Design, Synthesis, and Targeted Delivery of an Immune Stimulant that Selectively Reactivates Exhausted CAR T Cells

John Victor Napoleon, Boning Zhang, Qian Luo, Madduri Srinivasarao, Philip S. Low

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Article numbere202113341
JournalAngewandte Chemie - International Edition
Volume61
Issue number15
DOIs
StatePublished - Apr 4 2022

Keywords

  • Cancer
  • CAR T Cell Therapy
  • Immunology
  • T Cell Exhaustion
  • Toll-Like Receptor

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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