Engineering off-the-shelf universal CAR T cells: A silver lining in the cloud

Abstract

CAR therapy holds promise in treating aggressive hematological malignancies. Nonetheless, the present autologous CAR therapy regimen makes multiple patients ineligible for the therapy due to inadequate quantity, quality and purity of the product. Furthermore, timely manufacturing of benchmarked cell products is logistically challenging and unaffordable. Extensive genetic modifications may be required to overcome the biological, clinical and manufacturing limitations of the autologous CAR therapy. n the light of the numerous configurations of CAR therapy, engineering "off-the-shelf" universal CAR T cells (UCART) is emerging as a safer, effective and affordable alternative to conventional CAR T cells With UCART therapy, batch production of a quality-controlled product with multiplex genetic modification can be feasible in a shorter period of time. Currently vast majority of the UCART programs target CD19 followed by BCMA and CD70. In order to make universal CAR T cell therapy possible, it is imperative to have engineering strategies to curb graft versus host disease (GvHD) and graft rejection (GR). Moreover, approaches to offer alternate strategies for intense preparative chemotherapy, infection control and CAR T cell persistence need to be optimized. An ideal universal immune receptor (UIR) design should counter the antigen escape and further the therapeutic value and affordability. UIRs would allow flexibility to personalize the therapy based on the specific malignancy characteristics as well. With the innovations in the inducible molecular switch, split CAR design, CRISPR/Cas9 mediated gene targeting, rational subset composition and cryopreservation, the strategies to engineer universal CAR T therapy is fast advancing from bench to bedside.

Keywords: Cancer Immunotherapy; GvHD; Multiplex Gene Editing; Off-the-shelf; TCR; Universal CAR T cells.