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

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.

Redirecting T cells to hematological malignancies with bispecific antibodies

“…We and others have explored this strategy and have engineered T cells to secrete BiTEs for the adoptive immunotherapy of hematological malignancies. [93][94][95] In addition, we have shown that the expression of costimulatory molecules on T cells enhances BiTE-mediated T-cell activation, highlighting one of the advantages of cell-based BsAb delivery. 96 Lastly, the feasibility of engineering oncolytic viruses to secrete BiTEs targeting solid tumor antigens has been shown in preclinical models; however, no data are currently available for hematological malignancies.…”

Next-generation immuno-oncology agents: current momentum shifts in cancer immunotherapy

“…Yangbin Zhao from the University of Pennsylvania discussed his group's efforts with genetic engineering to improve T cell therapy for solid tumors. Zhao pointed out that the ideal T cells for cellular therapy might be effector memory T (T EM )-like cells with excellent proliferation and long-term in vivo persistance [77,78]. Zhao's update focused on the ongoing first US trial with universal CAR-T cells that were genetically edited using CRISPR/Cas9 technology to eliminate their expression of endogenous TCRs and PD-1.…”

CARs versus BiTEs: A Comparison between T Cell–Redirection Strategies for Cancer Treatment

“…Importantly, these ENG-T cells expanded in vivo and increased the production of BiTEs after activation, obviating the need for continuous infusion of engager molecules (95). Interestingly, a recent report compared the efficacy of RNAelectroporated ENG-T cells to the RNA-electroporated CAR T cells and concluded that the ENG-T cells showed more efficacy in the NALM6 leukemia model (98).…”