208 - Bridging Radiotherapy and Systemic Inflammation Prior to CAR T-Cell Therapy for B-Cell Lymphomas
Presenter(s)
R. R. Patel1, S. Samorodnitsky2, S. S. Raj2, G. L. Shah3, A. Saldia2, A. Parascondola2, B. A. Ucpinar2, H. Schoder4, M. Alhomoud2, P. B. Dahi3, R. J. Lin3, J. H. Park2, C. S. Sauter2, M. Scordo3, G. Salles5, M. L. Palomba3, J. Yahalom1, M. A. Perales3, R. Shouval3, and B. S. Imber2; 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 Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 5Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Purpose/Objective(s): Systemic inflammation prior to CAR-T cell therapy (CAR-T) in patients with relapsed/refractory B-cell lymphomas is associated with impaired CAR-T function and inferior outcomes. Bridging therapy (BT) is often used during CAR-T manufacturing for disease reduction/stabilization, yet its systemic inflammatory impact is poorly understood. Although radiotherapy (RT) is classically viewed as acutely pro-inflammatory, its influence on the systemic cytokine milieu during the CAR-T preparative window is unknown. We evaluated how BT modalities affect systemic inflammation and metabolic tumor volume (MTV) between apheresis and lymphodepletion (LD).
Materials/Methods: Using INFLAMIX (Raj et al, Nature Med 2025), a validated serum-based inflammatory signature associated with outcomes after CD19-directed CAR-T, we classified patients as “inflammatory” or “non-inflammatory” at pre-apheresis and pre-LD timepoints. Fisher's exact test evaluated associations between INFLAMIX classification, BT modality, and change in MTV. Overall survival (OS) and progression-free survival (PFS) were estimated from CAR-T infusion using the Kaplan-Meier method.
Results: Of 421 CAR T-treated patients, 59% received systemic bridging alone (ST), 16% received RT monotherapy, 6% received combined ST with RT, and 18% received no BT. Patients receiving any RT versus ST alone had lower rates of stage III/IV disease pre-apheresis (62% vs 77%, p<0.001), though 6% receiving ST had no detectable disease at apheresis (0% in RT group). Pre-apheresis MTV (p=0.4), LDH (255 vs 245 U/L, p=0.8), and presence of bulky disease =7.5 cm (11% vs. 9%, p=0.6) did not differ between any RT and ST alone groups. At apheresis, 44% of the entire cohort were classified as inflammatory, decreasing to 29% at LD. Those whose BT included RT (n=95) achieved significantly more normalization of inflammation (RT: apheresis 41% inflammatory ? LD 13%; ST alone 44% ? 35%; p<0.001). Conversion to an inflammatory phenotype after RT bridging was rare (4%, Table 1). At LD, noninflammatory status and lower LDH correlated with improved OS (p<0.001) regardless of baseline inflammatory status. MTV reduction was more likely in patients who converted to non-inflammatory versus inflammatory (86% vs 47%, p<0.001). Compared to all other patients, those with both a non-inflammatory phenotype at LD and a decrease in MTV during bridging had the highest PFS and OS (p<0.001) suggesting both biomarkers may independently influence outcomes.
Conclusion: Contrary to longstanding assumptions that RT amplifies inflammation, bridging RT significantly reduces systemic inflammation compared to ST alone. This may be mediated through rapid, effective cytoreduction pre-CAR-T. These findings support an expanded role for bridging RT beyond local control, positioning it as a systemic inflammatory modulator that may optimize the pre-CAR-T microenvironment to improve outcomes.