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

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TEM8/ANTXR1-specific CAR T cells mediate toxicity in vivo. / Petrovic, Kristina; Robinson, Joseph; Whitworth, Katie; Jinks, Elizabeth; Shaaban, Abeer; Lee, Steve.

In: PLoS ONE, Vol. 14, No. 10, e0224015, 17.10.2019.

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Petrovic, Kristina ; Robinson, Joseph ; Whitworth, Katie ; Jinks, Elizabeth ; Shaaban, Abeer ; Lee, Steve. / TEM8/ANTXR1-specific CAR T cells mediate toxicity in vivo. In: PLoS ONE. 2019 ; Vol. 14, No. 10.

Bibtex

@article{3425ace7c61c44a09f0fb10dc30b7ab6,
title = "TEM8/ANTXR1-specific CAR T cells mediate toxicity in vivo",
abstract = "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.",
author = "Kristina Petrovic and Joseph Robinson and Katie Whitworth and Elizabeth Jinks and Abeer Shaaban and Steve Lee",
year = "2019",
month = oct,
day = "17",
doi = "10.1371/journal.pone.0224015",
language = "English",
volume = "14",
journal = "PLoSONE",
issn = "1932-6203",
publisher = "Public Library of Science (PLOS)",
number = "10",

}

RIS

TY - JOUR

T1 - TEM8/ANTXR1-specific CAR T cells mediate toxicity in vivo

AU - Petrovic, Kristina

AU - Robinson, Joseph

AU - Whitworth, Katie

AU - Jinks, Elizabeth

AU - Shaaban, Abeer

AU - Lee, Steve

PY - 2019/10/17

Y1 - 2019/10/17

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85073544986&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0224015

DO - 10.1371/journal.pone.0224015

M3 - Article

C2 - 31622431

VL - 14

JO - PLoSONE

JF - PLoSONE

SN - 1932-6203

IS - 10

M1 - e0224015

ER -