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


Autoři: Kristina Petrovic aff001;  Joseph Robinson aff001;  Katharine Whitworth aff001;  Elizabeth Jinks aff001;  Abeer Shaaban aff002;  Steven P. Lee aff001
Působiště autorů: Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom aff001;  Histopathology Department, Queen Elizabeth Hospital, Birmingham, United Kingdom aff002
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224015

Souhrn

Engineering T-cells to express receptors specific for antigens present on tumour tissue is proving a highly effective treatment for some leukaemias. However, extending this to solid tumours requires antigens that can be safely and effectively targeted. TEM8, a marker overexpressed on the vasculature of some solid tumours, has been proposed as one such target. A recent report stated that T-cells engineered to express a TEM8-specific chimeric antigen receptor (CAR), when injected into mouse models of triple negative breast cancer, are both safe and effective in controlling tumour growth. Here we report contrasting data with a panel of TEM8-specific CAR-T-cells including one generated from the same antibody used in the other study. We found that the CAR-T-cells demonstrated clear TEM8-specific cytotoxic and cytokine release responses in vitro, but when injected into healthy C57BL6 and NSG mice they rapidly and selectively disappeared from the circulation and in most cases caused rapid toxicity. Infusing CAR-T-cells into a TEM8-knockout mouse indicated that selective loss of cells from the circulation was due to targeting of TEM8 in healthy tissues. Histological analysis of mice treated with a TEM8-specific CAR revealed evidence of inflammation in the lung and spleen with large collections of infiltrating neutrophils. Therefore our data raise concerns over potential on-target off-tumour toxicity with CARs targeting TEM8 and these should be considered carefully before embarking upon clinical trials with such agents.

Klíčová slova:

Basic cancer research – Cell staining – Mouse models – Spleen – T cells – Toxicity – Cancer immunotherapy – T cell receptors


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2019 Číslo 10