The Evolution of Chimeric Antigen Receptor T-Cell Therapy in Children, Adolescents and Young Adults with Acute Lymphoblastic Leukemia

Abstract

Chimeric antigen receptor T-cell (CAR T) therapy is a revolutionary treatment for pediatric, adolescent and young adult patients (AYA) with relapsed/refractory B-cell acute lymphoblastic leukemia. While the landscape of immunotherapy continues to rapidly evolve, widespread use of CAR T therapy is limited and many questions remain regarding the durability of CAR T therapy, methods to avoid CAR T therapy resistance and the role of consolidative stem cell transplant. Modified strategies to develop effective and persistent CAR T cells at lower costs and decreased toxicities are warranted. In this review we present current indications, limitations and future directions of CAR T therapy for ALL in the pediatric and AYA population.

CRISPR, CAR-T, and NK: Current applications and future perspectives

“… 41 , 42 On the other hand, T cell exhaustion, CAR T cell inviability, 43 and the autologous nature of products have limited the safety, efficiency, and availability of new therapeutic methods. 16 , 44 , 45 , 46 Many of these limitations can be overcome using the CRISPR-Cas9-based gene editing tool as an easy and available method. 47 Accordingly, current research efforts are focused on precise CAR T cell engineering with conventional CRISPR-Cas9 systems or novel editors that can generate the desired mutations with or without inducing a double-stranded DNA break into the genome.…”

Harnessing the Immune System: Current and Emerging Immunotherapy Strategies for Pediatric Acute Lymphoblastic Leukemia

“…CARs are autologous T cells genetically manufactured to target specific antigens on leukemic blasts and couple them with intracellular T-cell signaling domains of the T-cell receptor (TCR), therefore re-directing T-lymphocytes to leukemic blasts expressing the targeted antigen. There are now five generations of CARs in development, all employing different strategies to enhance the signal transduction leading to stronger activation, expansion, and persistence of CAR T-cells while also limiting associated toxicities such as CRS and neurotoxicity [32][33][34]. The FDA approval of tisagenlecleucel (Kymriah) in 2017 for patients up to age 25 with refractory or second or greater relapse of B-ALL significantly impacted the landscape of relapsed ALL in children and young adults.…”

“…The first demonstration of the utility and safety of UCART occurred in two infants with R/R B-ALL, who achieved CR following CD19 CAR T cells using TALEN gene-editing technology to disrupt the gene encoding for T-cell receptors (TCR) and the gene encoding for CD52 [69]. These disturbances helped to minimize the risk of graft-versus-host disease (GVHD) and to acquire resistance to anti-CD52 alemtuzumab so that the CAR T cells are resistant to destruction and not eliminated from recipients when receiving alemtuzumab as a conditioning agent [32,34,66,68]. Both infants were able to proceed with HSCT following CAR T successfully.…”