.[ 11 ] Tumor is able to evade immune destruction not only by modulating its own cellular characteristics but also by creating its own “tumor microenvironment (TME).” Many signaling molecules and cell types play a role in tumor-driven immune tolerance, from cytokines to both the innate and adaptive arms of the cellular immune system.[ 12 ]

MOLECULAR ESCAPE MECHANISMS

Tumor-derived factors.

The production of immunosuppressive cytokines, including transforming growth factor (TGF)-b, interleukin (IL)-6 and IL-10 inhibit T cell proliferation and effector functions. Tumor cells also deplete local micronutrients and overexpress indoleamine 2,3-dioxygenase, an enzyme responsible for depletion of tryptophan, which hinders T cell proliferation and activation. It has also been shown that exosomes secreted by HNSCC are enriched for suppressive compounds (including cyclooxygenase-2, TGF-b, programmed death 1 [Programmed cell death receptor 1] and cytotoxic T lymphocyte antigen 4 [Cytotoxic T lymphocyte associated molecule 4]) that promote CD8+ T cell apoptosis, inhibit CD4+ T cell proliferation, upregulate (regulatory T cells) Tregs and impair NK cell function.[ 12 ]

Beyond secreted cytokines and metabolites, HNSCCs have developed mechanisms of human leukocyte antigen (HLA) modulation for immune escape. HNSCC provoke genetic alterations in key genes associated with processing and presentation of neoantigens, including signal transducer and activator of signal 1 deficiency and downregulated transporter for antigen processing, without significantly affecting HLA expression itself.[ 12 ]

Suppressive cellular tumor infiltrate

HNSCC regulate and recruit immune populations capable of modulating T and NK cell responses, including Tregs, myeloid-derived suppressor cells, tumor-associated macrophages and cancer-associated fibroblasts. Immunomodulation enacted by these various cell populations contributes to a tumor-promoted microenvironment.[ 12 ]

IMMUNE CHECKPOINTS

In the healthy state, effector functions of the immune system must be held in check to prevent damage to self (autoimmunity) or prolonged activation. Checkpoint molecules are generally thought of as primarily immunosuppressive and the key inhibitory checkpoint receptors are PD-1, CTLA4, lymphocyte activating gene 3 and T cell immunoglobulin (IgG) and mucin domain-containing 3.[ 12 ]

Immunotherapy can be broadly divided into active and passive.[ 4 ]

Active immunotherapy

The active approach involves directing the host immune system to tumor-associated antigens on the surface of tumors. These antigens can be specific proteins or carbohydrates that are exclusively expressed or overly expressed in tumor cells.

Passive immunotherapy

Passive immunotherapy involves enhancing the standard anticancer response by the immune system using monoclonal antibodies (MoAbs), lymphocytes and cytokines.

TYPES OF IMMUNOTHERAPY

Adoptive cell therapy (act).

The central premise in ACT is that T cells are crucial for eliminating cancer cells and hence transfer of T cells in expanded numbers can augment anti-tumor immunity.[ 13 ] Adoptive cell therapy (ACT) utilizing either tumor-infiltrating lymphocyte (TIL)-derived T cells or T cells genetically engineered to express tumor recognizing receptors has emerged as a powerful and potentially curative therapy for several cancers.[ 14 ]

TYPES OF ADOPTIVE CELL THERAPY

Tumor-infiltrating lymphocyte therapy (unmodified cells).

ACT involves isolating TILs from cancers, growing them in culture and then reintroducing them to the patient who has undergone a lymphocyte depleting preparatory regimen. There is now a greater number of activated cells available, enhancing the body's anti-tumor immune response.

Engineered T-cell receptor therapy (modified cells)

With modern genetic engineering technology, specific antigen receptors can be introduced into T cells allowing them to recognize tumor specific antigens. These lymphocytes can then be produced on a large scale and used in patients. T-cell receptor (TCR)-modified T cells exert antigen recognition in a major histocompatibility complex-dependent manner.

