MSKCC Early Experience Using Radiotherapy As a Bridging Strategy for Relapsed Diffuse Large B Cell Lymphoma before CD19 CAR T Therapy
Authors: Imber Brandon , Palomba M. Lia , DeSelm Carl , Batlevi Connie Lee , Dahi Parastoo B. , Giralt Sergio A. , Noy Ariela , Park Jae H. , Sauter Craig S. , Scordo Michael , Shah Gunjan L. , Sadelain Michel , Perales Miguel-Angel , Yahalom Joachim 
Published: November 2019

Background: CD19-targeted chimeric antigen receptor T cell (CAR T) therapies have remarkable overall response rates (ORR) for relapsed diffuse large B cell lymphoma (DLBCL). There is strong rationale to use a radiotherapy (RT) bridge during the cell manufacturing process including palliation, local control and cytoreduction with limited count impact. Recent data from our institution suggests RT may augment an immune response and sensitize antigen negative cells to CAR-mediated death. This series details our early experience using RT conditioning.
Methods: 13 patients (median age 64 years) with DLBCL (n=9) or transformed follicular lymphoma (n=4) were analyzed. Overall, patients had a median of 2 prior therapies (range 1-8) including 3 with autologous transplant, 3 with distant RT and 1 with CAR T infusion. Several CAR products were used, including axicabtagene ciloleucel (n=8), JCAR017 (n=3, per NCT02631044), tisagenlecleucel (n=1) and EGFRt/19-28z/4-1BBL "armored" CAR (n=1, per NCT03085173). Most patients (n=10) began RT post apheresis with median duration between RT and CAR infusion of 20d (range 13-80, Figure 2). The most common RT regimen (n=8) was 20 Gy in 5 fractions (range 20-47 Gy) but 2 received our pre-transplant regimen of 30 Gy in 20 BID fractions. None received concurrent chemotherapy with RT but one had a cycle post RT and pre CAR. All had cyclophosphamide and fludarabine lymphodepletion. PET response was evaluated by Lugano criteria.
Results: Three patients had limited stage PET avid disease at RT and were treated comprehensively pre-CAR. The remaining 10 were advanced stage and were treated palliatively to limited sites. Irradiated sites included the pelvis/groin (n=4), neck (n=3), intraabdominal (n=2) and extremity (n=2). Most (n=10) had intensity modulated radiotherapy. RT fields were large (median planning treatment volume of 887 cc, range 163-1641). Post RT PET interpretation was challenging given a short interval since RT ended (median 11d) but of 11 evaluable patients, many (n=8, 73%) had partial response (PR). Though locally controlled, most (n=10, 91%) had out of field progressive disease (PD) pre-CAR. Post CAR T, no severe adverse events in the RT field were noted, 9/13 had cytokine release syndrome (n=1 grade 3, n=2 grade 2) and 4 had neurotoxicity (n=3 grade 3). At day 30, ORR was 90%; of 10 evaluable patients, 7 had complete response (CR) and 2 had partial response (PR). Of the 7 evaluable patients at day 90, 4 (57%) had continued CR and the other 3 (43%) had PD and subsequently died from DLBCL. One relapsed at 95d post armored CAR both in and out of the RT field, and the other relapsed at 64d post JCAR017 primarily out of field.
Conclusions: Use of RT as a CAR T bridging strategy is feasible and associated with excellent pre-CAR local control and initial post CAR ORR in a cohort of heavily pre-treated DLBCL patients. We observed moderate serious CAR toxicity that did not appear to be augmented by RT. Future efforts should clarify the optimal RT timing/dose and assess the potential for incremental immunogenicity with combined therapy.

Disclosures
Palomba: Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding; NIH: Research Funding; Janssen: Consultancy. Park:Amgen: Consultancy; Autolus: Consultancy; AstraZeneca: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Allogene: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Genmab: Consultancy; GSK: Consultancy; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Janssen: Research Funding; Amgen: Research Funding. Sadelain:Memorial Sloan Kettering Cancer Center: Employment; Juno Therapeutics: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics: Consultancy, Patents & Royalties. Perales:Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; MolMed: Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding.