BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy.
Combining immunotherapy with targeted therapy blocking oncogenic BRAFV600 may result in improved treatments for advanced melanoma. In this study, we developed a BRAFV600E-driven murine model of melanoma, SM1, which is syngeneic to fully immunocompetent mice. SM1 cells exposed to the BRAF inhibitor vemurafenib (PLX4032) showed partial in vitro and in vivo sensitivity resulting from the inhibition of MAPK pathway signaling. Combined treatment of vemurafenib plus adoptive cell transfer therapy with lymphocytes genetically modified with a T-cell receptor (TCR) recognizing chicken ovalbumin (OVA) expressed by SM1-OVA tumors or pmel-1 TCR transgenic lymphocytes recognizing gp100 endogenously expressed by SM1 resulted in superior antitumor responses compared with either therapy alone. T-cell analysis showed that vemurafenib did not significantly alter the expansion, distribution, or tumor accumulation of the adoptively transferred cells. However, vemurafenib paradoxically increased mitogen-activated protein kinase (MAPK) signaling, in vivo cytotoxic activity, and intratumoral cytokine secretion by adoptively transferred cells. Taken together, our findings, derived from 2 independent models combining BRAF-targeted therapy with immunotherapy, support the testing of this therapeutic combination in patients with BRAFV600 mutant metastatic melanoma.
Department of Surgery, Division of Surgical Oncology, Crump Institute for Molecular Imaging, UCLA Biomedical Physics Interdepartmental Graduate Program, Los Angeles, University of California Los Angeles, Los Angeles, California 90095-1782, USA. rkoya@mednet.ucla.edu
Richard C
RC
Koya
Stephen
S
Mok
Nicholas
N
Otte
Kevin J
KJ
Blacketor
Begonya
B
Comin-Anduix
Paul C
PC
Tumeh
Aspram
A
Minasyan
Nicholas A
NA
Graham
Thomas G
TG
Graeber
Thinle
T
Chodon
Antoni
A
Ribas
D000818:Animals; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007211:Indoles / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D008546:Melanoma, Experimental / Q000201:enzymology / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014407:Tumor Cells, Cultured; D000077484:Vemurafenib
D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf