Allogeneic Chimeric Antigen Receptor Therapy in Lymphoma

Abstract

Opinion statementThe therapeutic armamentarium has significantly expanded since the approval of various CD19-targeting chimeric antigen receptor T cell (CAR-T) therapies in non-Hodgkin lymphoma (NHL). These CAR-Ts are patient-specific and require a complex, resource, and time-consuming process. While this appears promising, autologous CAR-Ts are limited due to the lack of accessibility, manufacturing delays, and variable product quality. To overcome these, allogeneic (allo) CARs from healthy donors appear appealing. These can be immediately available as “off the shelf” ready-to-use products of standardized and superior quality exempt from the effects of an immunosuppressive tumor microenvironment and prior treatments, and potentially with lower healthcare utilization using industrialized scale production. Allogeneic CARs, however, are not devoid of complications and require genomic editing, especially with αβ T cells to avoid graft versus host disease (GvHD) and allo-rejection by the recipient’s immune system. Tools for genomic editing such as TALEN and CRISPR provide promise to develop truly “off the shelf” universal CARs and further advance the field of cellular immunotherapy. Several allogeneic CARs are currently in early phase clinical trials, and preliminary data is encouraging. Longer follow-up is required to truly assess the feasibility and safety of these techniques in the patients. This review focuses on the strategies for developing allogeneic CARs along with cell sources and clinical experience thus far in lymphoma.

The role of CAR-T cell therapy as second line in diffuse large B-cell lymphoma

“… 47 , 48 Other ongoing early trials include the anti-CD19 UCART019 (NCT03166878) and the CTX130 anti-CD70 allogeneic CRISPR-Cas9 (NCT04502446). 49 , 50 We look forward to seeing the results of the next wave of CAR-T trials currently under evaluation.…”

Adoptive cellular immunotherapy for solid neoplasms beyond CAR-T

“…However, UCB-derived NK cells manifest a less mature phenotype and express a lower level of CD16, KIRs, and NCRs, and a high level of inhibitory receptors, such as NKG2A [ 154 ]. On the one hand, multiple allogeneic donors can serve as sources for one patient to meet the clinical demand with “off the shelf” products; on the other hand, these heterogenous sources make it difficult to develop a common standard for commercialization [ 155 , 156 ].…”

CAR T-Based Therapies in Lymphoma: A Review of Current Practice and Perspectives

“…For example, patients with a high tumor burden or rapidly progressive disease were underrepresented in pivotal clinical trials. Resistance mechanisms described in auto-CAR T cell therapy include antigen-positive relapse, resulting from a specific CAR T cell phenotype affecting CAR T cell persistence and an immunosuppressive microenvironment, for example, and antigen-negative relapses where antigen loss may be driven by alternative splicing, epitope masking, antigen downregulation or lineage switching of the lymphoma [ 110 , 112 ]. Consequently, additional improvements in CAR T cells as a treatment modality are further warranted.…”

“…As well as being sourced from healthy donors that have previously not been exposed to cytotoxic chemotherapy and therefore may have fitter and less exhausted T cells, another advantage of allo-CARs is that they can be created from T cell subsets that may confer properties such as memory or stemness, which could be associated with better persistence and influence long-term efficacy outcomes, and also from other cell types such as natural killer (NK), gamma-delta and induced pluripotent stem cells [ 112 , 113 ].…”