Abstract A09: Telomerase activity as a biomarker to predict outcomes of CAR T-cell therapy

Abstract

Abstract Introduction: Chimeric antigen receptor T-cells (CAR T-cells) and T-cells in general, remain in a quiescent state when unstimulated, showing no proliferative activity. In contrast, upon specific antigenic stimulation, CAR T-cells rapidly divide and kill their target cancer cells. However, one of the immunologic changes with aging is the progressive impairment of T-cell responses. This physiologic immunosenescence is associated with the shortening of telomeres. The telomerase enzyme is transiently upregulated in stimulated CAR T-cells preventing dramatic telomere shortening during rapid CAR T-cell division. Our previous study showed that during T-cell expansion, the period during which telomerase is active and the magnitude of its activity correlates with the donor’s age and overall health status (“healthy aging”) [1]. The aim of this study is to investigate whether the magnitude of telomerase activity in stimulated CAR T-cells is a predictive biomarker of outcomes in patients receiving CAR T-cell therapy.Methods: The study population comprises of older adult patients (age range: 50-84 years) receiving autologous anti-CD19 CAR T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma, mantle cell lymphoma or follicular lymphoma. Peripheral blood samples are collected from patients pre-lymphodepletion and T-cells isolated from PBMCs (peripheral blood mononuclear cells). CAR T-cells are then generated from patient T-cells in the lab and telomerase activity analyzed over 2 weeks in culture. For each patient’s CAR T-cells, absolute values of telomerase activity are plotted to calculate the area under the curve (AUC). We are investigating the potential correlation of AUC of telomerase activity to disease response at 30- and 90-days post CAR T-cell infusion. Results: Preliminary data from eight patients is showing a clear correlation between telomerase activity and patient outcomes. Robust telomerase activity shows a positive correlation with complete responses on day 30 PET-CT scans and sustained clinical remission, while poor telomerase activity correlates with no response or progressive disease. We are expanding our study sample to 30-50 patients and updated data will be presented at the meeting. Conclusions: CAR T-cell therapy has been a game-changer for hematological malignancies; however therapeutic resistance and disease relapse remains a major concern. Understanding the mechanisms of resistance to CAR T-cell therapy is critical for advancing the field. Telomerase activity levels could be a potential predictive biomarker for CAR T-cell therapy outcomes and aid in personalizing treatment choices. Furthermore, future research on increasing telomerase activity may enhance CAR T-cell therapy function and ultimately patient outcomes. [1] Tedone et.al, Telomere length and telomerase activity in T cells are biomarkers of high-performing centenarians, Aging Cell, 2019 Citation Format: Mohammed E Sayed, Enzo Tedone, Emily Zhang, Helen Stephens, Farrukh T Awan, Jerry Shay, Praveen Ramakrishnan Geethakumari. Telomerase activity as a biomarker to predict outcomes of CAR T-cell therapy [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A09.