Immunotherapy
For Pancreatic Cancer

How is Immunotherapy for Pancreatic Cancer Changing the Outlook for Patients?

Reviewed by:

Mark O’Hara, MD
University of Pennsylvania

Immunotherapy for pancreatic cancer is currently in clinical trials, providing potential new options for patients with this difficult-to-treat cancer.

The pancreas is an organ of the digestive system located behind the stomach, bordering the spleen and small intestine. It has two primary functions: an endocrine function that releases insulin and glucagon into the bloodstream and an exocrine function that produces digestive enzymes that are released into the small intestine.

The incidence of pancreatic cancer is rising, and some reports project that the number of new pancreatic cancer cases and pancreatic cancer deaths will more than double by 2030. Pancreatic ductal adenocarcinoma (PDA) accounts for more than 90% of pancreatic cancer cases.

Pancreatic cancer is very difficult to detect or diagnose at early stages of disease. It often develops without early symptoms, there is no widely used method for early detection, and although some risk factors have been identified (such as tobacco use, family history of pancreatic cancer, and a personal history of pancreatitis, diabetes, or obesity), few patients diagnosed with pancreatic cancer have identifiable risk factors.

Pancreatic cancer is one of the world’s most lethal cancers and the third-leading cause of cancer-related death in the United States. Each year, an estimated 460,000 people globally—and 64,000 in the U.S.—are diagnosed with pancreatic cancer, and it causes approximately 430,000 deaths worldwide and 50,000 in the U.S.

Pancreatic ductal adenocarcinoma (PDA) is highly lethal; for all stages combined, the 1- and 5-year relative survival rates are 27% and 9%, respectively, making it the only cancer with an overall 5-year survival rate in the single digits.

There are currently limited effective treatments for patients with advanced disease who are ineligible for surgery, a prognosis representing the majority of pancreatic cancer diagnoses. Pancreatic cancer is significantly more resistant to chemotherapy in comparison to other cancer types, leaving patients with fewer options when it comes to treating the disease in its earlier stages.

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Pancreatic Cancer Treatment Options

Traditional treatments for pancreatic cancer include surgical resection, radiation, ablative treatments, and chemotherapy.

Currently, the only treatment for pancreatic cancer that has any chance of curing the patient of the disease is the complete surgical removal of the pancreas, a procedure for which fewer than 20% of those diagnosed are eligible. Many patients who do proceed with surgery will ultimately relapse, pointing to the urgent need for more effective treatments that are more likely to prevent eventual relapse.

Immunotherapy is a class of treatments that take advantage of a person’s own immune system to help kill cancer cells. There are currently two FDA-approved immunotherapy options for a small subset of patients with pancreatic cancer, and many more are being investigated in clinical trials.

Immunomodulators

  • Dostarlimab (Jemperli): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced pancreatic cancer that has DNA mismatch repair deficiency (dMMR)
  • Pembrolizumab (Keytruda®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced pancreatic cancer that has high microsatellite instability (MSI-H), DNA mismatch repair deficiency (dMMR), or high tumor mutational burden (TMB-H)

Due to its consistently poor outlook and the current lack of effective treatment options, pancreatic cancer patients are highly encouraged to seek clinical trials in all cases.

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CRI’s Impact on Pancreatic Cancer

At the Cancer Research Institute, we are dedicated to improving the quality of life and prognostic landscape for patients diagnosed with this destructive disease. With the aid of our donor network, we continue to provide funding to leading scientists working in the field of pancreatic cancer research and treatment.

CRI discoveries and ongoing work in pancreatic cancer research and treatment include:

