Developing Precision Immunotherapies

Immunotherapy is a type of treatment that helps the body’s immune system fight cancer. Several kinds of immunotherapy, including immune checkpoint inhibitors, adoptive cell transfer, and therapeutic vaccines are either commercially available or in clinical development. To date, six immune checkpoint inhibitors have been approved by FDA for the treatment of eight types of cancer.

One of the inhibitors has also been approved to treat any solid tumor that has a specific genetic feature. This was the first FDA approval of its kind and a major advance for precision cancer medicine, in which the molecular characteristics of a tumor are used to identify effective therapies. (Read more about this drug approval.)

Recent advances in cancer immunotherapy are the result of several decades of basic research, much of it supported by NCI, on the function of the immune system and how it can be used for the treatment of cancer.

FDA-Approved Immune Checkpoint Inhibitors
Inhibitor Target Cancer Type(s)

*patients age 12 and older

†pediatric and adult patients

Atezolizumab (Tecentriq®) PD-L1

Bladder cancer

Non-small cell lung cancer

Avelumab (Bavencio®) PD-L1

Bladder cancer

Merkel cell carcinoma*

Durvalumab (Imfinzi) PD-L1

Bladder cancer

Ipilimumab (Yervoy®) CTLA-4


Nivolumab (Opdivo®) PD-1

Bladder cancer

Head and neck cancer (squamous cell carcinoma)

Classical Hodgkin lymphoma


Mismatch repair deficient and microsatellite instability-high colorectal cancer*

Non-small cell lung cancer

Renal cell (kidney) cancer

Pembrolizumab (Keytruda®) PD-1

Bladder cancer

Head and neck cancer (squamous cell carcinoma)

Classical Hodgkin lymphoma


Mismatch repair deficient and microsatellite instability-high solid tumors

Non-small cell lung cancer

Despite the remarkable progress made to date in cancer immunotherapy, most patients do not benefit from currently available treatments, and these therapies can be toxic to some individuals. Understanding why these treatments are not beneficial for more patients is a pressing question for scientists. However, NCI-funded research has led to the identification of two biomarkers that can help determine which patients are more likely to respond to checkpoint inhibitor therapy: PD-L1 and a genetic feature called microsatellite status. Patients whose cancers have these biomarkers are more likely to respond to checkpoint inhibition than patients whose cancers do not. (Learn why more biomarkers are needed in the story about melanoma survivor T.J. Sharpe of Florida.)

NCI supports a wide range of research, from basic research to clinical trials, to advance the field of cancer immunotherapy. Through this work, the benefits of immunotherapy will be extended to more patients with cancer.

Research Priorities

Additional basic research, translational studies, and clinical trials are critical for further elucidating the mechanisms of immunotherapy response, resistance, and toxicity and for identifying additional biomarkers to guide treatment selection.

Advance Research on Mechanisms of Immunotherapy Response, Resistance, and Toxicity

The effectiveness of immunotherapy in patients is influenced by several factors, including interactions between cancer cells, immune cells, and stromal (connective tissue) cells in the tumor microenvironment and the characteristics of the cancer cells themselves. Research is leading to key discoveries about these factors, but more work is needed to increase this knowledge and translate it into safer and more-effective immunotherapy options for patients. This ongoing research includes studies of:

Infographic showing how cancer cells interact with a variety of normal cells
  • The tumor microenvironment: To eradicate cancer cells, immune cells (white blood cells) must travel to the site of the tumor and infiltrate it. However, some tumors, including pancreatic and prostate tumors, can exclude immune cells from their microenvironment, making then unresponsive to immunotherapy. These tumors are called “noninflamed” or “cold” tumors. In contrast, “inflamed” or “hot” tumors, such as melanoma, contain immune cells in the tumor microenvironment and, therefore, tend to respond better to immunotherapy. How noninflamed tumors exclude immune cells and whether they can be turned into inflamed tumors are major unanswered questions that NCI-supported research is addressing.
  • Immune cells: Although a particular type of white blood cell is directly responsible for killing tumor cells, many other types of immune cells are involved in either promoting or suppressing immune responses against cancer. Scientists aim to better understand how these different cells interact with one another. As an example, NCI-funded researchers discovered that breast cancer cells and immune cells called macrophages “talk” by secreting factors that support tumor growth and invasiveness. The cancer cells secrete a protein called colony stimulating factor 1 (CSF-1) that stimulates the macrophages to produce a protein called epidermal growth factor (EGF). The EGF, in turn, promotes further cancer cell production of CSF-1, thereby generating a positive feedback loop.
  • Cancer cells: Research funded by NCI and led by Suzanne Topalian, M.D., and her colleagues at Johns Hopkins University demonstrated that tumors with high levels of the protein PD-L1 tend to respond better to PD-1 inhibitors. PD-L1 binds to the PD-1 protein on immune cells, suppressing an immune response. This finding and additional research by others led to FDA-approved tests that measure PD-L1 expression on patients’ tumors—making PD-L1 the first approved biomarker to guide the use of cancer immunotherapy. In another area of research, NCI-funded scientists have identified specific gene mutations and patterns of gene expression in certain cancer types that indicate responsiveness or resistance to PD-1 inhibitors.

