Strategies to Circumvent the Side-Effects of Immunotherapy Using Allogeneic CAR-T Cells and Boost Its Efficacy: Results of Recent Clinical Trials

Abstract

Despite the outstanding results of treatment using autologous chimeric antigen receptor T cells (CAR-T cells) in hematological malignancies, this approach is endowed with several constraints. In particular, profound lymphopenia in some patients and the inability to manufacture products with predefined properties or set of cryopreserved batches of cells directed to different antigens in advance. Allogeneic CAR-T cells have the potential to address these issues but they can cause life-threatening graft-versus-host disease or have shorter persistence due to elimination by the host immune system. Novel strategies to create an “off the shelf” allogeneic product that would circumvent these limitations are an extensive area of research. Here we review CAR-T cell products pioneering an allogeneic approach in clinical trials.

Case Report: Unedited allogeneic chimeric antigen receptor T cell bridging to conditioning-free hematopoietic stem cell transplantation for a child with refractory Burkitt lymphoma

“…Second, these allogeneic T cells may be rapidly eliminated by the host immune system, limiting their antitumor activity. Some strategies have been reported for administering allogeneic CAR-T cells, such as the use of virus-specific memory T cells, non-αβ T cells, gene editing with TCR deletion in αβ T cells, donor-derived allogeneic T cells in stem cell transplant recipients, or induced pluripotent stem cells (iPSCs) as a source of allogeneic CAR-T cells ( 14 , 15 ).…”

Genetic engineering strategies to enhance antitumor reactivity and reduce alloreactivity for allogeneic cell-based cancer therapy

“…Engineering CD52 deficient CAR-T cells allows for concurrent treatment of alemtuzumab and CD19-CAR-T cells for combined host cell depletion and donor cell engraftment. Several clinical trials utilize this TALEN-mediated CD52-knockout for successful selective lymphodepletion in allogeneic CD19-CAR-T cell therapy ( 166 ). Genetically engineering a mechanism for selective lymphodepletion provides an opportune avenue for allogeneic transfer of CAR-T cells without the risk of GvHD.…”

Precision medicine: In vivo CAR therapy as a showcase for receptor-targeted vector platforms

“…This is a step toward off-the-shelf CAR T cells, although the resulting products will most likely not be completely universal, owing to human leukocyte antigen barriers that necessitate adaptation to patient subgroups. 18 Graft-versus-host reactions as well as manufacturing complexity are circumvented when CAR T cells are generated directly in vivo . Here, a single, universally applicable medicinal product in the form of systemically administered vectors encoding the CAR would be used to transduce the patient’s T cells directly in their body.…”