Combination of T Cell Therapy and Targeted Therapy as a Novel Strategy for Therapy-resistant Melanoma with Mutations in the BRAF Gene

PHILADELPHIA and TAMPA, Fla. — (Feb. 14, 2019) — Collaborative research by The Wistar Institute and Moffitt Cancer Center has demonstrated that BRAF targeted therapies render resistant melanoma more sensitive to the attack of killer T cells. This result, published online in Clinical Cancer Research, suggests that adoptive T cell therapy may benefit patients that have become resistant to BRAF inhibitors.

Approximately 50% of melanoma patients carry a mutation in the BRAF protein. Targeted therapy with inhibitors of BRAF and the downstream pathway is very effective in these patients, but long-term benefits are limited due to the onset of therapy resistance. Previous studies demonstrated that BRAF inhibitors (BRAFi) positively affect the antitumor immune response mediated by T cells, and a recent small clinical trial has shown positive clinical responses in patients treated with a combination of BRAFi and adoptive T cell therapy, or infusion of tumor infiltrating lymphocytes isolated from the same patient and expanded ex vivo.

“The combinatorial approach of BRAFi and adoptive cell therapy is very promising but the mechanisms mediating this interaction have not been elucidated,” said Dmitry I. Gabrilovich, M.D., Ph.D., Christopher M. Davis Professor and program leader of the Immunology, Microenvironment and Metastasis Program at Wistar and a co-corresponding author on the study. “More importantly, we had no proof that this strategy would also benefit patients who have developed resistance to BRAFi therapy.”

Research from the Gabrilovich Lab has shown that increased levels of a protein called mannose-6-phosphate receptor (M6PR) are important for the antitumor effects of combination treatment with immunotherapy and chemotherapy or radiation therapy in different mouse models of cancer.

“We asked whether BRAFi could induce the same upregulation of M6PR and whether this effect could be exploited to potentiate the effects of adoptive T cell therapy in BRAFi-resistant tumors, for which clinical options are still very limited,” said Amod Sarnaik, M.D., associate member of the Department of Cutaneous Oncology at Moffitt and a co-senior author on the study.

Importantly, M6PR is a receptor for granzyme B, a substance produced by activated CD8+ T cells, and mediates the intake of the toxic cargo released by these killer immune cells.

The team confirmed that BRAF inhibition induces higher expression of M6PR in melanoma cells in culture. Importantly, this effect was also seen in BRAFi-resistant cells. Furthermore, increased expression of M6PR correlated with higher intake of granzyme B and increased sensitivity of melanoma cells to the toxic activity of tumor infiltrating lymphocytes.

The translational relevance of these observations was evaluated in a pilot clinical trial in which 16 patients with metastatic melanoma were treated with the BRAFi vemurafenib followed by adoptive T cell therapy with tumor infiltrating lymphocytes. The combination treatment was well tolerated, and researchers observed that BRAFi caused a marked increase in M6PR in the patients’ tumors.

This study suggests that adoptive T cell therapy may be therapeutically useful for patients who experienced tumor progression on BRAFi.

Co-authors: Co-first authors Cigdem Atay and Taekyoung Kwak, Sergio Lavilla-Alonso, Laxminarasimha Donthireddy, Vito W. Rebecca, Min Xiao, Jiufeng Tan, Gao Zhang, and Meenhard Herlyn from Wistar; Allison Richards, Valerie Moberg, Shari Pilon-Thomas, Michael Schell, and Jane L. Messina from Moffitt; Jeffrey S. Weber from New York University Langone Health.

Work supported by: National Institutes of Health (NIH) grants Melanoma SPORE P50CA168536, Melanoma SPORE P50CA174523, 5P01CA114046, 1U54CA224070, NCI-K23CA178083; department of defense grant WX1XWH-16-1-0119 (CA150619); research grants from Genentech Inc., the Donald A. Adam Melanoma and Skin Cancer Center of Excellence at Moffitt Cancer Center; the Swim Across America Foundation, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and a Leo and Anne Albert American Cancer Society Foundation Research Scholar Grant. Core support for Wistar and Moffit was provided by Cancer Center Support Grants P30CA010815 and P30CA076292, respectively. Vemurafenib was provided by Genentech Inc. and IL-2 was provided by Prometheus Laboratories Inc.

Publication information: BRAF targeting sensitizes resistant melanoma to cytotoxic T cells, Clinical Cancer Research (2019). Advance online publication.

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About The Wistar Institute
The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious disease research, and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

About Moffitt Cancer Center
Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 49 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt’s scientific excellence, multidisciplinary research, and robust training and education. Moffitt is a Top 10 cancer hospital and has been nationally ranked by U.S. News & World Report since 1999. Moffitt devotes more than 2 million square feet to research and patient care. Moffitt’s expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. With more than 6,000 team members, Moffitt has an economic impact in the state of $2.1 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, Twitter and YouTube.

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