Custom CARs: Leveraging the Adaptability of Allogeneic CAR Therapies to Address Current Challenges in Relapsed/Refractory DLBCL

Abstract

Cellular therapies have transformed the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), which typically does not respond well to salvage chemotherapy. Recently, approximately 40% of r/r DLBCL patients across three different trials achieved a complete remission at 1 year after receiving treatment with autologous chimeric antigen receptor (CAR) T cells (auto-CARs). These successes have prompted studies of auto-CARs in second-line settings, in which axicabtagene ciloleucel and lisocabtagene maraleucel both showed improved event-free survival over autologous hematopoietic cell transplantation (AHCT). While encouraging, this data also highlights that 60% of patients relapse or progress following treatment with auto-CARs. Individual disease characteristics and logistical challenges of cell engineering also limit patients’ eligibility for auto-CARs. Allogeneic CAR T cells (allo-CARs) may address some of these limitations as they may mitigate delays associated with auto-CARs, thereby reducing the need for bridging chemotherapies and increasing availability of cellular products for patients with aggressive lymphomas. By being sourced from healthy donors who have never been exposed to cytotoxic chemotherapy, allo-CARs can be created from T cells with better fitness. Allo-CARs made from specific cellular subsets (e.g., stem cell memory or naïve/early memory T cells) may also have increased efficacy and long-term persistence. Additionally, allo-CARs have been successfully created from other cell types, including natural killer cells, gamma-delta T-cells and induced pluripotent stem cells. These cell types can be engineered to target viral antigens, enabling precision targeting of virally driven DLBCL. As allogeneic donor cells can be banked and cryopreserved in batches, they can be made more readily available, potentially reducing logistical hurdles and costs compared to engineering auto-CARs. This may ultimately create a more sustainable platform for cell therapies. Challenges with allo-CARs that will need to be addressed include graft versus host disease, alloimmunization, potentially decreased persistence relative to auto-CARs, and antigen escape. In short, the adaptability of allo-CARs makes them ideal for treating patients with r/r DLBCL who have progressed through standard chemotherapy, AHCT, or auto-CARs. Here, we review the published literature on patients with r/r DLBCL treated with allogeneic CAR products manufactured from various cell types as well as forthcoming allogeneic CAR technologies.

Chimeric Antigen Receptor-T Cell Therapy for Lymphoma: New Settings and Future Directions

“…Additionally, large quantities of allo-CAR-Ts can be derived from a single donor, enabling the creation of readily available batches of preserved CAR-T cells for immediate patient access. The increased availability of the product may result in a reduced need for bridging chemotherapy and lower costs [ 128 , 129 ]. Finally, since allo-CAR-Ts can be created from T-cell subsets that may confer properties such as memory or stemness, a better persistence might be obtained [ 127 , 130 ].…”

Efficacy, Safety, and Challenges of CAR T-Cells in the Treatment of Solid Tumors

“…One possibility for patients who do not respond to CAR T-cell therapy is that many auto-CAR T patients received three or more courses of chemo treatment before cell collection, so that the collected T cells for CAR T were less suitable at baseline [ 144 ].…”

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

“…Allogeneic CAR T cells (allo-CAR) may overcome some of these limitations; allo-CARs can be manufactured from healthy donor cells and could become available as an “off-the-shelf” product, increasing availability for patients and reducing the need for bridging chemotherapy [ 113 , 114 ]. Salient differences between auto-CAR and allo-CARs are summarized in Table 4 .…”

“…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 ].…”