Improved anti-leukemia activities of adoptively transferred T cells expressing bispecific T-cell engager in mice.

X Liu,D M Barrett,Y Zhao,M Kalos,C H June,S A Grupp,C Fang,S Jiang

doi:10.1038/bcj.2016.38

Abstract

Despite the impressive clinical efficacy of T cells engineered to express chimeric antigen receptors (CAR-Ts), the current applications of CAR-T cell therapy are limited by major treatment-related toxicity. Thus, safer yet effective alternative approaches must be developed. In this study, we compared CD19 bispecific T-cell engager (BiTE)-transferred T cells that had been transfected by RNA electroporation with CD19 CAR RNA-transferred T cells both in vitro and in an aggressive Nalm6 leukemia mouse model. BiTEs were secreted from the transferred T cells and enabled both the transferred and bystander T cells to specifically recognize CD19+ cell lines, with increased tumor killing ability, prolonged functional persistence, increased cytokine production and potent proliferation compared with the CAR-T cells. More interestingly, in comparison with CD3/CD28 bead-stimulated T cells, T cells that were expanded by a rapid T-cell expansion protocol (REP) showed enhanced anti-tumor activities for both CAR and BiTE RNA-electroporated T cells both in vitro and in a Nalm6 mouse model (P<0.01). Furthermore, the REP T cells with BiTE RNAs showed greater efficacy in the Nalm6 leukemia model compared with REP T cells with CAR RNA (P<0.05) and resulted in complete leukemia remission.

Highlights

Adoptive cell transfer (ACT) using chimeric antigen receptor (CAR-T) cells has demonstrated an unprecedented anti-leukemic response leading to the sustained remission in recent clinical trials.[1,2,3] the current ACT approach using lentivirally or retrovirally transduced chimeric antigen receptors (CAR-Ts) cells has limitations associated with the lack of control over their activation and expansion in vivo,[4] which has resulted in acute cases of tumor lysis syndrome and fatal cytokine release syndrome, as well as complications caused by the persistent on-target activity of CAR-Ts, such as long-term B-cell aplasia
The current ACT approach using lentivirally or retrovirally transduced CAR-T cells has limitations associated with the lack of control over their activation and expansion in vivo,[4] which has resulted in acute cases of tumor lysis syndrome and fatal cytokine release syndrome, as well as complications caused by the persistent on-target activity of CAR-Ts, such as long-term B-cell aplasia
It has been shown that bispecific T-cell engager (BiTE) are highly cytotoxic against various cell lines, using unstimulated human peripheral blood mononuclear cells in the absence of co-signaling, and that BiTEs can mediate the serial killing of many target cells.[19,21]

Summary

INTRODUCTION

Adoptive cell transfer (ACT) using chimeric antigen receptor (CAR-T) cells has demonstrated an unprecedented anti-leukemic response leading to the sustained remission in recent clinical trials.[1,2,3] the current ACT approach using lentivirally or retrovirally transduced CAR-T cells has limitations associated with the lack of control over their activation and expansion in vivo,[4] which has resulted in acute cases of tumor lysis syndrome and fatal cytokine release syndrome, as well as complications caused by the persistent on-target activity of CAR-Ts, such as long-term B-cell aplasia. A combination of T cells generated by REP and the RNA electroporation of a CD19 BiTE has the potential to cure CD19+ malignancies with controlled toxicities and without B-cell aplasia

MATERIALS AND METHODS

DISCUSSION

Findings

CONFLICT OF INTEREST