Chimeric antigen receptor-T cells with cytokine neutralizing capacity

Blood Adv. 2020 Apr 14;4(7):1419-1431. doi: 10.1182/bloodadvances.2019001287.

Abstract

Infusion of T lymphocytes expressing chimeric antigen receptors (CARs) can produce extraordinary antitumor activity in patients with leukemia, lymphoma, and myeloma. The signaling mechanisms activating T cells and provoking tumor cell killing also trigger cytokine secretion and macrophage activation, leading to cytokine release syndrome (CRS). CRS is a serious side effect of CAR-T cells, and proinflammatory interleukin-6 (IL-6) is central to its pathogenesis. To endow T cells with anti-CRS activity, we designed a nonsignaling membrane-bound IL-6 receptor (mbaIL6) constituted by a single chain variable fragment derived from an anti-IL-6 antibody linked to a transmembrane anchoring peptide. We found that mbaIL6 expressed on the surface of T cells could rapidly remove IL-6 from the culture supernatant. IL-6 removal was proportional to the number of mbaIL6+ cells, increased with T-cell proliferation, and neutralized IL-6 signaling and function. A construct encoding for mbaIL6 and an anti-CD19-41BB-CD3ζ CAR allowed simultaneous expression of both receptors. T cells with mbaIL6 and CAR neutralized macrophage-derived IL-6 while exerting powerful antitumor activity. Cytotoxicity and proliferation were identical to those of cells expressing CAR alone in vitro, and CAR-T cells were effective in xenograft models regardless of mbaIL6 expression. Levels of human IL-6 in mice, however, were greatly reduced if T cells expressed both receptors instead of CAR alone. Thus, CAR-T cells with on-board capacity to extinguish IL-6 represent a new approach to prevent CRS and suppress its severity without affecting the antitumor potential of CAR-T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cytokines
  • Humans
  • Immunotherapy, Adoptive
  • Mice
  • Receptors, Chimeric Antigen* / genetics
  • T-Lymphocytes

Substances

  • Cytokines
  • Receptors, Chimeric Antigen