Abstract
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.
Original language | English (US) |
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Article number | e202113341 |
Journal | Angewandte Chemie - International Edition |
Volume | 61 |
Issue number | 15 |
DOIs | |
State | Published - Apr 4 2022 |
Keywords
- CAR T Cell Therapy
- Cancer
- Immunology
- T Cell Exhaustion
- Toll-Like Receptor
ASJC Scopus subject areas
- Catalysis
- Chemistry(all)