  • A study by former CRI predoctoral fellow Eric Lutz, PhD, and CRI’s Scientific Advisory Council member and clinical trial researcher Elizabeth Jaffee, MD, found that a vaccine called GVAX could make a “non-immunogenic” pancreatic tumor more likely to be detected by the immune system.
  • In 2012, Lauren Bayne, PhD, a former CRI predoctoral fellow at the University of Pennsylvania, and Yuliya Pylayeva-Gupta, PhD, a 2009-2012 CRI postdoctoral fellow at NYU Langone Medical Center, independently showed that the mutation in the KRAS gene—which is mutated in nearly all pancreatic cancers—triggers expression of the immune stimulating molecule GM-CSF, which recruits immature immune cells that can suppress the anti-tumor activity of other immune cells.
  • CRI-funded graduate student Albert Lo validated FAP+ stromal cells as candidate targets for pancreatic cancer immunotherapy through preclinical studies of adoptive therapy with CAR T cells modified to target FAP.
  • CRI postdoctoral fellow Ingunn M. Stromnes, PhD, developed a mouse model of pancreatic ductal adenocarcinoma, discovered that the tumors were attracting Gr-MDSCs (a type of regulatory immune cell) by releasing GM-CSF (a protein), and administered a monoclonal antibody targeted against a particular antigen found on Gr-MDSCs, which allowed killer T cells to enter the tumors and launch an assault.
  • Robert Vonderheide, MD, DPhil, a member of CRI’s Scientific Advisory Council, is leading a CRI clinical trial that is targeting the CD40 pathway in combination with chemotherapy and checkpoint immunotherapy in patients with metastatic pancreatic cancer. Early results have demonstrated the promise of this approach.

See what pancreatic cancer-specific research we’re currently funding. With your help, we can fund more research and revolutionize the way cancer is treated—curing more people and saving more lives.

Donate to Pancreatic Cancer Research

Related Links

What is Immunotherapy
Immunotherapy Treatment Types
Immunotherapy by Cancer Type
Immunotherapy Stories
Understanding Clinical Trials
Immunotherapy Webinars

Pancreatic Cancer Statistics

3rd Leading cause of cancer-related deaths in the U.S.

9% Overall 5-year survival rate

460K Newly diagnosed patients each year globally

Pancreatic Cancer Clinical Trial Targets

Discover the different proteins, pathways, and platforms that scientists and physicians are pursuing to develop new pancreatic cancer treatments. Use this information to consider your clinical trial options.

Targeted antibodies are proteins produced by the immune system that can be customized to target specific markers on cancer cells, in order to disrupt cancerous activity, especially unrestrained growth. Antibody-drug conjugates (ADCs) are equipped with anti-cancer drugs that they can deliver to tumors. 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. Antibody targets under evaluation in pancreatic cancer clinical trials include:

  • EGFR: a pathway that controls cell growth and is often mutated in cancer
  • HER2: a pathway that controls cell growth and is commonly overexpressed in cancer and associated with metastasis
  • Mesothelin: a protein that’s commonly overexpressed in cancer and may aid metastasis
  • PDGFRα: a surface receptor that plays a role in stimulating cell division and growth
  • VEGF/VEGF-R: a pathway that can promote blood vessel formation in tumors
  • EpCAM: a pathway that controls cell growth and adhesion
  • FGF/FGF-R: a pathway that controls cell growth, death, and migration
  • Nectin-4: a pathway that controls cell growth and adhesion
  • VEGF/VEGF-R: a pathway that can promote blood vessel formation in tumors

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. Cancer vaccine targets under evaluation in pancreatic cancer clinical trials include:

  • CEA: a protein involved in cellular adhesion normally produced only before birth; often abnormally expressed in cancer and may contribute to metastasis
  • Mesothelin: a protein that is commonly overexpressed in cancer and may aid metastasis
  • MUC-1: a sugar-coated protein that is commonly overexpressed in cancer
  • P53: a tumor suppressor protein that is often mutated, nonfunctional, and overexpressed in cancer
  • Personalized neoantigens: these abnormal proteins arise from mutations and are expressed exclusively by tumor cells
  • Ras: a central signaling protein that is commonly mutated in cancer and has been linked to abnormal growth and cell division
  • Survivin: a protein that can prevent cellular death and is overexpressed by a number of cancer cell types
  • Telomerase: an enzyme that helps maintain the health of cellular DNA; exploited by cancer cells to achieve immortality
  • Tumor-associated antigens (TAAs): proteins often expressed at abnormally high levels on tumor cells that can be used to target them; also found on normal cells at lower levels
  • WT1: a protein that is often mutated and abnormally expressed in patients with cancer, especially Wilms’ tumor (WT)
  • Personalized neoantigens: these abnormal markers arise from mutations and are expressed exclusively by tumor cells
  • Tumor-associated antigens: antigens often expressed at abnormally high levels on tumor cells and can be used to target them; also found on normal cells at lower levels

