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

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

Esophageal cancer is one of the major cancer types for which new immune-based cancer treatments are currently in development. This page features information on esophageal cancer and immunotherapy clinical trials for esophageal cancer patients, and highlights the Cancer Research Institute’s role in working to develop immune-based treatments for esophageal cancer.

Featured Scientist
Monica M. Olcina, Ph.D.
Stanford University
Postdoctoral Fellow  |  2016
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Esophageal Cancer Statistics
Main types of esophageal cancer: squamous cell and adenocarcinoma
3 to 4
Times more common in men than women
Types of immunotherapy clinical trials
Brief Statistics

There are two main types of esophageal cancer: squamous cell carcinoma (cancer that begins in flat cells lining the esophagus) and adenocarcinoma (cancer that begins in cells that make and release mucus, which are usually associated with ectopic gastric mucosa).

In 2016, there will be roughly 16,910 new cases of esophageal cancer in the U.S, and 15,690 deaths. Risk factors for esophageal cancer include smoking tobacco and heavy alcohol use. Esophageal cancer is 3 to 4 times more common in men than in women.

Surgery, chemotherapy, and radiation work well against localized cancers, and an anti-HER2 targeted antibody—trastuzumab (Herceptin®)—is approved for patients with metastatic HER2-positive esophageal cancer. Ramuacirumab (CYRAMZA®), an anti-VEGFR2 targeted antibody, is also appproved for esophageal cancer patients, while pembrolizumab (Keytruda®), an anti-PD-1 checkpoint immunotherapy, is approved for patients with advanced cancers of the gastroesophageal junction that express PD-L1.

The 5-year relative survival rate for patients with esophageal cancer is 40% for patients with localized disease; 22% for regional disease; and 4% for metastatic disease. Better therapies to treat esophageal cancer are badly needed.

Clinical Trials for Esophageal Cancer

Several approaches to immunotherapy for esophageal cancer have shown promise in early clinical trials. These treatments can be broken into 5 main categories: checkpoint inhibitors/immune modulators, adoptive cell transfer, monoclonal antibodies, therapeutic vaccines, and cytokines.

  • Checkpoint Inhibitors/Immune Modulators
  • Adoptive Cell Therapy
  • Monoclonal Antibodies
  • Therapeutic Vaccines
  • Cytokines

A promising avenue of clinical research in esophageal cancer is the use of immune checkpoint inhibitors. These treatments work by targeting molecules that serve as checks and balances in the regulation of immune responses. By blocking inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to unleash or enhance pre-existing anti-cancer immune responses. Several checkpoint inhibitors, targeting multiple different checkpoints, are currently in development.

  • A phase III trial of nivolumab (Opdivo®), also called ONO-4538, a PD-1 antibody, for patients with unresectable advanced or recurrent esophageal cancers (NCT02569242).
  • A phase III study of pembrolizumab (Keytruda®, MK-3475) for patients with advanced esophageal or esophagogastric junction cancer that progressed after first-line therapy (NCT02564263).
  • A phase II trial of pembrolizumab (Keytruda®, MK-3475) for patients with advanced cancer of the esophagus or esophagogastric junction (NCT02559687).
  • A phase I/II study of pembrolizumab (Keytruda®, MK-3475) for patients with advanced cancer, including esophageal cancer (NCT02318901).
  • A phase I/II study to test LAG525, an antibody that targets LAG-3, +/- PDR001, a PD-1 antibody, in patients with advanced cancer, including esophageal cancer (NCT02460224).

Another major avenue of immunotherapy for esophageal cancer is adoptive T cell transfer. In this approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response. Several trials of adoptive T cell transfer techniques are currently under way for patients with esophageal cancer, including:

  • A phase II trial taking enriched tumor-infiltrating immune cells and re-infusing them in patients with metastatic digestive tract cancers, including esophageal cancer (NCT01174121).
  • A phase II study of T cells genetically reengineered to target the NY-ESO-1 antigen in patients with NY-ESO-1-positive cancers (NCT01967823). NY-ESO-1, a tumor-associated antigen, is not found on normal cells, with the exception of the testis.
  • A phase I study of T cells engineered to recognize the NY-ESO-1 marker (TBI-1301) in patients with solid tumors, including esophageal cancer (NCT02366546).
  • A phase I/II trial of T cells genetically reengineered to target the anti-MAGE-A3-DP4 protein in advanced cancer (NCT02111850).

Monoclonal antibodies are molecules, generated in the lab, that target specific antigens on tumors. Many mAbs are currently used in cancer treatment, and some appear to generate an immune response. Several mAbs are currently being tested in clinical trials:

  • A phase III trial testing nimotuzumab, an antibody designed to bind and inhibit signaling from EGFR, in patients with metastatic esophageal cancer (NCT02611700).
  • A phase I/II trial testing IMMU-132, an antibody-drug conjugate targeting Τrop-2, in patients with esophageal and other cancers (NCT01631552).
  • A phase I trial testing HuMax®, an antibody-drug conjugate targeting tissue factor, in patients with solid tumors, including esophageal cancer (NCT02552121).

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. One trial is currently enrolling patients:

  • A phase II trial of a vaccine that targets the NY-ESO-1 protein in patients with advanced cancer whose cancers express NY-ESO-1 (NCT01697527).

Cytokines are messenger molecules that help control the growth and activity of immune system cells.

  • A phase I trial to test interleukin 12 (IL-12) in patients with solid tumors (NCT01417546).

Go to our Clinical Trial Finder to find clinical trials of immunotherapies for esophageal cancer that are currently enrolling patients.

CRI Contributions and Impact

  • 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. Although NY-ESO-1 was isolated from an esophageal carcinoma patient, its expression in this type of cancer and its immunogenicity in esophageal cancer patients have not yet been fully elucidated. One hundred twenty three esophageal cancer specimens were analyzed for the expression of NY-ESO-1, and it was expressed in 41 of 123 (33%) esophageal cancer specimens. The high expression frequency of NY-ESO-1 indicates this as a feasible vaccine target in esophageal cancer.
  • 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. Three patients, two with lung cancer and one with esophageal cancer, showed stable disease. According to investigators, the immune responses were comparable to or stronger than those reported with various NY-ESO-1 protein vaccines, suggesting that vaccines using long peptides may be a promising approach to therapeutic cancer vaccination against the NY-ESO-1 antigen.

Sources: ACS Facts and Figures 2016,,, CRI documents, JAPIC Clinical Trials Information

Updated March 2016

*Immunotherapy results may vary from patient to patient.