Rankings
Publications
Sources
Publishers
Scholars
Organizations
About
Login
Register
Home
Publications
Data from Response to BRAF Inhibition in Melanoma Is Enhanced When Combined with Immune Checkpoint Blockade
Home
Publications
Data from Response to BRAF Inhibition in Melanoma Is Enhanced When Combined with Immune Checkpoint Blockade
Data from Response to BRAF Inhibition in Melanoma Is Enhanced When Combined with Immune Checkpoint Blockade
ZC
Zachary A. Cooper
Zachary A. Cooper
VJ
Vikram R. Juneja
Vikram R. Juneja
PS
Peter T. Sage
Peter T. Sage
DF
Dennie T. Frederick
Dennie T. Frederick
AP
Adriano Piris
Adriano Piris
DM
Devarati Mitra
Devarati Mitra
JL
Jennifer A. Lo
Jennifer A. Lo
FH
F. Stephen Hodi
F. Stephen Hodi
GF
Gordon J. Freeman
Gordon J. Freeman
MB
Marcus W. Bosenberg
Marcus W. Bosenberg
MM
Martin McMahon
Martin McMahon
KF
Keith T. Flaherty
Keith T. Flaherty
See more
Open Access
Publisher Website
Google Scholar
Cite
Download
Share
Download
3 April 2023
other
Published by
American Association for Cancer Research (AACR)
https://doi.org/10.1158/2326-6066.c.6548542.v1
Abstract
BRAF-targeted therapy results in objective responses in the majority of patients; however, the responses are short lived (∼6 months). In contrast, treatment with immune checkpoint inhibitors results in a lower response rate, but the responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8+ T-cell infiltrate and a decrease in immunosuppressive cytokines. There is also increased expression of the immunomodulatory molecule PDL1, which may contribute to the resistance. On the basis of these findings, we hypothesized that BRAF-targeted therapy may synergize with the PD1 pathway blockade to enhance antitumor immunity. To test this hypothesis, we developed a BRAF(V600E)/Pten−/− syngeneic tumor graft immunocompetent mouse model in which BRAF inhibition leads to a significant increase in the intratumoral CD8+ T-cell density and cytokine production, similar to the effects of BRAF inhibition in patients. In this model, CD8+ T cells were found to play a critical role in the therapeutic effect of BRAF inhibition. Administration of anti-PD1 or anti-PDL1 together with a BRAF inhibitor led to an enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor-infiltrating lymphocytes. These results demonstrate synergy between combined BRAF-targeted therapy and immune checkpoint blockade. Although clinical trials combining these two strategies are ongoing, important questions still remain unanswered. Further studies using this new melanoma mouse model may provide therapeutic insights, including optimal timing and sequence of therapy. Cancer Immunol Res; 2(7); 643–54. ©2014 AACR.
Keywords
BRAF INHIBITION
IMMUNE CHECKPOINT BLOCKADE
MOUSE MODEL
PDL1
MELANOMA
INFILTRATE
All Articles
Open Access