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, T cells are modified and equipped with chimeric antigen receptors (CARs) that enable superior anti-cancer activity. Natural killer cells (NKs) and tumor infiltrating lymphocytes (TILs) can also be enhanced and reinfused in patients. Cell-based immunotherapy targets under evaluation in pancreatic cancer clinical trials include:

  • CEA: a protein involved in cellular adhesion normally produced only before birth; often abnormally expressed in cancer and may contribute to metastasis
  • Epstein-Barr Virus (EBV)-related antigens: foreign viral proteins expressed by EBV-infected cancer cells
  • EGFR: a pathway that controls cell growth and is often mutated in cancer
  • Mesothelin: a protein that is commonly overexpressed in cancer and may aid metastasis
  • MUC1: a sugar-coated protein that is commonly overexpressed in cancer
  • PSCA: a surface protein that is found on several cell types and is often overexpressed by cancer cells
  • ROR1: an enzyme that is normally produced only before birth, but is often abnormally expressed in cancer and may promote cancer cell migration as well as prevent cancer cell death
  • WT1: a protein that is often mutated and abnormally expressed in patients with cancer, especially Wilms’ tumor (WT)
  • MAGE antigens: the genes that produce these proteins are normally turned off in adult cells, but can become reactivated in cancer cells, flagging them as abnormal to the immune system

Immunomodulators manipulate the “brakes” and “gas pedals” of the immune system. Checkpoint inhibitors target molecules on immune cells to unleash new or enhance existing immune responses against cancer. Cytokines regulate immune cell maturation, growth, and responsiveness. Adjuvants can stimulate pathways to provide longer protection or produce more antibodies. Immunomodulator targets under evaluation in bladder cancer clinical trials include:

  • CD40: activating this co-stimulatory pathway can kick start adaptive immune responses
  • CD73 or A2AR: blocking these pathways can help prevent the production of immunosuppressive adenosine
  • CSF1/CSF1R: blocking this pathway can help reprogram cancer-supporting macrophages
  • CTLA-4: blocking this pathway can help promote expansion and diversification of cancer-fighting T cells
  • CXCR4: blocking this pathway can promote the migration and recruitment of immune cells
  • IDO: blocking this enzyme’s activity can help prevent cancer-fighting T cells from being suppressed
  • IL-2/IL-2R: activating this cytokine pathway can help promote the growth and expansion of cancer-fighting T cells
  • PD-1/PD-L1: blocking this pathway can help prevent cancer-fighting T cells from becoming “exhausted,” and can restore the activity of already-exhausted T cells
  • STAT3: activating this intracellular signaling protein can help stimulate adaptive immune responses
  • Toll-like receptors (TLRs): activation of these innate immune receptors can help stimulate vaccine-like responses against tumors
  • CD137 (also known as 4-1BB): activating this co-stimulatory pathway can help promote the growth, survival, and activity of cancer-fighting T cells
  • CTLA-4: blocking this pathway can help promote expansion and diversification of cancer-fighting T cells
  • IL-2/IL-2R: activating this cytokine pathway can help promote the growth and expansion of cancer-fighting T cells
  • IDO: blocking this enzyme’s activity can help prevent cancer-fighting T cells from being suppressed
  • OX40: activating this co-stimulatory pathway can help promote T cell survival after activation
  • PD-1/PD-L1: blocking this pathway can help prevent cancer-fighting T cells from becoming “exhausted”, and can restore the activity of already-exhausted T cells
  • Toll-like receptors (TLRs): activation of these innate immune receptors can help stimulate vaccine-like responses against tumors

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. Viral platforms under evaluation in pancreatic cancer clinical trials include:

  • Adenovirus: a family of common viruses that can cause a wide range of typically mild effects including sore throat, fatigue, and cold-like symptoms
  • Herpes simplex virus: a virus that can cause the formation of sores on the mouth and genitals
  • Parvovirus: a virus that is associated with “slapped cheek” disease in children, anemia, and a type of arthritis
  • Reovirus: a family of viruses that can affect the gastrointestinal and respiratory tracts in a range of animal species
  • Vaccinia virus:  a virus that belongs to the poxvirus family and can cause smallpox in humans

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