Immunotherapy for Esophageal Cancer

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  • Esophageal Cancer
  • Treatment Options
  • CRI's Impact
  • Clinical Trials

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

Reviewed By: Hiroyoshi Nishikawa, M.D., Ph.D.
National Cancer Center Japan

Immunotherapy for esophageal cancer is being explored for first-line treatment, preventing recurrence, combination therapies, and in other innovative ways. 

Two main types of cancer affect the esophagus, a muscular tube through which food passes from the mouth to the stomach:

  • squamous cell carcinoma: cancer that begins in flat cells lining the esophagus
  • adenocarcinoma: cancer that begins in cells that make and release mucus, which are usually associated with ectopic gastric mucosa

Esophageal cancer is 3 to 4 times more common in men than in women. Risk factors for esophageal cancer include smoking tobacco and heavy alcohol use. Esophageal cancer is estimated to affect approximately 500,000 people globally each year. In the U.S. alone, there were an estimated 17,000 new cases and 16,000 deaths in 2018. The 5-year relative survival rate for patients with esophageal cancer is 43% for patients with localized disease found only in the esophagus; 23% for regional disease that has spread to nearby lymph nodes and organs; and 5% for metastatic disease that has spread to distant parts of the body.

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Esophageal Cancer Treatment Options

When esophageal cancer is caught early, there are several effective therapies available, including surgery, chemotherapy, and endoscopic treatments. But these options don’t work as well against metastatic tumors, or cancer that has spread. Surgery remains the most common treatment for esophageal cancer, and surgery, chemotherapy, and radiation work well against localized cancers.

Immunotherapy is class of treatments that take advantage of a person’s own immune system to help kill cancer cells. There are three FDA-approved immunotherapy options for esophageal cancer.

Targeted Antibodies

  • Ramucirumab (Cyramza®): a monoclonal antibody that targets the VEGF/VEGFR2 pathway and inhibits tumor blood vessel growth; approved for subsets of patients with advanced gastroesophageal cancer
  • Trastuzumab (Herceptin®): a monoclonal antibody that targets the HER2 pathway; approved for subsets of patients with advanced, HER2-positive gastroesophageal cancer, including as a first-line therapy


  • Pembrolizumab (Keytruda®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced, PD-L1-positive gastroesophageal cancer or squamous cell carcinoma of the esophagus

Immunotherapy research on esophageal cancer is ongoing and holds the promise of new treatment options. Several other immunotherapy approaches for esophageal cancer have shown promise in early clinical trials.

Find an Esophageal Cancer Clinical Trial

CRI's Impact on Esophageal Cancer

Immunotherapy has the potential to improve the outlook for patients and families affected by the disease and bring us ever closer to effective, lasting cures for esophageal cancer.

  • CRI researchers analyzed NY-ESO-1 cancer-testis (CT) antigen expression in esophageal cancer and have sought to correlate this expression with disease stage and clinical outcome (high expression frequency indicates a feasible vaccine target).
  • Clinical investigator Eiichi Nakayama, M.D., and colleagues at Okayama University Graduate School of Medicine and Dentistry in Japan reported in the International Journal of Cancer that a vaccine composed of the NY-ESO-1f long peptide administered with the immune stimulants Montanide ISA-51 and Picibanil OK-432 could elicit integrated immune responses including antibodies, CD4+ helper T cells, and CD8+ killer T cells in nine out of the ten patients enrolled in a phase I clinical trial.

Explore CRI’s current funding for esophageal cancer research in our funding directory.

Donate to Esophageal Cancer Research

Featured Patient

"They need me to be the rock, and I can be the rock because I did that trial."

Esophageal Cancer  |  Diagnosed 2016
Read My Story
Featured Scientist
Monica M. Olcina, Ph.D.
Stanford University
Postdoctoral Fellow  |  2016
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Esophageal Cancer Statistics

78% of cases occur in men
500K Newly diagnosed patients each year globally

Esophageal Cancer Clinical Trial Targets

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

  • Targeted Antibodies
  • Cancer Vaccines
  • Adoptive Cell Therapy
  • Immunomodulators
  • Oncolytic Virus Therapy

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 esophageal cancer clinical trials include:

  • cMET: a growth-related pathway that is often abnormally activated in cancer
  • EGFR: a pathway that controls cell growth and is often mutated in cancer
  • FGF/FGF-R: a pathway that controls cell growth, death, and migration
  • HER2: a pathway that controls cell growth and is commonly overexpressed in cancer and associated with metastasis
  • TROP2: a protein that is commonly overexpressed in cancer and appears to aid cancer cell self-renewal, proliferation, invasion, and survival
  • 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 esophageal cancer clinical trials include:

  • Human Papilloma Virus (HPV)-related antigens: foreign viral proteins expressed by HPV-infected cancer cells
  • Mesothelin: a protein that is commonly overexpressed in cancer and may aid metastasis
  • 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

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 esophageal cancer clinical trials include:

  • Epstein-Barr Virus (EBV)-related antigens: foreign viral proteins expressed by EBV-infected cancer cells
  • 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 esophageal cancer clinical trials include:

  • CD40: activating this co-stimulatory pathway can kick-start adaptive immune responses
  • 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
  • CXCR4: blocking this pathway can promote the migration and recruitment of immune cells
  • GITR: activating this pathway can help prevent immunosuppression and increase the survival of cancer-fighting T cells
  • ICOS: activating this co-stimulatory pathway on T cells can help enhance immune responses against cancer
  • 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
  • LAG3: blocking this pathway may be able to help prevent suppression of cancer-fighting T cells
  • 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
  • STAT3: activating this intracellular signaling protein can help stimulate adaptive immune responses

Oncolytic virus therapy uses modified viruses that can 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 esophageal 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
  • Maraba virus: a virus found exclusively in insects
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Sources: ACS Facts and Figures 2018;;; CRI documents; GLOBOCAN 2018; JAPIC Clinical Trials Information

Updated December 2018

*Immunotherapy results may vary from patient to patient. Consult a healthcare professional about your treatment options.

*Immunotherapy results may vary from patient to patient.