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

doi:10.1016/j.ccell.2021.07.023

Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy

Cancer Cell. 2021 Oct 11;39(10):1375-1387.e6. doi: 10.1016/j.ccell.2021.07.023. Epub 2021 Aug 19.

Authors

Yujue Wang¹, Sixue Liu¹, Zhentao Yang¹, Alain P Algazi², Shirley H Lomeli¹, Yan Wang¹, Megan Othus³, Aayoung Hong¹, Xiaoyan Wang⁴, Chris E Randolph⁵, Alexis M Jones⁶, Marcus W Bosenberg⁷, Stephanie D Byrum⁸, Alan J Tackett⁸, Henry Lopez⁹, Clayton Yates¹⁰, David B Solit⁶, Antoni Ribas¹¹, Marco Piva¹², Gatien Moriceau¹³, Roger S Lo¹⁴

Affiliations

¹ Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
² Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA 94143, USA.
³ Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁴ Division of General Internal Medicine, Department of Medicine, University of California, Los Angeles, CA 90095, USA.
⁵ Arkansas Children's Research Institute, Little Rock, AR 72202, USA.
⁶ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁷ Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
⁸ Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
⁹ MuriGenics Inc, Vallejo, CA 94592, USA.
¹⁰ Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, USA.
¹¹ Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Division of Surgical Oncology, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
¹² Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address: mpiva@cicbiogune.es.
¹³ Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address: gmoriceau@mednet.ucla.edu.
¹⁴ Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address: rlo@mednet.ucla.edu.

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 Braf^V600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by Kras^G12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γ^hi, 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Humans
Immune Checkpoint Inhibitors / pharmacology
Immune Checkpoint Inhibitors / therapeutic use*
Immunotherapy / methods*
Mice
Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
Neoplasms / drug therapy*

Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy

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