The first evidence of the feasibility and clinical potency of TCR gene therapy targeting the melanoma differentiation antigen MART-1, present in approximately 80%–95% of melanomas was demonstrated in 17 patients with progressive metastatic melanoma.[ 15 ]

Chimeric antigen receptor T-cell therapy (modified cells)

Chimeric antigen receptor (CAR) is introduced to the T lymphocyte surface with help of a viral vector [ Figure 1 ]. CARs are specialized structures with both antigen binding as well as intracellular signaling apparatus such that they can recognize antigens independent of APCs and can also drive cellular activation.[ 13 ]

Chimeric antigen receptor T-cell therapy is a type of treatment in which a patient's T cells (a type of immune cell) are changed in the laboratory so they will bind to cancer cells and kill them. Credit: National Cancer Institute US

IMMUNE CHECKPOINT INHIBITORS

Immune checkpoints are the normal components of immune system. T-cell activation is functionally determined by antigen presentation along with many co-stimulatory and co-inhibitory signals. In the presence of these co-inhibitory signals, the stimulatory signal will fail, leading to the induction of T-cell anergy or apoptosis, weakening the immune response due to failure to induce cytotoxicity.[ 16 , 17 ] Co-inhibitory molecules called checkpoints prevent exaggerated immune response and maintains immune tolerance in normal physiological conditions. These inhibitory checkpoints are overexpressed in the TME, contributing to tumor-promoting immunosuppression. These checkpoints are blocked by checkpoint inhibitors which are MoAbs.[ 18 ]

The most widely used targets for immune checkpoint inhibitors are

• CTLA4 – Cytotoxic T lymphocyte-associated molecule 4
• PD1 – Programmed cell death receptor 1
• Programmed cell death ligand 1.

The two major classes of checkpoint inhibitors currently used are anti CTLA-4 antibodies (e.g., Ipilimumab) and anti PD-1 [ Figure 2 ] (Nivolumab and Pembrolizumab) antibodies.[ 18 ]

Checkpoint proteins, such as PD-L1 on tumor cells and PD-1 on T cells, help keep immune responses in check. The binding of PD-L1 to PD-1 keeps T cells from killing tumor cells in the body (left panel). Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor (anti-PD-L1 or anti-PD-1) allows the T cells to kill tumor cells (right panel). Credit: National Cancer Institute US

TARGETED MONOCLONAL ANTIBODIES

It is a form of active immunity was MoAbs target specific antigen present on cancer cells. MoAbs can either be unconjugated or be conjugated with therapeutic drugs that would produce a cytotoxic effect on cancer cells. Overexpression of epidermal growth factor receptor (EGFR) has been noted in up to 90% of HNSCC and upon binding of EGF promotes tumor cell proliferation, angiogenesis and metastasis. MoAbs such as cetuximab and panitumumab are EGFR targeted therapies; they are proven to be effective against HNSCC either alone or in combination with radiotherapy. Cetuximab is a mouse–human chimeric IgG1 Ab targeting EGFR whereas Panitumumab is a fully human IgG2 antibody.[ 19 , 20 , 21 ]

Other promising antigens of HNSCC which can be targeted.

Vascular endothelial growth factor (VEGF) AND VEGFR, insulin-like growth factor receptor which are overexpressed in HNSCC.

ONCOLYTIC VIRUS THERAPY

Oncolytic virus therapy originated from the finding that virus-infected tumor cells are destroyed by the cytopathic effects of viruses.

