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Immunotherapy for Stomach Cancer

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

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

Reviewed By: Joseph Chao, M.D.
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Assistant Clinical Professor, City of Hope, Duarte, CA
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Stomach cancer, also called gastric cancer, is one of the major cancer types for which new immune-based cancer treatments are currently in development. This page features information on stomach cancer and immunotherapy clinical trials for stomach cancer patients, and highlights the Cancer Research Institute’s role in working to bring effective immune-based cancer treatments to people with this kind of cancer.

Worldwide, stomach cancer is the fifth most common diagnosis in cancer, with almost one million getting it yearly, and it is the third most deadly, with nearly 725,000 deaths. In the U.S., it is uncommon, with more than 26,000 diagnosed with stomach cancer every year, and nearly 11,000 deaths. This represents a substantive change since the very first estimates in 1975, when stomach cancer was the most common cancer. The reasons for this decline are not completely known, but may be linked to increased use of refrigeration for food storage.

The number of people diagnosed with the disease in the U.S. is declining. But in countries such as Japan, where stomach cancer is very common, mass screening of the population has helped find many cases at an early, localized stage, when the 5-year survival rate is 65%. If the cancer has invaded other organs, the 5-year survival rate drops to 5%.

Infection with bacteria called H. pylori is a common cause of gastric cancer. Risk factors may also include smoking and a diet of highly processed or salty foods.

About 90% to 95% of cancers of the stomach are adenocarcinomas. These cancers develop from the cells that form the innermost lining of the stomach. Other types of stomach cancer are gastrointestinal carcinoid tumors and gastrointestinal stromal tumors.

Treatment

Treatment of stomach cancer depends to a large degree on where the cancer started in the stomach and how far it has spread.

In Stage 0 to 3, surgery is the main treatment for patients with this disease, with either subtotal gastrectomy (removal of part of the stomach) or total gastrectomy (removal of the entire stomach). In the case of localized tumors, surgery may completely eliminate the cancer. When the cancer has invaded the stomach wall or the lymph nodes, chemotherapy (sometimes in combination with radiation therapy) is administered before or after surgery.

For Stage 4 cancer, which has spread to distant organs, treatments include surgery, chemotherapy, and/or radiation therapy. These can often help shrink the cancer and relieve some symptoms, as well as help patients live longer. Combinations of chemotherapy drugs are most commonly used, but which combination is best is not clear.

Immunotherapy can also be helpful in treating advanced cancers. Trastuzumab (Herceptin®) can be added to chemotherapy for patients whose tumors are HER2-positive. Ramucirumab (Cyramza®), a targeted antibody against VEGFR2, may also be an option at some point. It can be given by itself or added to chemotherapy. Most recently, pembrolizumab (Keytruda®), an anti-PD-1 checkpoint immunotherapy, was approved for patients with advanced, relapsed stomach cancer that expresses PD-L1.

CRI Contributions and Impact

Current and recent CRI-funded studies on immunotherapy for stomach cancer include:

  • CRI researchers, including Lloyd J. Old, M.D., and Sacha Gnjatic, Ph.D., analyzed 11 cancer-testis (CT) antigen expression in gastric cancer and have sought to correlate this expression with disease stage and clinical outcome. These are markers for cancer, called an antigen, that are not expressed on normal cells, with the exception of the testis. 101 samples were taken from patients with gastric cancer. They found that NY-ESO-1 and MAGE-3 were expressed in 11.9% and 41.65%, respectively, on these cancers. Additionally, an immune response to NY-ESO-1 was detected in 6 out of 12 gastric cancer patients, indicating that it could be used in therapeutic vaccines.
  • The CRI-SU2C Cancer Immunology Dream Team at Memorial Sloan Kettering Cancer Center, led by Michel Sadelain, M.D., Ph.D., is taking a new approach to chimeric antigen receptor (CAR) T cell therapy in the lungs. CAR T cells are genetically engineered immune cells with enhanced capability to recognize and destroy cancer cells. Unlike ongoing CAR T cell therapy trials, Sadelain constructed a CAR treatment where the primary route of administration is via the intrapleural membranes around the lungs, as opposed to the customary intravenous infusion. A clinical trial testing the approach in humans is underway. If proven to be successful, this approach can be extended to other mesothelin-expressing cancers, such as gastric cancer.
  • Vladimir Vigdorovich, Ph.D., a CRI postdoctoral fellow at Albert Einstein College of Medicine, studies B7x, which is an immune checkpoint molecule that can inhibit T cell function. B7x is absent in most human tissues and immune cells, but it is overexpressed on a number of cancers, including stomach cancer, making it a promising target for cancer immunotherapy. Vigdorovich and colleagues developed a system to screen monoclonal antibodies directed at B7x and found one that inhibited the growth of B7x-expressing tumors. These finding suggest that antibodies targeting B7x might be a promising immunotherapy for different cancer types.
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Stomach Cancer Statistics

