A Proof-of-Principle of Split-Course Bridging Radiotherapy (SC-BRT) Prior to CAR T-Cell Therapies for Relapsed or Refractory B-Cell Lymphomas: A Phase 1a Pilot Cohort
Authors: Imber Brandon S. , Brosoff Anna , Roszak Emma , McAvoy Devin , Hosszu Kinga K. , Boardman Alexander P. , Dahi Parastoo B , Shah Gunjan L. , Scordo Michael , Park Jae H. , Perales Miguel-Angel , Salles Gilles , Palomba Maria Lia , Yahalom Joachim 
Published: December 2024

Introduction/Objectives: 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 (DeSelm et al. Mol Ther 2018), 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 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, pts receive 3Gy x 1 comprehensively to all PET avid sites to condition tumor cells to CART-mediated cell death. Eligible pts are not planned to receive any systemic bridging, including steroids. 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 kinetics were performed by flow cytometry.
Results: Phase 1a included six pts: relapsed/refractory diffuse large BCL (n=4), high grade BCL (n=1) and primary mediastinal BCL (n=1). Half had localized disease (cervical neck/oropharynx, axilla, inguinal) and the rest advanced stage. The feasibility outcome was achieved, as all pts successfully received SC-BRT and standard cyclophosphamide/fludarabine LD followed by commercial lisocabtagene maraleucel (n=4) or axicabtagene ciloleucel (n=2). Median maximum SUV prior to SC-BRT was 19.9 (range: 15.5-31.1) which reduced to 4.2 (range: 3.0-15.6) prior to LD. All 6 pts had a metabolic partial response within the radiation-treated field, and 2/6 developed new intercurrent sites of lymphoma during the bridging period.
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. One patient was treated with steroids and tocilizumab for mild CRS and the patient with grade 5 CRS received steroids, tocilizumab and siltuximab but expired on day +6.
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 (WBC). The patient with grade 5 toxicity had the highest CAR+ expansion of all 6 pts at day +5 in absolute terms, but not as a percentage of total CD45+ WBC, likely reflective of the overactive immune state. All 5 survivors were in PET complete response (by Lugano criteria) at 28 and 90d post-CART and have remained without evidence of active lymphoma with a median post-CART follow-up of 12.2 mos (range: 7.2-15.7). Additional translational correlatives are under analysis.
Conclusion: Early data suggests the innovative SC-BRT+CART strategy is safe and feasible for BCL pts with the potential for strong CART expansion. This is the first reported delivery of any form of RT following administration of LD chemotherapy potentially opening the door for novel CART conditioning approaches. Given successful completion of Phase 1a, 14 additional patients are now being recruited to the Phase 1b expansion cohort (9 already accrued, data not presented) to confirm safety, assess preliminary outcomes and explore possible immune augmentation.