T-cell and targeted combination therapy strategy for resistant melanoma with BRAF mutation

PHILADELPHIA and TAMPA, Fla. – (February 14, 2019) – Collaborative research by the Wistar Institute and the Moffitt Cancer Center has shown that BRAF-targeted therapies make resistant melanoma more susceptible to killer T-cell attack . This result, published online in Clinical research on cancer, suggests that adoptive T-cell therapy may be beneficial for patients who have become resistant to BRAF inhibitors.

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

"The combinatorial approach of BRAFi and adoptive cell therapy is very promising but the mediating mechanisms of this interaction have not been elucidated," said Dmitry I. Gabrilovich, MD, Ph.D., Christopher Dr. Davis, Professor and Head of the Immunology Program, Microenvironment and Metastasis Program at Wistar and Co-Corresponding Author of the Study. "More importantly, we had no evidence that this strategy would also benefit patients who have developed resistance to BRAFi treatment."

The Gabrilovich laboratory research has shown that an increase in the levels of a protein called mannose-6-phosphate receptor (M6PR) is important for the antitumor effects of a combination therapy 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, MD, badociate member of Moffitt's Department of Skin Oncology and co-lead author of the study.

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

The team confirmed that inhibition of BRAF induces higher expression of M6PR in melanoma cells in culture. Importantly, this effect has also been observed in BRAFi-resistant cells. In addition, an increase in M6PR expression correlated with increased granzyme B consumption and increased sensitivity of melanoma cells to the toxic activity of tumor-infiltrating lymphocytes.

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

This study suggests that adoptive T-cell therapy may be therapeutically useful for patients with tumor progression under BRAFi.

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

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

Publication Information: Targeting BRAF Sensitizes Melanoma Resistant to Cytotoxic T Lymphocytes, Clinical research on cancer (2019). Early online publication.

The Wistar Institute is an international leader in biomedical research with particular 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 holds the prestigious Cancer Center designation from the National Cancer Institute since 1972 as possible. wistar.org.

Moffitt is dedicated to a rescue mission: to contribute to the prevention and treatment of cancer. The Tampa Center is one of 49 Cancer Centers designated by the National Cancer Institute, recognizing Moffitt's scientific excellence, multi-disciplinary research, and strong training and education. Moffitt is one of the top 10 cancer hospitals and has been nationally ranked by the US News & World Report since 1999. Moffitt spends more than 2 million square feet on patient research and care. Moffitt's expert nursing staff is recognized by the American Nurses Credentialing Center as Magnet®, its highest honor. With over 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 move on Facebook, Twitter, and YouTube.

For Wistar:

Darien Sutton

(215) 898-3988

[email protected]

For Moffitt:

Kim Polacek

(813) 745-7408

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