11/11/2011 from the 2011 International Melanoma Symposium in Tampa
Combining BRAF inhibitors and immunotherapy
Antoni Ribas, M.D. Stephen Mok, Nicholas Otte, Thinle Chodon, M.D.,Ph.D., Begonya Comin-Anduix, Ph.D., Richard C. Koya, M.D.,Ph.D Jonsson Comprehensive Cancer Center (JCCC) at UCLA, Los Angeles, CA.
11/11/2011 from the 2011 International Melanoma Symposium in Tampa
Combining BRAF inhibitors and immunotherapy
Antoni Ribas, M.D. Stephen Mok, Nicholas Otte, Thinle Chodon, M.D.,Ph.D., Begonya Comin-Anduix, Ph.D., Richard C. Koya, M.D.,Ph.D Jonsson Comprehensive Cancer Center (JCCC) at UCLA, Los Angeles, CA.
Targeted therapies that specifically block oncogenic signaling in cancer without affecting the functions of lymphocytes may be used as immune sensitizing agents to improve the antitumor activity of cancer immunotherapy (Begley and Ribas Clinical Can Res 2008). This premise of immune sensitization could be achieved by combining BRAF inhibitors and immunotherapy. The compatibility of such combination approach requires that BRAF inhibitors do not have detrimental effects against the function of antitumor lymphocytes at therapeutic doses. When tested at a wide range of concentrations of the BRAF inhibitor vemurafenib (PLX 4032) using the in vitro human T cell cultures (Comin-Anduix, Chodon,et.al Clinical Res 2010). We then developed a BRAF V600E – driven murine melanoma model to test this combination in fully synergic and immunocompetent C57BL/6 mice. The murine melanoma line SM1 is a spontaneously arising melanoma in transgenic mice with the BRAF V600E mutation under the tyrosinase promoter. SM1 cells exposed to vemurafenib had partial in vitro and in vivo sensitivity resulting from the inhibition of of MAPK pathway signaling, while murine lymphocytes were spared. Combined treatment of vemurafenib plus adoptive cell transfer (ACT) therapy with lymphocytes genetically modified with a T cell receptor (TCR) recognizing chicken ovalbumin (OVA) expressed by expressed by SM1-OVA tumors, or pmel-1 TCR transgenic lymphocytes recognizing gp100 endogenously expressed by SM1, resulted in superior antitumor responses compared to either therapy alone. Analysis of adoptively transferred T cells in spleen and tumor biopsies, and molecular imaging-based in vivo T cell tracking, demonstrated that vemurafenib did not significantly alter the expansion, distribution or tumor accumulation of the adoptively transferred T cells. However there was evidence of increased T cell activation in tumor infiltrating lymphocytes (TILS) upon antigen recognition. In conclusion, these studies support the clinical testing of combined oncogenic BRAF inhibitor and immunotherapy for BRAF V600E mutant metastatic melanoma.
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