SUMMARY:
UCLA researchers in the Department of Microbiology, Immunology and Molecular Genetics have developed a novel chimeric antigen receptor (CAR)-T cell manufacturing process to prevent premature CAR-T cell dysfunction and enhance CAR-T cell durability and potency.
BACKGROUND:
Chimeric antigen receptor (CAR)-T cell therapy is an emerging pillar in cancer treatment and has provided remarkable patient response in select cancers including B-cell leukemia and lymphoma. CAR-T cell therapy takes advantage of the patient’s own immune system, utilizing T cells drawn from the patient and modified in a laboratory setting with added receptors to better target cancerous cells. In most cases, the T cells isolated from a patient must be expanded to larger quantities ex vivo to result in a clinically efficacious response in patients; this step, however, introduces additional barriers and limitations. Current manufacturing processes are suboptimal as they utilize cell growth conditions that can lead to CAR-T cell dysfunction, ultimately reducing the applicability of the therapy. Tonic signaling, referring to CAR signaling activation in the absence of tumor-cell encounter, can further contribute to CAR-T cell dysfunction and lead to early T-cell exhaustion. Given the expanding need and market of CAR-T based therapies, there exists great clinical and economic incentive for improved manufacturing methods to limit or prevent T-cell dysfunction and subsequently increase the efficacy and duration of CAR-T therapy across multiple disease contexts.
INNOVATION:
Researchers at UCLA led by Dr. Yvonne Yu-Hsuan Chen in the Department of Microbiology, Immunology and Molecular Genetics have developed a novel method of pre-conditioning CAR-T cells with pharmacological inhibitors to enable researcher-defined control over CAR-T cell tonic signaling. They found that when CAR-T cells were cultured in the presence of pharmacological inhibitors targeting a bevy of signaling pathways, the CAR-T cells demonstrated decreased activation and exhaustion marker expression. In in vivo murine models of lymphoma, survival could be altered depending on the CAR-T cell pre-conditioning regimen. Pre-conditioned CAR-T cells showed improved durability upon adoptive transfer into the lymphoma murine models. Taken together, a novel pharmacological inhibitor cocktail for pre-conditioning CAR-T cells during manufacturing could boost more rapid translation of novel CARs into the clinic.
POTENTIAL APPLICATIONS:
• Novel manufacturing process of CAR-T cells that can modulate tonic signaling as well as CAR-T cell function
• Decrease the required iterations of CAR design-build-test cycles
ADVANTAGES:
• Decreases premature CAR-T cell exhaustion
• Improves turnaround time for CAR-T cell therapy to be delivered to patients
• Increases overall CAR-T cell therapy durability and efficacy
DEVELOPMENT-TO-DATE:
The researchers have demonstrated that their novel method of pre-conditioning CAR-T cells with a pharmacological inhibitor cocktail significantly reduces premature T-cell exhaustion and increases anti-tumor potency in multiple in vitro contexts and in vivo murine models.