Replacing CAR-T cell resistance with persistence by changing a single residue

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Sustained persistence of chimeric antigen receptor T (CAR-T) cells is crucial for long-term remission in hematologic malignancies.
• Enhancing CAR-T cell persistence and functionality is vital for expanding therapy applications, particularly for solid tumors.

Purpose of the Study:

• To investigate the impact of a single amino acid substitution in the CD28 costimulatory domain on CAR-T cell persistence and function.
• To explore strategies for limiting T cell exhaustion and improving CAR-T cell efficacy.

Main Methods:

• Engineered CD28-based mesothelin CAR-T cells with a specific amino acid substitution.
• Evaluated CAR-T cell persistence and functionality in a xenograft model of pancreatic cancer.
• Reciprocally altered inducible costimulator (ICOS)-containing CAR-T cells.

Main Results:

• A single amino acid substitution in the CD28 costimulatory domain improved CAR-T cell persistence and functionality in a pancreatic cancer model.
• Reciprocal alteration in ICOS-containing CAR-T cells led to reduced antitumor activity and persistence.
• Demonstrated that simple alterations in costimulatory domains can enhance CAR-T cell persistence.

Conclusions:

• Targeted modifications of costimulatory domains represent a promising strategy to enhance CAR-T cell persistence and antitumor effects.
• Further evaluation in other CD28-costimulatory CARs is warranted to improve durable antitumor responses.
• Findings suggest potential for improved CAR-T cell therapy, especially in solid tumors.