Strategies for having a more effective and less toxic CAR T-cell therapy for acute lymphoblastic leukemia

Abstract

In the recent years, using genetically modified T cells has been known as a rapid developing therapeutic approach due to the heartwarming results of clinical trials with patients suffering from relapsed or refractory (R/R) hematologic malignancies such as R/R Acute Lymphoblastic Leukemia (R/R ALL). One of these renowned approaches is Chimeric antigen receptors (CARs). CARs are synthetic receptors with the ability to be expressed on the surface of T lymphocytes and are specifically designed to target a tumor-associated antigen (TAA) of interest. CAR-expressing T cells have the capability of proliferating and maintaining their immunological functionality in the recipient body but like any other therapeutic approach, the safety, effectiveness, and specificity enhancement of CAR T cells still lingers in the ambiguity arena. Genetic manipulation methods, expansion protocols, infusion dosage, and conditioning regimens are all among crucial factors which can affect the efficacy of CAR T cell-based cancer therapy. In this article, we discuss the studies that have focused on various aspects that affect the efficacy and persistence of CAR T-cell therapy for ALL treatment and provide a widespread overview regarding the practical approaches capable of elevating the effectiveness and lessening the relative toxicities attributed to it.

In Like a Lamb; Out Like a Lion: Marching CAR T Cells Toward Enhanced Efficacy in B-ALL

“…Generally, B-cell aplasia, as characterized by CAR T cell-mediated elimination of healthy CD19-expressing B cells, is an established hallmark of successful CAR T therapy (2). However, B-cell aplasia can result in hypogammaglobulinemia and increased risk of viral as well as bacterial infections (2). Such patients often require precise monitoring and (healthy donor-derived) plasma to complete their CAR T cell treatment.…”

“…While the five-year overall survival rate is 80-90%, disease recurrence (relapse) can occur and is characterized by a poor response to conventional treatments (refractory). This lack of durable efficacy underscores the need for alternate approaches with enhanced effectiveness against cancer (1,2). Improved outcomes in patients with relapsed or refractory (R/R) B-ALL have been obtained through the use of adoptively transferred T cells.…”

“…Chimeric antigen receptor (CAR) transgenes have been effectively used to generate tumor-reactive T cells. The unprecedented successes of CAR-expressing T cells have given rise to a succession of US Food and Drug Administration (FDA) approvals including Kymriah ™ (Tisagenlecleucel) for pediatric patients and young adults with R/R B-ALL, Yescarta ™ (Axicabtagene ciloleucel) and Breyanzi™ (Lisocabtagene maraleucel) for patients with diffuse large B-cell lymphoma (DLBCL), and Tecartus ™ (Brexucabtagene autoleucel) for adults with mantle cell lymphoma (MCL) (2,3).…”

Strategies for Dodging the Obstacles in CAR T Cell Therapy

“…Chimeric antigen receptor (CAR) T cells are genetically engineered T cells that possess the ability to specifically recognize and target tumor cells with significant discrimination from healthy tissues. Unlike the conventional cancer treatment methods such as surgery, radiotherapy, and chemotherapy, CAR T cells target tumor-specific antigens (TSAs) or tumor-associated antigens (TAAs) expressed on the surface of their target tumor cells with the delicate specificity granted to them by their antibody fragment-equipped targeting domain in a non-major histocompatibility complex (MHC) manner ( 1 , 2 ).…”

“…In detail, CARs are made of an extracellular domain comprised of a targeting domain and a hinge, a transmembrane (TM) domain, and an intracellular domain composed of one or more co-stimulatory domains and an activation domain. The targeting domain of CARs are commonly composed of a single-chain variable fragment (scFv) derived from a monoclonal antibody (mAb) but other targeting domains such as single variable domains of heavy-chain antibodies (VHH, also known as Nanobodies ® ), ligands, and toxins have also been used, even though less commonly ( 2 – 4 ). Researchers have demonstrated the potential of VHH-based CAR T cells against solid tumors and in targeting their tumor microenvironments (TME) ( 3 , 5 ).…”