A Proof-of-Principle Study of Split-Course Bridging Radiotherapy Prior to Commercial CD19 CAR T-Cell Therapies for Patients With Relapsed or Refractory B-Cell Lymphomas

Abstract

Chimeric antigen receptor T-cell therapies (CART) have revolutionized the treatment of aggressive B-cell lymphomas. Bridging radiotherapy (BRT) may serve two roles including cytoreduction and potential immune augmentation but has not been prospectively studied. Preclinical data suggests maximal tumor sensitization occurs roughly 4 days after irradiation, but the safety of administering RT just prior to CART is unknown.This is a single arm, Phase I trial designed to describe the feasibility and safety of a standardized BRT regimen prior to standard of care, commercial, anti-CD19 CART. The BRT approach will be a novel split-course program (SC-BRT) delivered in 2 phases following apheresis to exploit BRT's dual roles. Phase I will deliver 3 Gy x 9 fractions using ISRT focally to areas requiring cytoreduction/palliation prior to conditioning chemotherapy. Later, following conditioning chemotherapy, and immediately prior to CART-T cell infusion, Phase II will deliver 3 Gy x 1 comprehensively to all sites of PET avid disease. The larger field, low-dose RT is principally to condition tumor cells to CART-mediated death. Eligible patients will have an aggressive B-cell lymphoma, be planned for any commercial CART product, and not be expected to receive any form of systemic bridging therapy. The primary aim is the safety of SC-BRT at day +30 post CART and will be structured using 3+3 rules with the possibility of an expansion cohort. Secondary aims include feasibility of using ISRT principles for comprehensive BRT and several efficacy outcomes. Exploratory outcomes include tissue and blood correlatives. Tumor biopsies will be obtained pre-BRT, post BRT Phase I and day +7 after CART, enabling mechanistic investigation of immune augmentation.In total, we intend to enroll 23-26 patients on this protocol with 2 years of post-treatment follow-up. The protocol is currently under IRB review and we would present the detailed design and early results at the conference.To our knowledge, this is the first prospective study of BRT administered systematically with a cellular therapy. This study may serve as the clinical foundation for a novel, expanded role for RT in the treatment of B-cell lymphomas. Furthermore, the correlative program aims to expand our understanding of the impact of both RT and RT+CART on tumor signaling and the lymphoma microenvironment.