CAR T-cells for cancer therapy

Abstract

Chimeric antigen receptor (CAR) T-cells are redirected T-cells that can recognize cancer antigens in a major histocompatibility complex (MHC)-independent fashion. A typical CAR is comprised of two main functional domains: an extracellular antigen recognition domain, called a single-chain variable fragment (scFv), and an intracellular signaling domain. Based on the number of intracellular signaling molecules, CARs are categorized into four generations. CAR T-cell therapy has become a promising treatment for hematologic malignancies. However, results of its clinical trials on solid tumors have not been encouraging. Here, we described the structure of CARs and summarized the clinical trials of CD19-targeted CAR T-cells. The side effects, safety management, challenges, and future prospects of CAR T-cells for the treatment of cancer, particularly for solid tumors, were also discussed.

Neuroblastoma Origin and Therapeutic Targets for Immunotherapy

“…If these limitations are not overcome, the tremendous success of CAR T cell adoptive immunotherapies in eradicating hematological malignancies will likely not be extrapolated to solid tumors and, specifically, to neuroblastoma [ 265 ]. A variety of approaches are currently being developed to overcome the aforementioned limitations, including, among others, the introduction of costimulatory molecules (primarily 4-1BB) into the intracellular domain of the receptor, blockade of checkpoint inhibitors (e.g., PD-1), constitutive activation of proliferative and inhibition of apoptotic signal pathways in CAR T cells, and modification of the structure of the chimeric antigen receptor and its density on the surface of T cells [ 264 , 266 – 268 ].…”

Designed Ankyrin Repeat Protein (DARPin) to target chimeric antigen receptor (CAR)-redirected T cells towards CD4+ T cells to reduce the latent HIV+ cell reservoir

“…For HIV-1 reactivation, J-Lat_8. 4 were cultivated in T cell medium with a final 5 µM Prostatin (Sigma) and 2.…”

“…These first-generation CARs, however, failed to reduce the viral burden in patients for prolonged periods, probably in large part due to a lack of a co-stimulation to sustain CAR T cell persistence. Since then, second-, third-and fourth-generation CARs employ additional intracellular costimulatory domains, rendering them more persistent, less susceptible to exhaustion and equipped with functional capacities [4]. However, using HIV gp120 as a target, CAR T cells will not eradicate the virus completely, due to the presence of latent provirus in cellular reservoirs that persist even under successful anti-gp120 CAR T cell therapy since they do not express viral antigens, making their identification challenging [5].…”

Pediatric Acute Lymphoblastic Leukemia: Recent Advances for a Promising Future

“…Adoptive T-cell therapy involves engineering T-cell receptors (TCRs) to bind to specific antigens present on tumor cells. These modified TCRs, known as CARs, allow the immune system to specifically target and destroy tumor cells in an MHC independent manner, bypassing the immune escape mechanisms of downregulation of MHC class I antigens and altered antigen processing by tumor cells [171]. These modified T cells have the capacity to expand and proliferate in the host, produce cytokines to kill tumor cells, as well as cross blood-brain barrier as shown by Maude et al [172].…”