DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Engineering Immunotherapies for Mesothelioma and Other Solid Tumors

Posted February 19, 2016
Michel Sadelain, M.D., Ph.D., Memorial Sloan Kettering Cancer Center

Drs. Adusumilli, Sadelain, and Riviere U.S. Military Veterans are at particularly high risk for mesothelioma through past exposure to asbestos. Although its use for some processes was banned in the United States by the 1970s, asbestos was widely used throughout much of the 20th century - in clothing, piping, roofing, ships, brakes, clutches, paper, flooring, and, in general, the full spectrum of modern life. During Operations Enduring Freedom and Iraqi Freedom, armed forces personnel continued to be exposed, through its presence in military equipment, including gas masks, and in construction projects. Active duty personnel can also be exposed to asbestos fibers in older military ships and buildings as well as overseas in areas where asbestos is still used, so the risk of developing mesothelioma remains a threat. The association between asbestos exposure and the subsequent development of mesothelioma has been well documented in humans and confirmed in the laboratory in multiple animal species. Mesothelioma is a cancer affecting the membrane lining of the lungs, abdomen, or heart, often with patients presenting symptoms 30 to 40 years after the exposure to asbestos occurred. The most common type of mesothelioma is malignant pleural mesothelioma (MPM), which has a median survival time of only 4 to 12 months. About one-third of patients with MPM have unresectable tumors because they are locally advanced, with only 8% of tumors having distant metastases. Dr. Michel Sadelain saw these localized cancers as potentially accessible and an optimal target for regional, targeted therapies. In 2011, he was awarded a Technology/Therapeutic Development Award from the Peer Reviewed Medical Research Program to advance his idea of targeting MPM using a novel method called chimeric antigen receptor (CAR) therapy.

His group re-engineered T-cells, the body's natural immune defense to invading cells or viruses, to target MPM cancer cells, which overexpress a protein called mesothelin. Mesothelin is a cell surface protein that is associated with regional invasions and is overexpressed in more than 90% of epithelioid MPM. Interestingly, mesothelin was also found to be strongly to intermediately expressed in 69% of lung adenocarcinomas, 36% of triple-negative breast cancers, and 46% of esophageal adenocarcinomas. The expression of this protein has been consistently associated with tumor aggressiveness and decreased survival. Other researchers have used CARs for the treatment of blood cancers, but administering CARs to solid tumors has been problematic. Dr. Sadelain proposed to use mesothelin-targeted CARs in combination with or without the current standard of chemoradiation therapy in animals. The findings published in Science Translational Medicine showed that CAR injections into the pleural cavity, an area in the chest outside the lungs, had antitumor efficacy and T-cell persistence for 200 days.

The significance of these results moved the group to apply for FDA approval for an Investigational New Drug (IND) application in 2014, and, more recently, Dr. Sadelain and Dr. Clifford Hudis were awarded a Breakthrough Award for Clinical Trials with the Department of Defense Breast Cancer Research Program (BCRP). The BCRP-funded project will utilize the same mesothelin-targeted CAR therapy to target triple-negative breast cancer, one of the most biologically aggressive and unresponsive types of breast cancer. Dr. Prasad Adusumilli from MSK's Thoracic Oncology service will lead the clinical trials. Dr. Isabelle Rivière, director of MSK's Cell Therapy and Cell Engineering Facility, will oversee CAR T cell production. Cancer immunotherapy has received wide praise from the scientific community including being named the scientific breakthrough of the year in 2013 by Science magazine.

Publications:

Adusumilli PS, Cherkassky L, Villena-Vargas J, Colovos C, Servais E, Plotkin J, Jones DR, and Sadelain M. 2014. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Science Translational Medicine 6(261):261ra151.

Kachala SS, Bograd AJ, Villena-Vargas J, Suzuki K, Servais EL, Kadota K, Chou J, Sima CS, Vertes E, Rusch VW, Travis WD, Sadelain M, and Adusumilli PS. 2014. Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma. Clinical Cancer Research 20(4):1020-1028.

Servais EL, Colovos C, Rodriguez L, Bograd AJ, Nitadori J, Sima C, Rusch VW, Sadelain M, and Adusumilli PS. 2012. Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients. Clinical Cancer Research 18(9):2478-2489.

Links:

Public and Technical Abstracts: Regional Immune Interventions to Enhance Mesothelin-Targeted Immunotherapy of Malignant Pleural Mesothelioma

Public and Technical Abstracts: Tumor Antigen-Targeted T-Cell Therapy for Metastatic Breast Cancer

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Last updated Friday, February 19, 2016