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TEM8/ANTXR1-specific CAR T cells mediate toxicity in vivo

Kristina Petrovic1, Joseph Robinson1, Katharine Whitworth1

  • 1Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.

Plos One
|October 18, 2019
PubMed

Insights

Chimeric antigen receptor T-cell (CAR-T) therapy targeting TEM8 shows promise for solid tumors. However, this study found TEM8-CAR-T cells caused rapid toxicity in mice due to targeting healthy tissues, raising safety concerns.

Area of Science:

  • Immunology
  • Oncology
  • Biotechnology

Background:

  • Chimeric antigen receptor (CAR) T-cell therapy is effective for certain leukemias.
  • Targeting solid tumors with CAR-T therapy requires identifying safe and effective tumor-specific antigens.
  • TEM8, a marker overexpressed on the vasculature of some solid tumors, has been proposed as a potential target.

Purpose of the Study:

  • To evaluate the safety and efficacy of TEM8-specific CAR-T cells for solid tumor treatment.
  • To investigate potential on-target, off-tumor toxicities associated with TEM8-targeted CAR-T cells.

Main Methods:

  • Generation and in vitro testing of a panel of TEM8-specific CAR-T cells.
  • In vivo administration of CAR-T cells into healthy C57BL6 and NSG mice, as well as TEM8-knockout mice.
  • Histological analysis of major organs to assess inflammation and cellular infiltration.

Main Results:

  • In vitro, TEM8-CAR-T cells exhibited specific cytotoxic and cytokine release responses against TEM8-expressing targets.
  • In vivo, CAR-T cells rapidly disappeared from circulation in healthy mice, correlating with rapid toxicity.
  • TEM8-knockout mice studies indicated that TEM8 expression in healthy tissues caused selective CAR-T cell loss.
  • Histological examination revealed inflammation and neutrophil infiltration in the lungs and spleen of treated mice.

Conclusions:

  • TEM8-specific CAR-T cells may cause significant on-target, off-tumor toxicity due to TEM8 expression in healthy tissues.
  • These findings raise concerns regarding the clinical application of TEM8-targeted CAR-T therapies for solid tumors.
  • Further careful consideration is needed before initiating clinical trials with TEM8-targeting CAR agents.

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