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To address this limitation, we have exploited the abilities of recently designed universal CARs to bind fluorescein and internalize a fluorescein\u2010TLR7 agonist conjugate by CAR\u2010mediated endocytosis. We demonstrate here that anti\u2010fluorescein CAR\u2010mediated uptake of a fluorescein\u2010TLR7\u20103 conjugate can reactivate exhausted CAR T cells, leading to dramatic reduction in T cell exhaustion markers (PD\u20101\n                    <jats:sup>+<\/jats:sup>\n                    Tim\u20103\n                    <jats:sup>+<\/jats:sup>\n                    ) 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\u2010targeted 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.\n                  <\/jats:p>","DOI":"10.1002\/anie.202113341","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T22:29:55Z","timestamp":1643322595000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Design, Synthesis, and Targeted Delivery of an Immune Stimulant that Selectively Reactivates Exhausted CAR T Cells"],"prefix":"10.1002","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8115-8357","authenticated-orcid":false,"given":"John Victor","family":"Napoleon","sequence":"first","affiliation":[{"name":"Department of Chemistry and Institute for Drug Discovery Purdue University  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