Viruses are infectious agents that are capable of infecting living cells, hijacking their genetic machinery, which allows the viruses to replicate inside them.In this therapy genetically modified viruses are used to infect tumor cells. The virus-infected tumor cells are destroyed by the cytopathic effects of viruses which stimulate a pro inflammatory environment to augment systemic antitumor immunity. Cell death induced by viral infections in tumor tissues also promotes inherent tumor immunity in cancer patients. Several DNA and RNA viruses have been proposed as candidates for this treatment through in vitro and in vivo studies as well as clinical trials. They are termed “oncolytic viruses” as they are designed to target tumor cell specifically.[ 5 , 22 ]

The first oncolytic virus therapy was approved by the US Food and Drug Administration (FDA) in 2015 – talimogene laherparepvec (T-VEC) for the treatment of melanoma. T-Vec, also known as Imlygic, a genetically modified herpes simplex virus, demonstrates impressive clinical benefits for patients with advanced melanoma and has been approved for the treatment of unresectable metastatic melanoma.

CANCER VACCINES

Cancer vaccines are sub classified as

• Prophylactic vaccines
• Therapeutic cancer vaccines.

Prophylactic vaccines are used for the prevention of primary and secondary cancer which is aimed at reducing cancer incidence, morbidity and mortality.

They are designed to alert the immune system to a specific virus so that it can recognize and attack the virus before it is able to cause an infection. This type of vaccine is administered to healthy individuals.[ 23 ]

The U. S. FDA have approved two prophylactic vaccines, including one for hepatitis B virus that can cause hepatocellular carcinoma and another for human papillomavirus (Gardasil) accounting for about 70% of cervical cancer.[ 24 ]

Therapeutic cancer vaccines are administrated to cancer patients and designed to eradicate cancer cells through strengthening patient's own immune responses. Based on their content, they may be classified into several major categories, which include cell vaccines (tumor or immune cell), protein/peptide vaccines and genetic (DNA, RNA) vaccines.

Bacillus Calmette–Guérin (BCG) and sipuleucel-T (Provenge ® ) are two examples of therapeutic cancer vaccines. The BCG vaccine is approved for patients with early-stage bladder cancer and sipuleucel-T (Provenge ® ) are approved for asymptomatic metastatic castrate-resistant prostate cancer. Sipuleucel-T works by inducing an immune response, targeting the prostatic acid phosphatase antigen, which is overexpressed in the majority prostate cancers.[ 23 , 24 ]

Cytokines are molecular messengers that allow the cells of the immune system to communicate with one another to generate a coordinated, robust, but self-limited response to a target antigen. Cytokines are secreted or membrane-bound proteins that act as mediators of intercellular signaling to regulate homeostasis of the immune system. They are produced by cells of innate and adaptive immunity in response to microbes and tumor antigens.[ 25 , 26 ]

Two cytokines currently approved by the FDA for clinical purposes are interferon α (IFN α) and IL-2.

Interferon α

These cytokines when injected subcutaneously in renal cell carcinoma have shown tumor regression.[ 27 ] These have shown excellent results in stage 3 melanoma. The combination of IFN α and IL-2 showed partial response and higher toxicity. IFN α plays multifaceted roles in tumor control, including directly eradicating tumor cells through inducing senescence and apoptosis and boosting effective antitumor immune responses through the stimulation of DC maturation and the enhancement of T-cell cytotoxicity.

Interleukin-2

It is an US FDA-approved cytokine for metastatic melanoma.[ 27 ] These cytokines increase level of NK cells and TILs in the lesion. Perilymphatic IL-2 administration has increased the survival rate of patients with HNSCC; increased tumor reactive T cells were found in patients who underwent MoAb therapy after surgery.

Cancer immunology is a rapidly evolving field. Understanding the behavior of cancer cells, identifying target antigens and detailing immune system pathways have allowed scientists to explore new approaches in immunotherapies. Despite impressive advances in immunotherapies there are few challenges including limited response rates, the inability to predict clinical efficacy and potential side effects such as autoimmune reactions or cytokine storm. In order to augment responses, rational combinations of immunotherapeutic agents and new immunotherapy technologies are being vigorously investigated.

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Conflicts of interest.

There are no conflicts of interest.

In two early trials, blood cancer treatment appears promising for deadly brain tumor

Two early trials published Wednesday showed promise in treating one of the deadliest types of cancer, glioblastoma . 

