Low-Strength Type I Interferon Signaling Promotes CAR T-Cell Treatment Efficacy

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Chimeric antigen receptor (CAR) T-cell therapy, specifically CD19-directed CAR T-cell therapy, has shown promise for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL).
• However, a significant proportion of patients (up to 60%) do not achieve a complete response, necessitating strategies to improve therapeutic efficacy.

Purpose of the Study:

• To identify molecular determinants of response to axicabtagene ciloleucel in r/r DLBCL patients.
• To develop a novel strategy to enhance CAR T-cell therapy efficacy by modulating type I interferon (IFN-I) signaling during ex vivo manufacturing.

Main Methods:

• Single-cell transcriptomics analysis of CAR T-cell infusion products from eight r/r DLBCL patients with varying clinical responses.
• Ex vivo incorporation of low-strength and high-strength IFN-I signaling during the manufacturing of CD28- and 4-1BB-costimulated CAR T-cells.
• Assessment of CAR T-cell cytotoxicity and in vivo efficacy in preclinical models.

Main Results:

• Infusion products from complete responders exhibited enriched type I interferon (IFN-I) signaling signatures compared to those with progressive disease.
• Low-strength IFN-I signaling enhanced CAR T-cell cytotoxicity and in vivo efficacy for both CD28- and 4-1BB-based CAR constructs.
• High-strength IFN-I signaling impaired CAR T-cell viability and in vivo efficacy.

Conclusions:

• Type I interferon (IFN-I) is a potent, costimulation-independent enhancer of CAR T-cell efficacy.
• Incorporating low-strength IFN-I signaling during ex vivo manufacturing represents a translationally feasible approach to improve CAR T-cell therapies for r/r DLBCL.
• This strategy leverages an FDA-approved agent and is compatible with existing CAR T-cell manufacturing processes.