Targeted Rejuvenation of Exhausted Chimeric Antigen Receptor T Cells Regresses Refractory Solid Tumors.

Abstract

Chimeric antigen receptor (CAR) T-cell therapies have proven to be effective in treating hematologic malignancies but demonstrate only marginal efficacy in eradicating solid tumors. Although several mechanisms can account for these differences, a major cause is thought to derive from CAR T-cell exhaustion, where chronic exposure to tumor antigen can activate feedback pathways that suppress CAR T-cell cytotoxicity. We describe here a strategy to reverse this CAR T-cell exhaustion using a universal anti-fluorescein CAR that concurrently serves as (i) a cancer recognition receptor that enables engagement of multiple cancer cell clones upon addition of a cocktail of bispecific fluorescein-linked tumor-targeting ligands, and (ii) a drug-internalizing receptor that mediates uptake of a CAR T-cell activator comprised of fluorescein linked to an immune stimulant. By attaching a Toll-like receptor 7 agonist (TLR7-1A) to fluorescein, we enable the anti-fluorescein CAR to bind and internalize TLR7-1A, leading to both downregulation of exhaustion markers (i.e., PD-1, TIM3, LAG3) and reactivation of exhausted CAR-T cells without causing the toxicities commonly associated with systemic administration of TLR7 agonists. The resulting rejuvenated CAR-T cells are observed to regress otherwise refractory solid tumors. Moreover, because no other immune cells are altered by this treatment, the data demonstrate that the exhaustion state of the CAR-T cells constitutes a major property that determines the efficacies of CAR T-cell therapies in solid tumors.

IMPLICATIONS:

A novel strategy for rejuvenating exhausted CAR-T cells is described previously that promotes downregulation of exhaustion markers and renewed eradication of cancer cells in a tumor mass.

• Authors: Qian Luo, John V Napoleon, Xin Liu, Boning Zhang, Suilan Zheng, Philip S Low
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 20 Issue 5 Pg. 823-833 (05 04 2022) ISSN: 1557-3125 [Electronic] United States
• PMID: 35135862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• Fluoresceins
• Receptors, Chimeric Antigen
• Toll-Like Receptor 7

Topics

• Fluoresceins (metabolism)
• Humans
• Neoplasms (metabolism)
• Receptors, Chimeric Antigen (genetics, metabolism)
• Rejuvenation
• T-Lymphocytes (metabolism)
• Toll-Like Receptor 7 (metabolism)