The aggressive brain cancer, which took the lives of John McCain and Beau Biden , is only diagnosed at stage 4, and the five-year survival rate is around 10% . 

The disease has no cure and, according to Dr. Michael Vogelbaum, chief of neurosurgery and program leader of neuro-oncology at Moffitt Cancer Center in Tampa, Florida, there have been no new drug approvals in the past two decades that have extended the lives of patients with glioblastoma.

The two clinical trials published Wednesday were extremely small, conducted on just nine patients in total, and much more research is needed, with larger trials, to determine how effective the therapy might be in the long run. 

“All of these results are preliminary but encouraging,” said Vogelbaum, who wasn’t involved with either trial.

In the two unrelated trials, a novel take on an existing treatment for blood cancer was shown to be safe and it shrank tumors –– at least temporarily. 

Both studies looked at the effects of a personalized immunotherapy called chimeric antigen receptor T-cell therapy — CAR-T therapy for short — in patients whose glioblastoma had returned after their initial treatment. 

CAR-T therapy involves harvesting a person’s own immune cells and modifying them in a lab to seek out specific tumor proteins. The cells are then reintroduced into the body where they replicate, creating a surge of cancer-fighting immune cells. 

The treatment is highly effective for certain blood cancers , but scientists are still studying whether modified versions of CAR-T therapy can be used for solid tumors like glioblastoma. These tumors, which account for the majority of cancers, present challenges that blood cancers do not. 

Many blood cancers are homogeneous, meaning their cells are uniform. This gives CAR-T therapy a clear target to latch onto and attack. But solid tumors tend to have a variety of different cell types that can differ within individual tumors. This is particularly true for glioblastoma, which contains a large number of abnormal-looking cells. 

“We had previous experience using a regular CAR in brain tumors but it wasn’t enough,” said Dr. Marcela Maus, director of the Cellular Immunotherapy Program at the Massachusetts General Cancer Center in Boston. Maus led one of the new studies, the results of which were published in The New England Journal of Medicine .

The original studies testing CAR-T therapy for glioblastoma only had one target, which is how the therapy has worked in blood cancers. 

The cells targeted a protein with a specific mutation, but Maus said that not everyone with glioblastoma had the mutation. What’s more, even in patients who had the mutation, not every one of their tumor cells necessarily had it. “Even if we got the right cells, we didn’t get all of them because other tumors had other targets,” she said. 

Expanding an existing therapy

Both phase 1 clinical trials used CAR-T cells that were programmed to attack two targets instead of one, with the hope that multiple targets would better equip the cells to destroy solid tumors. 

“It gives you more shots on goal, at targeting the protein, because these are not completely overlapping targets on any given tumor,” said Dr. Vincent Lam, an assistant professor of oncology at the Johns Hopkins Cancer Center, who specializes in immunotherapies and wasn’t involved with either trial.

In Maus’ clinical trial, which included three patients, T-cells were engineered to seek out and attack a protein called EGRF that’s often found in abundance in glioblastoma tumors but is not present in healthy brain tissue. The second target was a variant of EGRF that’s also commonly found in the tumors.

When used to treat blood cancer, CAR-T cells are transferred back into the body intravenously. Maus’ team chose a more targeted approach for their experimental therapy: injecting the cells directly into the cerebrospinal fluid that surrounds the brain and spinal cord. 

This prompted more of the cancer-fighting cells to stick around the site of the brain tumors and, the researchers hypothesized, would reduce the amount of the immunotherapy elsewhere in the body. 

Confining the therapy to the brain was important: While the target, EGFR, is not found in healthy brain tissue, it is found in healthy cells elsewhere in the body. If the CAR-T cells went beyond the brain, they could potentially attack these cells.

To further prevent the CAR-T cells from escaping, the researchers bulked them up by binding them to an antibody, which made it more difficult for the cells to cross the blood-brain barrier and enter the bloodstream. 

