TY - JOUR
T1 - Targeted Rejuvenation of Exhausted Chimeric Antigen Receptor T Cells Regresses Refractory Solid Tumors
AU - Luo, Qian
AU - Napoleon, John V.
AU - Liu, Xin
AU - Zhang, Boning
AU - Zheng, Suilan
AU - Low, Philip S.
N1 - Funding Information:
This work was funded by a grant from Umoja Biopharma (No. 40003064) and gift from the Hurvis Foundation (No. 14121659). Q. Luo, J.V. Napoleon, S. Zheng, and P.S. Low were supported by the grant from Umoja Biopharma. B. Zhang was supported by the Hurvis Foundation. The authors would like to acknowledge the Purdue Center for Cancer Research, the Purdue Institute for Drug Discovery, the Purdue Flow Cytometry Core, the Purdue Imaging Facility and the Chemical Genomic Facility for their services.
Publisher Copyright:
© 2022 American Association for Cancer Research
PY - 2022/5
Y1 - 2022/5
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-21-0711
DO - 10.1158/1541-7786.MCR-21-0711
M3 - Article
C2 - 35135862
AN - SCOPUS:85129997021
VL - 20
SP - 823
EP - 833
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 5
ER -