Optimizing CAR-T Cell Therapy: Reducing Manufacturing Time and Examining T Cell Memory Phenotypes in B Cell Lymphoma
Authors: Pavlic Jordan , Fury Brian , Mayo Jen , Herrera Xayra , Jones Sierra , Bergum Dane , Moser Annett Geralyn , Logan White Jeannine , Esteghamat Naseem S. , Abedi Mehrdad , Nolta Jan A. 
Published: December 2024

Chimeric Antigen Receptor T cell (CAR-T) cell therapy has emerged as a groundbreaking treatment modality in oncology, leveraging genetic modification to enable T-cells to target and eradicate cancer cells more effectively. This transformative approach has demonstrated significant success across various clinical trials, offering new hope for patients with otherwise refractory cancers. Among these trials, our study at UC Davis (IND 26979) has focused on CAR-T cell therapy for B cell lymphoma. This study has achieved an impressive 85% response rate and a 78% remission rate among 17 enrolled patients. Building on these encouraging outcomes, our study aims to further refine and improve CAR-T cell therapy by examining patient retention samples to explore T cell memory phenotypes, while also optimizing the cell manufacturing process.

Traditionally, the manufacturing of autologous CAR-T cells spans 12 days and includes cell cryopreservation, followed by a 3-week hold for release testing, resulting in a prolonged time before patient infusion. This delay can negatively impact patient outcomes and increase therapy costs. To address these challenges, our study aimed to reduce the CAR-T cell manufacturing time to 8 days with the option of a fresh cell infusion while maintaining product efficacy and safety. To achieve this, we conducted a comparative analysis of the traditional 12-day CAR-T cell manufacturing process with our newly developed 8-day protocol. Key metrics evaluated included Vector Copy Number (VCN), Replication Competent Lentivirus Levels (RCL), anti-CD19 CAR transduction efficiency, and cell viability. Our cohort for this study included 3 patients who underwent CAR-T cell therapy, with a manufacturing success rate of 100% for the 8-day process, comparable to the 12-day process. Immunophenotype analysis revealed positive clinical outcomes, with patients treated thus far using the 8-day protocol demonstrating a 100% survival rate and a significant reduction in overall treatment costs. Implementing a fresh cell infusion, as opposed to infusing cryopreserved product after a 3-week hold, allows patients to receive cells 3 weeks sooner than previously possible. This innovation led to an FDA-approved process amendment to our clinical trial, signifying a pivotal advancement in CAR-T cell therapy. Additionally, we examined T cell memory phenotypes from all patients to assess their relationship with clinical outcomes.

Our study not only shortens the time to treatment and reduces costs without compromising efficacy and safety but also deepens the insight into the connection between patient immune cell phenotypes and therapeutic effectiveness. This approach holds promise for a broader application, potentially improving access to CAR-T cell therapy for a larger patient population and advancing personalized medicine in the context of B cell lymphoma treatment. Moreover, our detailed examination of patient retention samples to explore T cell memory phenotypes, specifically, cytotoxic T central memory cells, cytotoxic T effector memory cells, helper T central memory cells, and helper T effector memory cells, seeks to further elucidate the relationship between immune responses and therapeutic efficacy. Initial findings indicate a potential correlation between depleted helper T memory cells and adverse clinical outcomes.