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Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade

Davis Y Torrejon1, Gabriel Abril-Rodriguez1,2, Ameya S Champhekar1

  • 1Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, California.

Cancer Discovery
|May 30, 2020
PubMed

Insights

Strategies to overcome resistance to programmed cell death protein 1 (PD-1) blockade therapy were developed using genetic models. Combination therapies targeting Janus kinase (JAK) and Beta-2-microglobulin (B2M) mutations can restore anti-tumor immunity.

Area of Science:

  • Immunology
  • Cancer Biology
  • Genetics

Background:

  • Resistance to PD-1 blockade therapy poses a significant clinical challenge.
  • Genetic mutations in JAK1, JAK2, and B2M can lead to acquired resistance.
  • Understanding these resistance mechanisms is crucial for developing effective treatment strategies.

Purpose of the Study:

  • To develop and characterize genetic models of acquired resistance to PD-1 blockade.
  • To identify mechanism-based combination therapies to overcome this resistance.
  • To elucidate the immunological pathways involved in restoring anti-tumor activity.

Main Methods:

  • Gene knockout was used to create JAK1, JAK2, and B2M loss-of-function models in human and murine cell lines.
  • Resistance to PD-1 therapy was assessed both in vitro and in vivo.
  • Combination therapies involving intratumoral Toll-like receptor 9 agonists and bempegaldesleukin were tested.

Main Results:

  • JAK1/2 knockout models showed resistance to interferon-induced anti-tumor effects.
  • B2M knockout models were resistant to T-cell-mediated cytotoxicity due to impaired antigen presentation.
  • JAK1/2 resistance was overcome by combining anti-PD-1 with TLR9 agonists, activating NK and CD8 T cells.
  • B2M resistance was overcome by bempegaldesleukin, activating NK and CD4 T cells.

Conclusions:

  • Mechanistically designed combination therapies can overcome genetic resistance to PD-1 blockade.
  • Activating interferon signaling and stimulating NK cells are key to overcoming resistance.
  • These strategies hold promise for improving PD-1 blockade efficacy in the clinic.

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