Oncogenic BRAF contributes to immune escape in melanoma.
MAPK pathway inhibition can release suppression.
BRAF inhibition improves T-cell immune response against cancer.
PHILADELPHIA - Combined targeted therapy against the BRAF/MAPK pathway with immunotherapy shows promise as a new therapeutic approach for the treatment of melanoma, according to results of a preclinical study published in Cancer Research, a journal of the American Association for Cancer Research.
"Our results provide preclinical evidence for the rational combination of BRAF-targeted therapy and immunotherapy in the treatment of this most dangerous type of skin cancer," said lead researcher Jennifer A. Wargo, M.D., division of surgical oncology at Massachusetts General Hospital, Boston.
"By blocking the oncogenic BRAF, tumor antigen expression may be restored. This would make the melanoma tumors susceptible to strategies incorporating immunotherapy," she said.
Previous studies have shown that melanoma treatment with selective BRAF inhibitors are very effective and result in a high initial response rate, but the response is temporary. An alternative approach would be to combine other agents and extend the duration of treatment response.
Using biopsies of melanoma tumors, the researchers investigated the effects of mitogen-activated protein kinase (MAPK) pathway inhibition vs. selective inhibition of BRAF-V600E on T-cell function.
Inhibition of the MAPK pathway with a specific inhibitor of BRAF-V600E resulted in increased expression of antigens, which was associated with improved recognition by antigen-specific T-cell. T-cell function was not compromised after treatment with BRAF-V600E.
Mario Colombo, Ph.D., director of molecular immunology at the Italian National Cancer Institute and senior editor for Cancer Research, said these results advance cancer research by offering new arguments to sustain the combination of selective targeted therapy with immunotherapy.
"This study shows the need for considering the effect of off-targeted drug therapy on the many aspects of host immune response to make real the combination of chemo- and immunotherapy," Colombo said. "It also prompts the idea of performing vaccination in the attempt to eradicate the disease and prevent recurrence."
Several clinical trials are underway using agents that selectively inhibit BRAF-V600E in patients with metastatic melanoma. These studies have shown impressive response rates, though durability of response remains an issue, according to Wargo.
Results of this study provide a basis for combining this type of therapy with immunotherapy, with the goal of improving durability of responses.
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The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, the AACR is the worlds oldest and largest professional organization dedicated to advancing cancer research. The membership includes 31,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants, research fellowship and career development awards. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. The AACR publishes six major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; and Cancer Prevention Research. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.