Posted November 2, 2015
Prasad S. Adusumilli, M.D., Memorial Sloan Kettering Cancer Center
Currently, no biomarkers have been validated that can be used to inform decision making for chemotherapy-resistant lung cancers. Dr. Adusumilli, at the Memorial Sloan Kettering Cancer Center, has taken on this challenge. Through a project funded by a Fiscal Year 2011 Lung Cancer Research Program Promising Clinician Research Award, Dr. Adusumilli has identified a biomarker that corresponds with the presence of aggressive, therapy-resistant tumors and has begun work using immunotherapy for targeting this antigen to improve treatment outcomes.
Dr. Adusumilli discovered that mesothelin, a cancer-cell surface antigen, is overexpressed in 69% of lung adenocarcinoma tumors with minimal or no expression in normal tissues. In vitro studies confirmed that mesothelin overexpression correlates to increases in tumor cell proliferation, migration, and invasion, while mouse studies revealed that high mesothelin expression corresponds to a decrease in overall survival. These observations were further validated in 1200 lung adenocarcinoma patients. These data suggested mesothelin expression is a reasonable biomarker for tumor aggressiveness and may be an attractive target for immunotherapies.
As a next step, Dr. Adusumilli developed and investigated the anti-tumor efficacy of CAR (chimeric antigen receptor) T cells, patients own immune cells genetically engineered to kill cancer cells expressing mesothelin. Based on this successful identification of mesothelin as a biomarker and development of T-cell therapy, Dr. Adusumilli has been able to successfully launch a series of clinical trials. Among these are studies investigating the effectiveness of T-cell therapies engineered to target mesothelin-expressing tumor cells, as well as work designed to evaluate mesothelin's capacity as a biomarker in other cancers.
Dr. Adusumilli's success at the identification of an evaluative biomarker indicative of aggressive behavior and resistance to currently available therapies as well as his progress toward a targeted T-cell therapy for lung cancer patients is a step forward in a promising field for lung cancer treatment.
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, 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. Clin Cancer Res 20(4):1020-1028. Erratum in: Clin Cancer Res 2014 20(14):3896.
Adusumilli PS, Cherkassky L, Villena-Vargas J. 2014. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci Transl Med 6(261):261ra151.