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 - Publisher Copyright:
© 2022 American Association for Cancer Research
PY - 2022/5
Y1 - 2022/5
N2 - UNLABELLED: 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 - UNLABELLED: 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.
KW - Fluoresceins/metabolism
KW - Humans
KW - Neoplasms/metabolism
KW - Receptors, Chimeric Antigen/genetics
KW - Rejuvenation
KW - T-Lymphocytes/metabolism
KW - Toll-Like Receptor 7/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85129997021&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129997021&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-21-0711
DO - 10.1158/1541-7786.MCR-21-0711
M3 - Article
C2 - 35135862
AN - SCOPUS:85129997021
SN - 1541-7786
VL - 20
SP - 823
EP - 833
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 5
ER -