ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells.

Area of Science:

• Immunotherapy
• Cellular Therapy
• Oncology

Background:

• Chimeric antigen receptor (CAR) T cell therapy efficacy is limited in non-B-cell malignancies, with poor expansion and persistence observed.
• Current CAR T cell designs often struggle to overcome the suppressive tumor microenvironment in solid tumors and certain hematologic cancers.

Purpose of the Study:

• To investigate the potential of incorporating the inducible costimulator (ICOS) intracellular domain into CAR T cells.
• To evaluate if ICOS signaling enhances T cell effector function, cytokine production, and persistence in the context of CAR T cell therapy.

Main Methods:

• Primary human T cells were redirected with CARs encoding the ICOS intracellular domain.
• Comparison of ICOS-based CARs against CARs with CD3ζ, CD28, or 4-1BB domains.
• Analysis of cytokine production (IL-17A, IL-17F, IL-22, IFN-γ) and TH17/TH1 molecular signatures.
• Assessment of anti-tumor efficacy and persistence in mouse models with established tumors.

Main Results:

• ICOS signaling promoted the generation of tumor-specific IL-17-producing effector T cells with enhanced persistence.
• ICOS-based CARs increased secretion of IL-17A, IL-17F, and IL-22, while maintaining a TH17 signature and inducing TH17/TH1 bipolarization.
• In vivo studies demonstrated superior anti-tumor responses and improved CAR T cell persistence compared to CD28- or 4-1BB-based CARs.

Conclusions:

• Redirection of T cells with an ICOS-based CAR is a promising strategy to improve CAR T cell function and persistence.
• This approach holds potential for augmenting CAR T cell efficacy in hematologic malignancies beyond B-cell cancers.