Radiotherapy Priming Chimeric Antigen Receptor T Cell Therapy Is a Safe and Promising Approach in Relapsed/Refractory Diffuse Large B Cell Lymphoma Patients with High Tumor Burden

Background: Chemoresistance is a core challenge in successful treatment of diffuse large B cell lymphoma (DLBCL). Chimeric antigen receptor T cells (CAR-T) therapy, as a novel immunotherapy modality, demonstrates impressive efficacy and durable remissions in relapsed/refractory(R/R) B-cell malignancies including DLBCL. However, CAR-T therapy is also associated with potentially fatal toxicities, including cytokine release syndrome (CRS) and neurological toxicities which limit the clinical application of CAR-T therapy in R/R DLBCL with high tumor burden. How to improve the prognosis of this population is urgently underway. Here, we conducted a trial testing efficacy and toxicities of CAR-T therapy in R/R lymphoma patients (This study is registered at www.clinicaltrials.gov as NCT03196830).

Methods:Human T cells were collected from autologous/allogenous peripheral blood mononuclear cells (PBMC) . CD3+T cells were separated from PBMS of patients or donors by degradable anti-CD3 magnetic microbeads followed by 24h stimulation with CD3 and CD28 monoclonal antibody (5ug/ml). Then CD3+T cells were transduced with lentivirus particles incorporated with a humanized CAR construct targeting CD19, CD20 and CD22 and further expanded for 7 to 10 days in vitro. The transfection efficacy, ratio of CD4+ versus CD8+, antitumor activities, pathogen detection as well as cytokines releasing of CAR-T cells were evaluated before infusion to patients. In this ongoing trial, 14 patients were diagnosed as R/R DLBCL with high tumor burden. Two debulking conditioning regimens including intensive combined chemotherapy or radiation (40 gray in 20 fractions) were carried out before CAR-T therapy followed by sequential FC regimen (cyclophosphamide 300mg/m2 and fludarabine 30mg/m2 X 3d) for lymphodepletion chemotherapy. Two days after FC regimen, autologous/allogenous CAR-T cells targeting CD19 and CD20 or CD22 provided by the unicar-therapy bio-medicine technology co.(Shanghai, China) at average dose of 1-2×107 cells for each target per kilogram(kg) were infused within 3 days.

Results: 14 R/R DLBCL patients with high tumor burden were enrolled in the study. Patients ranged from 39 to 66 years of age had received two to four prior lines of therapy. Out of the 14 patients, 7 patients received intensive second-line chemotherapy (median age, 46 years) and 7 received radiotherapy (median age, 63years) to debulking tumor after leukapheresis and during CAR-T cells preparation. All Adverse Events occurring within 30 days of CAR-T cells infusion were graded and reported for the 14(100%) treated patients. All patients experienced CAR-T-related CRS of any grade with severe CRS (grade 3/4/5) reported in all patients of chemotherapy cohort experienced and mild CRS (grade 1/2) reported in all patients of radiation cohort. 4 patients (57.1%) in chemotherapy cohort manifested with neurological toxicity while no patient in radiation cohort manifested with neurological toxicity. Comparable hematological toxicity as well as non-hematological and non-neurological toxicity were observed in two groups.

Four of seven (57.1%) patients achieved an objective response after CAR-T infusion, with three of seven (42.9%) achieving a CR in chemotherapy cohort, while seven of seven (100%) achieved an objective response after CAR-T therapy, with four of seven (57.1%) achieving a CR in radiation cohort.

Conclusions:Our clinical trial indicates that compared to intensive second-line chemotherapy, radiation is a better approach to enhancing efficacy and decreasing toxicity of CAR-T therapy in R/R DLBCL patients with high tumor burden. Radiotherapy in combination with CAR-T cell infusion may be the optimal alternative treatment model of R/R DLBCL with high tumor burden.