TY - JOUR
T1 - BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy
AU - Koya, Richard C.
AU - Mok, Stephen
AU - Otte, Nicholas
AU - Blacketor, Kevin J.
AU - Comin-Anduix, Begonya
AU - Tumeh, Paul C.
AU - Minasyan, Aspram
AU - Graham, Nicholas A.
AU - Graeber, Thomas G.
AU - Chodon, Thinle
AU - Ribas, Antoni
PY - 2012/8/15
Y1 - 2012/8/15
N2 - Combining immunotherapy with targeted therapy blocking oncogenic BRAF V600 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.
AB - Combining immunotherapy with targeted therapy blocking oncogenic BRAF V600 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.
UR - http://www.scopus.com/inward/record.url?scp=84865112760&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84865112760&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-11-2837
DO - 10.1158/0008-5472.CAN-11-2837
M3 - Article
C2 - 22693252
AN - SCOPUS:84865112760
SN - 0008-5472
VL - 72
SP - 3928
EP - 3937
JO - Cancer Research
JF - Cancer Research
IS - 16
ER -