2692 - Low-Dose Hypofractionated Bridging Radiation (4Gy x 2 Fractions) Prior to CAR T-Cell Therapy for Relapsed/Refractory DLBCL
Presenter(s)
J. Baron1, G. Singh1, F. Costabile1, C. Chavez Perez1, M. Perez-Guillermo Cuev Sr1, E. Chong2, C. Thomas3, J. Carter3, S. D. Nasta3, D. J. Landsburg3, N. Kostopoulos1, S. Barta3, J. Svoboda3, S. Schuster3, E. A. Chong3, J. P. Plastaras1, M. J. LaRiviere1, A. Facciabene1, and H. G. Hubbeling1; 1Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, 2Hospital of the University of Pennsylvania, Philadelphia, PA, 3Department of Medicine, Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA
Purpose/Objective(s): Bridging radiation therapy (RT) prior to chimeric antigen receptor T cell (CAR T) therapy is increasingly used in relapsed/refractory (R/R) lymphoma; however, the optimal dose and fractionation remain unknown. In a syngeneic A20 CART-19 model, we previously observed that low-dose fractionated RT (4 Gy × 2) enhanced systemic immune activation and abscopal control compared with 8 Gy × 1. To determine whether immune priming relates to fractionation pattern rather than total dose, we compared 4 Gy × 2 with 4 Gy × 5 in a preclinical model and then, prompted by these findings, retrospectively assessed the real-world feasibility of 4 Gy × 2 bridging RT prior to CAR T in diffuse large B-cell lymphoma (DLBCL).
Materials/Methods: Preclinical comparisons of 4 Gy × 2 versus 4 Gy × 5 were performed in an A20 CART-19 dual-tumor model, assessing primary and abscopal tumor control, CD8? T-cell infiltration, CAR T-cell trafficking, and systemic effector programs. The clinical analysis was a descriptive feasibility and safety case series prompted by the preclinical findings. We retrospectively identified adults with R/R DLBCL who received 4 Gy × 2 bridging RT before CAR T from 2020–2025 due to bulky/whole-organ disease with high anticipated toxicity from higher-dose RT, poor performance status, or short timelines before CART. Acute RT toxicity was graded per CTCAE v5.0; cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) per ASTCT criteria. Response was assessed on first post–CAR T imaging.
Results: In the preclinical model, despite higher cumulative dose with 4 Gy × 5, control of irradiated primary tumors was comparable between regimens. In contrast, 4 Gy × 2 produced stronger abscopal tumor suppression, greater CD8? and CAR T-cell infiltration in non-irradiated tumors, and enhanced systemic effector gene activation, suggesting fractionation-dependent immune engagement not explained by higher cumulative dose. Guided by these findings, we identified seven patients with R/R DLBCL (all stage IV; ECOG 1–3) who received 4 Gy × 2 bridging RT. RT targets included whole lung/liver (n=4), bulky nodal/pelvic disease (n=2), and multi-site disease (n=1). All completed RT without interruption or CAR T delay. Acute RT toxicity was limited to grade 1 (G1) events (n=4). After CAR T, CRS occurred in all patients (G1, n=4; G2, n=3) and ICANS in two (both G1). Median follow-up was 5.4 months (2.7–16.4). On first imaging, overall response rate was 86% (6/7) with five complete responses; at last follow up, three patients ultimately progressed (in-field n=2; out-of-field n=1).
Conclusion: Preclinical data demonstrated that 4 Gy × 2 was associated with greater systemic/abscopal immune-associated effects compared with 4 Gy × 5, despite similar primary tumor control. In a high-risk clinical cohort where 4 Gy × 2 was selected for pragmatic reasons, bridging RT was feasible and well tolerated. Prospective evaluation of 4 Gy × 2 as a practical, immune-informed bridging strategy is needed.