All three patients — two who were in their 70s and one in her late 50s — responded quickly to the treatment. Brain scans showed their tumors shrunk significantly within a day of receiving the therapy. In the 57-year-old woman, an MRI taken five days after her infusion of the modified cells showed her tumor was nearly gone.

The results, however, were temporary. 

“We’re still in the early phases of the study. Two patients had their disease recur in the first six months and we want to aim for something better,” Maus said. 

While some CAR-T cells did pass beyond the brain, they didn’t do so in large enough numbers to cause damage, the trial found.

Striking a balance

The other trial , published in Nature Medicine, included six patients with recurrent glioblastoma. Their CAR-T cells also sought out EGFR, but used another protein, called IL13Rα2, which is found in 75% of glioblastoma tumors, as their second target. 

All six patients underwent radiation to shrink their tumors before they started the immunotherapy, and each was given a single injection of the cells.  

The team also delivered the immunotherapy locally, injecting it directly into the cerebrospinal fluid. All of the patients saw a reduction in their tumor size within the first two days of treatment, and they also experienced a significant spike in active CAR-T cells in their spinal fluid for several weeks after injection, meaning the cells were successfully dividing as well as concentrating in the area surrounding tumors. 

“That was striking to us. We didn’t expect that kind of expansion, proliferation and maintenance in the spinal fluid,” said Dr. Donald O’Rourke, director of the Glioblastoma Translational Center of Excellence at the Abramson Cancer Center at Penn Medicine in Philadelphia, who co-led the trial. 

O’Rourke and his team also used two different doses to get closer to an understanding of what the ideal number of CAR-T cells is for an infusion. 

The ideal number would provide the most potent therapeutic effect without causing side effects so severe they negate the cancer-killing benefits, but striking a balance is tricky. 

CAR-T therapy is different from a regular drug; it’s considered a “living drug” because the modified cells keep dividing once they’re in the body, meaning the amount in the initial infusion isn’t the final amount a patient will have, O’Rourke said. 

All immunotherapies come with risk of neurological side effects, including confusion, language difficulties and sleepiness. The trial found that these side effects came on more quickly when CAR-T cells were injected into the cerebrospinal fluid, but that starting with a lower dose may be able to remedy this. The first three patients were given a lower dose of CAR-T. While they did experience signs of neurotoxicity, it was milder than the neurotoxicity in the three who received the higher dose.

Participants in both trials did experience at least some side effects of CAR-T therapy, which included fever and vomiting as well as neurological effects such as aphasia . 

The two trials come just a week after the results of another CAR-T therapy clinical trial for glioblastoma were published in Nature Medicine. That trial used a single target, IL-13Rα2 — also used in the Penn Medicine trial — in 65 patients and also determined that CAR-T therapy is safe and could be an effective treatment for glioblastoma. 

Lam, of Johns Hopkins, said that CAR-T has shown promise in glioblastoma in studies over the past five years. The biggest takeaway the two newest trials bring to the table, he said, is that CAR-T therapy appears to be able to safely target two proteins commonly found in glioblastoma tumors. 

The question now is whether the results are durable. The results of the early trials don’t necessarily mean the therapy will work long term. 

Both teams plan to continue with their ongoing phase 1 trials and modify their approach to home in on the best combination of treatments for glioblastoma. 

Maus said she believes CAR-T therapy may be more effective if a tumor is first weakened by radiation and chemotherapy. Other researchers are also exploring cancer-fighting vaccines , which may be able to be used in tandem with CAR-T therapy. 

“We’re learning from each other. I think that’s really a tremendous model, and what we are all seeing is that this sort of therapy has legs for brain tumor patients,” Maus said. “It may not be the final version yet, but we’re onto something.” 

Kaitlin Sullivan is a contributor for NBCNews.com who has worked with NBC News Investigations. She reports on health, science and the environment and is a graduate of the Craig Newmark Graduate School of Journalism at City University of New York.