Abstract
Adoptive cellular immunotherapy using immune cells expressing chimeric antigen receptors (CARs) has shown promise, particularly for the treatment of hematological malignancies. To date, the majority of clinically evaluated CAR cell products have been derived from autologous immune cells. While this strategy can be effective it also imposes several constraints regarding logistics. This includes i) availability of center to perform leukapheresis, ii) necessity for shipment to and from processing centers, and iii) time requirements for product manufacture and clinical release testing. In addition, previous cytotoxic therapies can negatively impact the effector function of autologous immune cells, which may then affect efficacy and/or durability of resultant CAR products. The use of allogeneic CAR cell products generated using cells from healthy donors has the potential to overcome many of these limitations, including through generation of “off the shelf” products. However, allogeneic CAR cell products come with their own challenges, including potential to induce graft-versus-host-disease, as well as risk of immune-mediated rejection by the host. Here we will review promises and challenges of allogeneic CAR immunotherapies, including those being investigated in preclinical models and/or early phase clinical studies.
Highlights
Adoptive cellular therapy refers to the isolation of immune cells, followed by ex vivo manipulation and subsequent delivery into patients as a therapeutic intervention
The most successful chimeric antigen receptors (CARs) cell therapy approach far has been the treatment of patients with highly relapsed/refractory CD19-positive hematological malignancies using CD19-CAR T cells derived from autologous T cells
The process includes navigating the logistics of performing successful leukapheresis for a patient with relapsed/refractory malignant disease, accessing a manufacturing/treatment facility, and shipping and manufacturing times that commonly take several weeks. This time delay can be significant, in a group of patients with aggressive relapsed/resistant cancers, who are at risk of clinical deterioration which could preclude proceeding with CAR cell therapy
Summary
Adoptive cellular therapy refers to the isolation of immune cells, followed by ex vivo manipulation and subsequent delivery into patients as a therapeutic intervention. Across numerous institutions, using a variety of CAR constructs and manufacturing strategies, CD19-CAR T cell therapy has been extremely efficacious [4, 5] The autologous (patient-derived) CAR T cell paradigm has highlighted the limitations of such therapies, including the challenges of leukapheresis, manufacturing and efficacy in an often heavily pre-treated patient population [14]. Seeking to overcome these barriers, allogeneic CAR strategies are actively being developed. Significant challenges of using allogeneic cells exist and center upon the inherent immunologic mismatch between donor and recipient Despite these challenges, allogeneic CAR strategies hold the potential to offer quicker, more efficacious and more accessible CAR therapies. We will highlight clinical experiences with allogeneic CAR cell therapies and on-going clinical trials to treat malignancies
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