Regulation of CAR T cell-mediated cytokine release syndrome-like toxicity using low molecular weight adapters

Nat Commun. 2019 Jun 18;10(1):2681. doi: 10.1038/s41467-019-10565-7.

Abstract

Although chimeric antigen receptor (CAR) T cell therapies have demonstrated considerable success in treating hematologic malignancies, they have simultaneously been plagued by a cytokine release syndrome (CRS) that can harm or even kill the cancer patient. We describe a CAR T cell strategy in which CAR T cell activation and cancer cell killing can be sensitively regulated by adjusting the dose of a low molecular weight adapter that must bridge between the CAR T cell and cancer cell to initiate tumor eradication. By controlling the concentration and dosing schedule of adapter administration, we document two methods that can rapidly terminate (<3 h) a pre-existing CRS-like toxicity and two unrelated methods that can pre-emptively prevent a CRS-like toxicity that would have otherwise occurred. Because all four methods concurrently enhance CAR T cell potency, we conclude that proper use of bispecific adapters could potentially avoid a life-threatening CRS while enhancing CAR T cell tumoricidal activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Engineering / methods
  • Cell Line, Tumor
  • Cytokines / immunology
  • Fluorescein / metabolism
  • Folate Receptors, GPI-Anchored / metabolism
  • Folic Acid / metabolism
  • Humans
  • Immune System Diseases / etiology
  • Immune System Diseases / prevention & control*
  • Immunotherapy, Adoptive / adverse effects*
  • Immunotherapy, Adoptive / methods
  • Lymphocyte Activation / immunology
  • Mice
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Receptors, Chimeric Antigen / immunology*
  • Receptors, Chimeric Antigen / metabolism
  • Single-Chain Antibodies / immunology
  • Single-Chain Antibodies / metabolism
  • Syndrome
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / transplantation
  • Xenograft Model Antitumor Assays

Substances

  • Cytokines
  • Folate Receptors, GPI-Anchored
  • Receptors, Chimeric Antigen
  • Single-Chain Antibodies
  • Folic Acid
  • Fluorescein