331 - Prospective Study of Split-Course Bridging Radiotherapy (SC-BRT) Prior to CAR T-Cells for Relapsed/Refractory B-Cell Lymphomas
Presenter(s)
B. S. Imber1, A. Brosoff2, E. Roszak2, B. King2, D. McAvoy2, K. Hosszu2, A. Boardman3, P. B. Dahi3, R. J. Lin3, G. L. Shah3, M. Scordo3, J. H. Park2, M. A. Perales3, G. Salles4, M. L. Palomba3, and J. Yahalom1; 1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 2Memorial Sloan Kettering Cancer Center, New York, NY, 3Department of Medicine, Bone Marrow Transplant Division, Memorial Sloan Kettering Cancer Center, New York, NY, 4Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Purpose/Objective(s): Anti-CD19 chimeric antigen receptor T-cells (CART) are now standard of care for relapsed or refractory B-cell lymphomas (BCL). Bridging radiotherapy (BRT) may serve dual roles including cytoreduction and immune augmentation but has not been prospectively studied. Preclinical data suggests maximal tumor sensitization occurs within a week post-irradiation, but the safety of administering BRT post-lymphodepletion (LD) is unclear.
Materials/Methods: This is a prospective study (NCT05574114) of a novel, split-course BRT approach (SC-BRT) prior to commercial anti-CD19 CART. SC-BRT is given post-apheresis in two phases to capture BRT's dual roles. BCL patients (pts) receive 3Gy x 9 fractions using ISRT focally to sites requiring cytoreduction pre-LD. Later, post-LD and immediately pre-CART infusion (day -2), pts receive comprehensive 3Gy x 1 to all PET avid sites to prime tumor cells to CART-mediated cell death. Eligible pts are not planned to receive any systemic bridging. We previously reported successful completion of a Phase 1a pilot (n=6) and now report the primary endpoint (safety at day +30 post-CART) and initial clinical outcomes for the full study cohort. Response was assessed by Lugano criteria.
Results: We included 20 pts (median age 60) with large BCL (n=17), primary mediastinal BCL (n=2) and follicular lymphoma (n=1). 45% had localized disease at apheresis and the rest advanced stage. All successfully received SC-BRT followed by standard LD and lisocabtagene maraleucel (n=15) or axicabtagene ciloleucel (n=5). The study met its primary safety endpoint with only 1/20 severe toxicity event, a grade 5 cytokine release syndrome (CRS) in a high grade BCL pt with significant comorbidities and high burden disease who received axicabtagene. The SC-BRT+CART regimen was otherwise well tolerated with grade 1-2 BRT-related toxicities. By day +30, 13/20 had CRS (n=7 grade 1, n=5 grade 2, n=1 grade 5) and 2/20 had ICANS (n=1 grade 2, n=1 grade 3). Of the 19 survivors, overall response rate (ORR) was 89% at day +30 (n=13 complete, n=4 partial). 14/19 survivors (74%) remained in complete response at day +90. Peak CART expansion enumerated by flow cytometry typically occurred between day +7 and +10. Additional translational correlatives are under analysis.
Conclusion: Early data suggests the innovative SC-BRT+CART strategy is safe for BCL pts with the potential for rapid CART expansion. This is the first reported delivery of any RT following LD chemotherapy potentially opening the door for novel CART conditioning approaches to exploit mechanisms of immune augmentation prior to cell therapy.