256 - A Proof-of-Principle Study of Split-Course Bridging Radiotherapy (SC-BRT) prior to Commercial CAR T-Cell Therapies for Relapsed or Refractory B-Cell Lymphomas: Results from Phase 1a Pilot Cohort

B. S. Imber^1,2, M. L. Palomba³, A. Brosoff³, E. Roszak³, D. McAvoy³, K. Hosszu³, A. Boardman³, P. B. Dahi³, R. J. Lin³, G. L. Shah³, M. Scordo⁴, J. H. Park³, M. A. Perales³, G. Salles³, and J. Yahalom⁵; ¹Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, ²Early Drug Development Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, ³Memorial Sloan Kettering Cancer Center, New York, NY, ⁴Department of Medicine, Bone Marrow Transplant Division, Memorial Sloan Kettering Cancer Center, New York, NY, ⁵Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY

Purpose/Objective(s): Anti-CD19 chimeric antigen receptor T-cells (CART) have revolutionized the treatment of B-cell lymphomas (BCL). Bridging radiotherapy (BRT) may serve two 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 unknown. Materials/

Methods: This is a single arm, Phase I trial (NCT05574114) of a standardized BRT regimen prior to commercial CART. The novel SC-BRT program is delivered in 2 phases post-apheresis to exploit BRTs dual roles. BCL patients (pts) receive 3Gy x 9 fractions using ISRT focally to sites requiring cytoreduction/palliation pre-LD. Later, post-LD and immediately pre-CART infusion, pts receive 3Gy x 1 comprehensively to all PET avid sites to condition tumor cells to CART-mediated death. Eligible pts are not planned to receive any systemic bridging. The study began with a Phase 1a pilot cohort using 3+3 rules to assess for severe toxicity events (STE) defined as toxicities above expectation of the normal CART safety profile. The primary aim is safety of SC-BRT+CART at day +30 with numerous secondary and translational aims. CART enumeration was performed by flow cytometry.
Results: Phase 1a included six pts with relapsed/refractory diffuse large BCL (n=4), high grade BCL (n=1) and primary mediastinal BCL (n=1). Half had localized disease and the rest advanced stage. The feasibility outcome was met as all successfully received SC-BRT, standard cyclophosphamide/fludarabine LD followed by commercial lisocabtagene maraleucel (n=4) or axicabtagene ciloleucel (n=2). Phase 1a also met its primary safety objective with 1/6 STE. The STE was grade 5 cytokine release syndrome (CRS) in a high grade BCL pt with significant medical comorbidities and rapidly progressive, high burden disease who received axicabtagene. Otherwise, SC-BRT+CART was well-tolerated; remaining pts had grade 1-2 toxicities including 2 pts with grade 1 CRS and no reported ICANS. For the 5 survivors, CART expansion peaked between day +5 and +10 and at peak, CAR+ cells were 3.8-51% (median 21%) of all CD45+ white blood cells. All 5 survivors were in PET complete response (by Lugano criteria) at 28 and 90d post-CART. Additional translational correlatives will be presented at the meeting.
Conclusion: Early data suggests the novel SC-BRT+CART strategy is safe and feasible for BCL patients with the potential for strong CART expansion. Given successful completion of Phase 1a, additional patients are now being recruited to the Phase 1b expansion (n=14) cohort to confirm safety, assess preliminary outcomes and explore possible immune augmentation.