After introducing the different generations of Chimeric Antigen Receptors (i.e., 1st-3rd CARs generations), Dr. Melenhorst explained the therapeutic workflow, which involves collecting T cells from patients, CAR gene insertion, T cell expansion, and ultimately infusion into the patients.
CLL is one of the most prevalent leukemia types in the western hemisphere affecting predominantly the elderly. Current treatment for CLL is based on small molecule inhibitors (e.g., Idelalisib and Venetoclax), which are not curative; in contrast, CAR-T cells provide a curative approach.
Clinical trials for Chronic lymphocytic leukemia (CLL) with CAR-T therapy were initiated in 2010 and lead to dramatic and durable remission. Dr. Melenhorst shared that one of the lessons learned from this initial clinical trial was the positive correlation between CAR-T expansion and clinical efficacy. Additionally, CAR-T cells recovered from patients showed persistent polyfunctionality even after three years post-infusion (e.g., IFN and IL2 production). Moreover, single-cell analysis of CAR-Ts recovered after over nine years post-infusion demonstrated that long-term persistent CAR-T cells were highly proliferative, functional, and metabolically active.
Because both CAR-T clonal expansion and persistence correlated with the patient’s response, Dr. Melenhorst hypothesized that the intrinsic properties of T cells were vital for the efficacy of the therapeutic product. Single-cell expression analysis confirmed transcriptomic differences between CAR-T cells infused in responder and non-responder patients. These studies allowed Dr. Melenhorst’s team to identify several genes differentially expressed between responder and non-responders. Significantly, non-exhaustion and early memory T cell signatures were enriched in responders. Therefore, his team has been focusing on the intrinsic properties of T cells before CAR-T cell manufacturing, which could determine therapeutic success. Their work has allowed them to identify T cell biomarkers (CD27+CD45RO-) associated with CAR-T therapeutic efficacy in CLL, identifying a CD8+ T cell population or early memory T cells. Lastly, Dr. Melenhorst also discussed how his team worked to understand extrinsic or tumor factors influencing CAR-T cell efficacy in CLL.
