Challenges and opportunities of allogeneic donor-derived CAR T cells

Abstract

Purpose of review As T cells engineered with chimeric antigen receptors (CARs) are entering advanced phases of clinical trial testing with promising results, the potential implications of use in an allogeneic environment is emerging as an important consideration. This review discusses the use of allogeneic CAR therapy, the potential effects of T cell receptor (TCR) signaling on CAR T cell efficacy, and the potential for TCR elimination to generate an off-the-shelf product. Recent findings The majority of preclinical and clinical data regarding allogeneic T cells are focused on safety of their use given the potential for graft versus host disease (GVHD) mediated by the T cell receptor expressed with the introduced CAR. Recent clinical trials using donor derived CAR T cells are using either rigorous patient selection or T cell selection (such as enrichment for virus-specific T cells, VST). Although no GVHD has been reported, the efficacy of the allogeneic CAR treatment needs to be optimized. Several pre-clinical models limit allogeneic CAR-driven GVHD by utilizing memory T cell selection, VST, gene-editing techniques or suicide gene engineering. Summary In the allogeneic environment, the potential effects of TCR signaling on the efficacy of CAR could affect the clinical responses with the use of donor-derived CAR T cells. Better understanding of the functionality of donor-derived T cells for therapy is essential for the development of universal effector cells for CAR therapy.

Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells

“…Indeed, there is interest in developing allogeneic CAR T cells (recently reviewed in ref. 51), especially for developing an off-the-shelf product.…”

A retrospective comparison of allogenic and autologous chimeric antigen receptor T cell therapy targeting CD19 in patients with relapsed/refractory acute lymphoblastic leukemia

“…GVL effect is seen not only after allo-HSCT, but also following delayed infusion of donor-T-cells-the so-These authors contributed equally: Yongxian Hu, Jiasheng Wang called donor lymphocyte infusion (DLI)-which has welldefined, yet limited capability of re-inducing remission in relapsed patients [4,5]. Therefore, the added effect of GVL to alloCAR T cells might influence the anti-leukemia efficacy [6]. However, similar to DLI, graft-versus-host disease (GVHD) is a potential concerning side effect following alloCAR T-cell infusion.…”

Sequential allogeneic and autologous CAR-T–cell therapy to treat an immune-compromised leukemic patient

“…Rigorous donor selection or selection of virus-specific allogeneic T cells may reduce these side effects. 18 Although no GVHD has been reported using the select allo-CAR-T approaches (#NCT01475058, #NCT01430390, and #NCT01195480), the efficacy of allo-CAR-Ts may be suboptimal because of limited T-cell life spans after overexpansion and reduced cytolytic CAR-T functions. Unlike the majority allo-CAR-T studies, the allo-CAR-T cells in this study were engineered from the bulk T cells of the patient's mother, manufactured within 5 to 7 days without selection and sequentially infused in a low number of cells.…”