Short-Interval Sequential CAR-T Cell Infusion May Enhance Prior CAR-T Cell Expansion to Augment Anti-Lymphoma Response in B-NHL.

Yuan Meng,Jinlong Xu,Biping Deng,Zhuojun Ling,Weiliang Song,Chuo Li,Jiajia Duan,Jing Pan,Xiaoming Feng,Zelin Wang,Luan Rong,Xiujuan Xiong,Xiaoli Chen,Alex H Chang

doi:10.3389/fonc.2021.640166

Abstract

Chimeric antigen receptor (CAR)-T cell therapy emerges as a new treatment for refractory or relapsed (r/r) B-cell non-Hodgkin lymphoma (B-NHL); however, the overall response rate (ORR) of which in the B-NHL patients is much lower compared to the patients with r/r B acute lymphoblastic leukemia (B-ALL). We previously confirmed that sequential infusions of CD20 and CD22 CAR-T cells significantly improved the prognosis of the B-NHL patients, while some advanced patients still progressed to death during these CAR-T cell treatments. In this study, we showed that timely sequential administration of the second CAR-T cells could enhance expansion of prior CAR-T cells with stronger tumor-killing capacity in vitro and in vivo. We further conducted compassionate treatments on two advanced B-NHL patients with short-interval sequential infusions of CD19/22/20 CAR-T cells. Disease progression was observed in both patients after primary CAR-T cell infusion but robust re-expansion of prior CAR-T cells and anti-tumor effects was induced by infusion of a secondary CAR-T cells. These results indicate sequential infusions of CAR-T cells with a short interval may improve therapeutic efficacy in the B-NHL patients by promoting expansion of prior CAR-T cells.

Highlights

Aggressive B-cell lymphomas encompass a heterogeneous group of diseases, including diffuse large B-cell (DLBCL) and Burkitt lymphoma (BL) [1]
With extended duration of Chimeric antigen receptor (CAR)-T cell expansion which was contributed by separated expansion of each kind of CAR-T cells, 70.6% overall complete remission rate (CR) rate was further achieved in 6 months after traditional sequential CAR-T cell therapies
CD19 CAR-T cells were usually undetectable by flow cytometry (FCM) in peripheral blood (PB) in our center after infusion for one month

Summary

INTRODUCTION

Aggressive B-cell lymphomas encompass a heterogeneous group of diseases, including diffuse large B-cell (DLBCL) and Burkitt lymphoma (BL) [1]. With extended duration of CAR-T cell expansion which was contributed by separated expansion of each kind of CAR-T cells, 70.6% overall CR rate was further achieved in 6 months after traditional sequential CAR-T cell therapies. The cocktail CD19/22 CAR-T cell therapies improved the outcome of aggressive B-cell lymphoma with 72.2% ORR and 50% CR rate, in which the CAR-T cells with different targets contributed to enhanced antitumor effects [13], while there were mainly DLBCL patients and few BL patients enrolled. Sequential infusions of different CAR-T cells with short interval augmented CAR-T cells and enhanced anti-tumor effects, which is consistent with the synergistic effects of multi-agent immunotherapies on eradicating disease and prolonging remission in the patients with relapsed hematologic malignancies [14]. Validation experiments in vitro and in animal model were conducted first, and we hypothesize that such short-interval sequential CAR-T infusion was critical in therapeutic outcomes observed in two advanced B-cell lymphomas

METHODS

Findings

ETHICS STATEMENT