La Trobe
1186986_White,M_2021.pdf (2.48 MB)
Download file

Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma

Download (2.48 MB)
journal contribution
posted on 23.11.2021, 04:31 by MG White, R Szczepaniak Sloane, RG Witt, A Reuben, PO Gaudreau, Miles AndrewsMiles Andrews, N Feng, S Johnson, CA Class, C Bristow, K Wani, C Hudgens, L Nezi, T Manzo, MP De Macedo, J Hu, R Davis, H Jiang, P Prieto, E Burton, P Hwu, H Tawbi, J Gershenwald, AJ Lazar, MT Tetzlaff, W Overwijk, SE Woodman, ZA Cooper, JR Marszalek, MA Davies, TP Heffernan, JA Wargo
Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (α-CTLA-4 or α-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (>4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf-mutant murine melanoma model (BrafV600E/Pten−/−). Short-term treatment with α-PD-1 and α-CTLA-4 monotherapies were relatively ineffective, while treatment with α-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined α-OX40/α-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/α-CTLA-4/α-PD-1 or DT/α-OX40/α-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies.

Funding

This work was supported by the Cancer Prevention Research Institute of Texas [RP150030]; the American Association for Cancer Research [SU2CAACR-IRG-19-17]; National Institutes of Health [T32CA009599]; National Institutes of Health [1R01CA219896-01A1]; National Institutes of Health [1U54CA224070-03]; National Institutes of Health [P30 CA016672]; National Institutes of Health [1 P50 CA221703-02]; Melanoma Research Alliance [4022024]; National Health and Medical Research Council of Australia [1148680]; Fonds de Recherche QuebecSante [32667]; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation and the MD Anderson Moon Shots ProgramTM.

History

Publication Date

01/01/2021

Journal

OncoImmunology

Volume

10

Issue

1

Article Number

e1992880

Pagination

12p.

Publisher

Taylor & Francis

ISSN

2162-4011

Rights Statement

© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Usage metrics

Categories

Exports