TY - JOUR
T1 - Hypoxia-sensing CAR T cells provide safety and efficacy in treating solid tumors
AU - Kosti, Paris
AU - Opzoomer, James W
AU - Larios-Martinez, Karen I
AU - Henley-Smith, Rhonda
AU - Scudamore, Cheryl L
AU - Okesola, Mary
AU - Taher, Mustafa Y M
AU - Davies, David M
AU - Muliaditan, Tamara
AU - Larcombe-Young, Daniel
AU - Woodman, Natalie
AU - Gillett, Cheryl E
AU - Thavaraj, Selvam
AU - Maher, John
AU - Arnold, James N
N1 - Funding Information:
The authors thank Dr. Yasmin Haque, King's College London, for cell sorting and flow cytometry assistance; Dr. Adam Ajina (KCL) for taking blood samples; Miss Dominika Sosnowska for help with tail vein injections; and Dr. Gilbert Fruhwirth for helpful discussions. This work was funded by the European Research Council (335326) and King's Commercialisation Institute. P.K. and J.W.O. are supported by the UK Medical Research Council (MR/N013700/1) and are KCL members of the MRC Doctoral Training Partnership in Biomedical Sciences. K.I.L.-M. is supported by the Consejo Nacional de Ciencia y Tecnolog?a (CONACyT) and Leucid Bio. The research was supported by the Cancer Research UK King's Health Partners Centre and Experimental Cancer Medicine Centre at King's College London and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. P.K. J.M. and J.N.A. conceived the project, designed the approach, interpreted the data, and wrote the manuscript. P.K. J.W.O. K.I.L.-M. R.H.-S. C.L.S. M.O. M.Y.M.T. T.M. and D.L.-Y. performed experiments and interpreted the data. D.M.D. N.W. C.E.G. and S.T. provided key expertise and interpretation. J.M. is co-founder and chief scientific officer, T.M. is an employee, and D.M.D. and D.L.-Y. are consultants of Leucid Bio, a spinout company focused on development of cellular therapeutic agents. J.N.A. J.M. and P.K. are named inventors on a patent submitted in relation to this work.
Funding Information:
The authors thank Dr. Yasmin Haque, King’s College London, for cell sorting and flow cytometry assistance; Dr. Adam Ajina (KCL) for taking blood samples; Miss Dominika Sosnowska for help with tail vein injections; and Dr. Gilbert Fruhwirth for helpful discussions. This work was funded by the European Research Council ( 335326 ) and King’s Commercialisation Institute . P.K. and J.W.O. are supported by the UK Medical Research Council ( MR/N013700/1 ) and are KCL members of the MRC Doctoral Training Partnership in Biomedical Sciences. K.I.L.-M. is supported by the Consejo Nacional de Ciencia y Tecnología (CONACyT) and Leucid Bio . The research was supported by the Cancer Research UK King’s Health Partners Centre and Experimental Cancer Medicine Centre at King’s College London and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King’s College London . The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.
Publisher Copyright:
© 2021 The Author(s)
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/4/20
Y1 - 2021/4/20
N2 - Utilizing T cells expressing chimeric antigen receptors (CARs) to identify and attack solid tumors has proven challenging, in large part because of the lack of tumor-specific targets to direct CAR binding. Tumor selectivity is crucial because on-target, off-tumor activation of CAR T cells can result in potentially lethal toxicities. This study presents a stringent hypoxia-sensing CAR T cell system that achieves selective expression of a pan-ErbB-targeted CAR within a solid tumor, a microenvironment characterized by inadequate oxygen supply. Using murine xenograft models, we demonstrate that, despite widespread expression of ErbB receptors in healthy organs, the approach provides anti-tumor efficacy without off-tumor toxicity. This dynamic on/off oxygen-sensing safety switch has the potential to facilitate unlimited expansion of the CAR T cell target repertoire for treating solid malignancies.
AB - Utilizing T cells expressing chimeric antigen receptors (CARs) to identify and attack solid tumors has proven challenging, in large part because of the lack of tumor-specific targets to direct CAR binding. Tumor selectivity is crucial because on-target, off-tumor activation of CAR T cells can result in potentially lethal toxicities. This study presents a stringent hypoxia-sensing CAR T cell system that achieves selective expression of a pan-ErbB-targeted CAR within a solid tumor, a microenvironment characterized by inadequate oxygen supply. Using murine xenograft models, we demonstrate that, despite widespread expression of ErbB receptors in healthy organs, the approach provides anti-tumor efficacy without off-tumor toxicity. This dynamic on/off oxygen-sensing safety switch has the potential to facilitate unlimited expansion of the CAR T cell target repertoire for treating solid malignancies.
KW - Animals
KW - Cell Line, Tumor/metabolism
KW - Disease Models, Animal
KW - Genes, erbB/genetics
KW - Humans
KW - Hypoxia/genetics
KW - Immunotherapy, Adoptive/methods
KW - Mice, Transgenic
KW - Receptors, Chimeric Antigen/genetics
KW - T-Lymphocytes/immunology
KW - Tumor Microenvironment/immunology
KW - Xenograft Model Antitumor Assays/methods
UR - http://www.scopus.com/inward/record.url?scp=85104446549&partnerID=8YFLogxK
U2 - 10.1016/j.xcrm.2021.100227
DO - 10.1016/j.xcrm.2021.100227
M3 - Article
C2 - 33948568
AN - SCOPUS:85104446549
SN - 2666-3791
VL - 2
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 4
M1 - 100227
ER -
