Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy
Yujue Wang, Sixue Liu, Zhentao Yang, Alain P Algazi, Shirley H Lomeli, Yan Wang, Megan Othus, Aayoung Hong, Xiaoyan Wang, Chris E Randolph, Alexis M Jones, Marcus W Bosenberg, Stephanie D Byrum, Alan J Tackett, Henry Lopez, Clayton Yates, David B Solit, Antoni Ribas, Marco Piva, Gatien Moriceau, Roger S Lo, Yujue Wang, Sixue Liu, Zhentao Yang, Alain P Algazi, Shirley H Lomeli, Yan Wang, Megan Othus, Aayoung Hong, Xiaoyan Wang, Chris E Randolph, Alexis M Jones, Marcus W Bosenberg, Stephanie D Byrum, Alan J Tackett, Henry Lopez, Clayton Yates, David B Solit, Antoni Ribas, Marco Piva, Gatien Moriceau, Roger S Lo
Abstract
Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.
Trial registration: ClinicalTrials.gov NCT02196181.
Keywords: BRAF/NRAS/KRAS/NF1; MAPK/BRAF/MEK inhibitor resistance; anti-CTLA-4; anti-PD-1/L1; brain metastasis; colorectal carcinoma; melanoma; pancreatic ductal adenocarcinoma; sequential-combination therapy; tumor immune microenvironment.
Conflict of interest statement
Declaration of interests R.S.L.: research support from Merck, Pfizer, BMS, and OncoSec. Consultant for Amgen, Novartis, Array BioPharma, Genentech, and Merck. A.R.: consultant for Amgen, BMS, Chugai, Genentech, Merck, Novartis, Roche, Sanofi, and Vedanta. Advisory board member for and stock shareholder of Advaxis, Apricity, Arcus, Compugen, CytomX, Five Prime, Highlight, ImaginAb, Isoplexis, Kalthera, Kite-Gilead, Merus, PACT Pharma, RAPT, Rgenix, and Tango. Research funding from Agilent and BMS through SU2C. A.P.A.: research support, advisory board member, consultant, shareholder and honorarium recipient, OncoSec. Advisory board member for and stock shareholder in Valitor Biosciences. Advisory board member and honorarium recipient for Regeneron and Array. Research support from Acerta, Amgen, AstraZeneca, BMS, Dynavax, Genentech, Idera, Incyte, ISA, LOXO, Merck, Novartis, Sensei, and Tessa. M.O.: consultant for Merck, Biosight, and Daiichi Sankyo; independent data safety monitoring committee member for Celgene and Glycomimetics. C.Y.: consultant for QED Therapeutics and Riptide Biosciences and owner of stocks in Riptide Biosciences. H.L.: co-founder and Executive Vice President of Riptide Biosciences. M.W.B.: consultant for Eli Lilly and research support from AstraZeneca. D.B.S.: consultant for Pfizer, Loxo/Lilly Oncology, Vividion Therapeutics, Fore Therapeutics, and BridgeBio.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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Source: PubMed