Repeat Infusion of CD19-Specific Chimeric Antigen Receptor T-Cell Could Improve the Efficacy with Consistent Safety in Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Authors: Hu Jianda , Yang Ting , Yang Xiaozhu , Xian Na , Chen Yanxin , Jiang Peifang , Huang Gangxiong 
Published: October 2019

Abstract
Backgroun d
Patients with relapse and/or chemo-refractory (R/R) diffuse large B cell lymphoma (DLBCL) are often fail to conventional therapy and suffer dismal prognosis. Recently CD19-targeted immunotherapy using chimeric antigen receptor (CAR)-modified T cells (CART cells) has produced the most promising clinical outcomes in patients with R/R B-cell leukemia and lymphoma, including R/R DLBCL, with overall response rate (ORR) at 50%-80%. However, a part of R/R DLBCL patients, who had restricted durability of clinical response after CD19-specific CART (CD19-CART) cell therapy were at the risks of disease progression. Considering the majority of the existing studies generally used a single infusion of CART cells, with a limited remission duration in which 20%-40% R/R DLBCL patients lost response within 6 months, the purpose of this study is to investigate whether repeat infusions could raise therapeutic response and extend its persistence, and thus improve the clinical outcomes in R/R DLBCL patients. Herein, we conducted a clinical trial (ClinicalTrials.gov Identifier: NCT03391726) to evaluate the efficacy and safety of repeat infusion of CD19-CART cells to patients with R/R DLBCL.
Methods
Following chemotherapy consisting of cyclophosphamide and fludarabine for lymphodepletion, the enrolled R/R DLBCL patients received an infusion of CD19-CART cells at a dose of 0.7-6×106 cells/kg. The CD19-CART cells were generated by modifying autologous T cells with a lentiviral vector encoding a CAR comprising a murine derived anti-CD19 scFv, 4-1BB and CD3ζ domains. Four of eight (50.0%) patients were given a repeat infusion of CART cells at 3 to 10 months after the initial infusion.
R esults
From June 2017 to July 2018, eight patients (median age, 52 years; range, 27-70 years) with R/R DLBCLs that were relapsed or resistant to primary or salvage chemotherapy or local radiotherapy, or fail to other clinical trial were enrolled (5 cases of DLBCL; 1 case of DLBCL with central nervous system infiltration;1 case of primary central nervous system lymphoma (PCNSL); 1 case of primary mediastinal large B cell lymphoma (PMBL)). Patients were evaluated for efficacy and safety at four weeks after initial infusion. 1/8(12.5%) patients reached complete remission (CR), 5/8(62.5%) patients had a partial remission (PR), while 2/8(25.0%) patients had stable disease (SD). The ORR (CR and PR) was 75.0% (6 of 8). With a median follow-up of 8.5 months, among 4 patients who had received a second infusion of the CART cells, 1 patient with RR DLBC remained in CR, 1 patient with primary refractory DLBCL remained in PR with constant improvement in symptom and iconography, 1 patient with primary refractory DLBCL had SD after initial infusion and reached PR after a second infusion, and 1 patient with PCNSL remained in SD. Of the 4 patients receiving single infusion of CART cells, 2 patients with primary refractory DLBCL remained in PR, 1 patient with RR DLBCL with CNSL infiltration was SD and 1 patient with refractory PMBL developed to progress disease after reaching PR and finally died. Overall survival (OS) and progression free survival (PFS) rates at 12 months were 87.5 % and 87.5 %, respectively. The most common adverse events of grade 3 or higher during the treatments were neutropenia and anaemia (in 87.5% and 25% of the patients, respectively). Grade 1 cytokine release syndrome (CRS) was observed in 5/8 (62.5%) patients. Neither CRS of > grade 2 nor neurologic events occurred in any patients. No prolonged B cell aplasia and hypogammaglobinemia was observed in repeat infusion patients.
Conclusion
Patients with R/R DLBCL who were treated CD19-CART cells had promising clinical responses with a safety profile. A repeat infusion of CD19-CART cells may lead to prolonged persistence, and sustained responses without elevated side effect. The tendency of improved OS by repeat infusion need to be further evaluated in more patients.
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Disclosures
No relevant conflicts of interest to declare.