Support Collaboration and Data Sharing to Discover and Validate Immunotherapy Biomarkers

Sharing samples and data through research and clinical trial networks will help advance research in cancer immunotherapy. There are several NCI-supported efforts that will help facilitate this sharing.

  • The Cancer Immunotherapy Trials Network (CITN), which was established in 2010 to design, facilitate, and conduct early-phase immunotherapy clinical trials and support research on patient tumor specimens. The network currently has 30 participating trial sites and has conducted 10 clinical trials to date. CITN works with academic, industry, and nonprofit partners to advance promising immunotherapies to the clinic more efficiently and cost effectively. For example, the network led a phase II clinical trial that demonstrated the effectiveness of the checkpoint inhibitor pembrolizumab in patients with Merkel cell carcinoma, a rare but aggressive form of skin cancer.
  • Other NCI clinical trial networks, including the Experimental Therapeutics Clinical Trials Network and the National Clinical Trials Network, which provide infrastructure, funding, and sponsorship for immunotherapy and other treatment trials. Since 2010, more than 90 phase I to phase III trials have been initiated in NCI networks for immunotherapy agents and novel combinations involving immunotherapy. Most trials incorporate research on biomarkers and other studies to better understand why these therapies work for some patients and not others.
  • In 2017, NCI announced the formation of a new network of laboratories that will be responsible for the comprehensive molecular analysis of clinical trial specimens for biomarkers associated with response to immunotherapy. The Cancer Immune Monitoring and Analysis Centers (CIMACs) will conduct correlative studies and profiling of tumors and immune cells for NCI-funded early trials of immunotherapy. Part of this effort includes the creation of a Cancer Immunologic Data Commons (CIDC) to support the bioinformatics needs of the CIMACs. The database created by the CIDC will serve as a resource for the identification of novel biomarkers and targets for patient selection and treatment, as has been done with NCI's Genomic Data Commons for genomic data.
  • As part of the Cancer Moonshot℠, NCI is establishing two networks to accelerate the translation of immunotherapy research discoveries to clinical applications for adult and pediatric cancers. For adult cancers, the Immuno-Oncology Translational Network aims to improve outcomes for patients who are treated with immunotherapy and to prevent cancers before they can occur through immunoprevention approaches. The Pediatric Immunotherapy Discovery and Development Network will identify new targets for immunotherapies, developing new pediatric immunotherapy treatment approaches, and defining the biological mechanisms by which pediatric tumors evade the immune system.

Stories of Impact

Additional research investments in developing biomarker-guided immunotherapy approaches will improve the effectiveness and safety of this class of therapies for the benefit of patients.

Making the Case for Biomarkers

In August 2012, just weeks after the birth of his second child, 37-year-old T.J. Sharpe walked into his local emergency room with a spiking fever and did not leave for more than 2 weeks. He was blindsided by the diagnosis he received: metastatic melanoma. Twelve years earlier, a stage IB melanoma had been removed from his chest. T.J. had been careful about his sun exposure ever since. But now, melanoma tumors riddled his lungs, liver, spleen, and small intestine.

Developing the First Precision Medicine

In May 2017, the Food and Drug Administration (FDA) approved the first drug to treat tumors based on their genetic characteristics, regardless of where in the body the cancer originated. Until now, drugs have been approved based on their cell or tissue of origin, such as the breast or the lung. But pembrolizumab (Keytruda®) doesn’t target the genetic abnormalities of cancer cells specifically—it targets the immune system.

Key Takeaways

  • NCI supports research to develop safe and effective immunotherapy options for all cancer patients.
  • NCI funds research to determine the mechanisms of immunotherapy response, resistance, and toxicity to aid in the discovery of biomarkers that will be useful in guiding clinical decision making.
  • NCI facilitates sharing samples and data through research and clinical trial networks that advance research in cancer immunotherapy.