Development of novel CAR T cells targeting gamma delta T cell receptors

Authors

  • LC Cutmore
  • N Lam
  • C Amatya
  • K Weissler
  • DA Natrakul
  • JN Kochenderfer

Abstract

Chimeric antigen receptor (CAR) T cell therapies have revolutionized the treatment of many hematological malignancies. Limited treatments currently exist to treat malignancies arising from gamma delta T cells, a type of cancer associated with high rates of relapse and mortality. Gamma delta T cell receptors (γδ TCRs) are made up of a gamma chain and a delta chain, each composed of a constant and variable region. The γδ TCR offers a promising CAR T cell target as it is only expressed by γδ T cells and not present on any other tissue.
We designed a second-generation CAR to target the constant region of the γδ TCR and optimized it to produce the most efficacious CAR, MGDL-28Z. In-vitro MGDL-28Z CAR T cells specifically recognized the constant domain of the γδ TCR in assays of degranulation, cytokine release, and proliferation.
We evaluated the efficacy of the MGDL based CARs in-vivo. Immunocompromised NSG mice received intravenous injections of the MOLT-13-luciferase T cell acute lymphoblastic leukemia cell line. When all mice had detectable tumor burdens, mice received varying doses of MGDL-28Z CAR T cells. Mice treated with 2 or 8 million MGDL-28Z CAR T cells cleared the tumor while untreated mice had progressive tumor growth.
In summary, we have designed and tested a novel γδ TCR targeting CAR. MGDL-28Z CAR T cells specifically recognized the γδ TCR in-vitro, and they eradicated tumors in mice. MGDL-28Z is promising for clinical treatment of γδ TCR expressing malignancies.

Scientific Focus Area: Cancer Biology

This page was last updated on Tuesday, August 6, 2024