Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/28017
Title: Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma.
Austin Authors: White, Michael G;Szczepaniak Sloane, Robert;Witt, Russell G;Reuben, Alexandre;Gaudreau, Pierre Olivier;Andrews, Miles C;Feng, Ningping;Johnson, Sarah;Class, Caleb A;Bristow, Christopher;Wani, Khalida;Hudgens, Courtney;Nezi, Luigi;Manzo, Teresa;De Macedo, Mariana Pettaccia;Hu, Jianhua;Davis, Richard;Jiang, Hong;Prieto, Peter;Burton, Elizabeth;Hwu, Patrick;Tawbi, Hussein;Gershenwald, Jeffrey;Lazar, Alexander J;Tetzlaff, Michael T;Overwijk, Willem;Woodman, Scott E;Cooper, Zachary A;Marszalek, Joseph R;Davies, Michael A;Heffernan, Timothy P;Wargo, Jennifer A
Affiliation: Translational Sciences Oncology, MedImmune, Gaithersburg, MD, USA
Olivia Newton-John Cancer Research Institute
School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia
Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Oncology Research, Nektar Therapeutics, San Francisco, CA, USA
Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Translational Research to AdvanCe Therapeutics and Innovation in ONcology (TRACTION), University of Texas MD Anderson Cancer Center, Houston, TX, USA
Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Issue Date: Nov-2021
Date: 2021
Publication information: Oncoimmunology 2021; 10(1): 1992880
Abstract: 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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/28017
DOI: 10.1080/2162402X.2021.1992880
ORCID: 0000-0003-4510-0382
0000-0001-8312-7485
0000-0003-4519-5369
0000-0002-6395-4499
0000-0002-0977-0912
Journal: Oncoimmunology
PubMed URL: 34777916
Type: Journal Article
Subjects: MAP-kinase
Melanoma
OX-40
checkpoint blockade
immunotherapy
targeted therapy
toxicity
Appears in Collections:Journal articles

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