期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 61, 期 15, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202113341
关键词
CAR T Cell Therapy; Cancer; Immunology; T Cell Exhaustion; Toll-Like Receptor
Administering a CAR-targeted TLR7 agonist can reverse CAR T cell exhaustion and successfully treat solid tumors.
Although chimeric antigen receptor (CAR) T cells have demonstrated significant promise in suppressing hematopoietic cancers, their applications in treating solid tumors have been limited by onset of CAR T cell exhaustion that accompanies continuous CAR T cell exposure to tumor antigen. To address this limitation, we have exploited the abilities of recently designed universal CARs to bind fluorescein and internalize a fluorescein-TLR7 agonist conjugate by CAR-mediated endocytosis. We demonstrate here that anti-fluorescein CAR-mediated uptake of a fluorescein-TLR7-3 conjugate can reactivate exhausted CAR T cells, leading to dramatic reduction in T cell exhaustion markers (PD-1(+)Tim-3(+)) and shrinkage of otherwise resistant tumors without inducing systemic activation of the immune system. We conclude that CAR T cell exhaustion can be reversed by administration of a CAR-targeted TLR7 agonist, thereby enabling the CAR T cells to successfully treat solid tumors without incurring the systemic toxicity that commonly accompanies administration of nontargeted TLR7 agonists.
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