65% 5-year survival rate for localized disease
5th Most common cancer diagnosis worldwide
90-95% Of stomach cancers are adenocarcinomas
4 Types of immunotherapy clinical trials

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Clinical Trials for Stomach Cancer

Several approaches to immunotherapy for stomach cancer have shown promise in early clinical trials. These treatments can be broken into four categories: monoclonal antibodies, checkpoint inhibitors and immune modulators, cancer vaccines, and adoptive cell therapy.

Therapies
  • Monoclonal Antibodies
  • Checkpoint Inhibitors/Immune Modulators
  • Cancer Vaccines
  • Adoptive Cell Therapy

Monoclonal antibodies are molecules, generated in the lab, that target specific antigens on tumors. Several monoclonal antibodies are currently being tested in clinical trials:

  • A phase I/II trial of personalized antibodies that are targeted to work against a specific abnormality for patients with gastric or gastroesophageal junction cancer. There will be the following treatments: trastuzumab (Herceptin®), a HER2 antibody; ramucirumab (Cyramza®), a VEGFR2 antibody; ABT-806, an EGFR antibody; and two antibodies to be determined to the MET mutation and the FGFR2 mutation (NCT02213289).
  • A phase I trial of DKN-01, which targets DKK1 that restores the pathways required for cell growth and differentiation, for patients with relapsed or refractory gastroesophageal junction cancer (NCT02013154).
  • A phase I study of MEDI4276, a HER2 antibody, in patients with HER2-expressing advanced cancer (NCT02576548).
  • A phase I study of FS102, a HER2 antibody, in patients with HER2-expressing cancer (NCT02286219).
  • A phase I trial of FPA144, an FGFR2b antibody, in patients with FGFR2b-overexpressing advanced cancer (NCT02318329).

 

A promising avenue of clinical research in stomach cancer is the use of immune checkpoint inhibitors. These treatments work by targeting molecules that serve as checks and balances on immune responses. By blocking these inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to unleash or enhance pre-existing anti-cancer immune responses. The following trials are currently recruiting patients:

  • A phase III study of avelumab, a PD-L1 antibody, for patients with third-line unresectable, recurrent, or metastatic gastric or gastroesophageal junction cancer (NCT02625623).
  • A phase III study of avelumab for patients with unresectable, recurrent, or metastatic gastric or gastroesophageal junction cancer (NCT02625610).
  • A phase III study of pembrolizumab (Keytruda®, MK-3475), a PD-1 antibody, for patients with gastric or gastroesophageal junction cancer, as a first-line therapy with chemo (NCT02494583).
  • A phase I/II study of durvalumab, a PD-L1 antibody, and/or tremelimumab, a CTLA-4 antibody, for patients with recurrent or metastatic gastric or gastroesophageal junction cancer (NCT02340975).
  • A phase I/II trial testing durvalumab, a PD-L1 antibody, with INCB024360, an IDO inhibitor, which blocks an immunosuppressive molecule produced by tumor cells, in patients with gastric or gastroesophageal junction cancer (NCT02318277).
  • A phase I trial of pembrolizumab and ramucirumab (Cyramza®) for patients with recurrent or metastatic gastric or gastroesophageal junction cancer (NCT02443324).

 

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 clinical study of a cancer vaccine for stomach cancer is open: 

  • A phase I trial of a HER2 vaccine in patients with advanced cancer, including stomach cancer (NCT01376505).
  • A phase I/II trial of a gp96 vaccine in patients with gastric cancer (NCT02317471).

 

In this approach, immune 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. Clinical trials include:

  • A phase I/II study of chimeric antigen receptor (CAR) therapy targeting the MUC1 marker for patients with MUC1-positive cancers, including gastric or gastroesophageal junction cancer (NCT02617134).
  • A phase I study of chimeric antigen receptor (CAR) therapy targeting the carcinoembryonic antigen (CEA) for patients with CEA-positive cancers, including gastric cancer (NCT02349724).
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LEARN MORE ABOUT CLINICAL TRIALS

National Cancer Institute Physician Data Query (PDQ); American Cancer Society Facts & Figures 2016; GLOBOCAN 2012; National Comprehensive Cancer Network (NCCN) Guidelines for Patients; ClinicalTrials.gov; CRI grantee progress reports and other grantee documents

Last Updated March 2016

*Immunotherapy results may vary from patient to patient.

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