Optimizing the Clinical Impact of CAR-T Cell Therapy in B-Cell Acute Lymphoblastic Leukemia: Looking Back While Moving Forward

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy has been successful in creating extraordinary clinical outcomes in the treatment of hematologic malignancies including relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). With several FDA approvals, CAR-T therapy is recognized as an alternative treatment option for particular patients with certain conditions of B-ALL, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, or multiple myeloma. However, CAR-T therapy for B-ALL can be surrounded by challenges such as various adverse events including the life-threatening cytokine release syndrome (CRS) and neurotoxicity, B-cell aplasia-associated hypogammaglobulinemia and agammaglobulinemia, and the alloreactivity of allogeneic CAR-Ts. Furthermore, recent advances such as improvements in media design, the reduction of ex vivo culturing duration, and other phenotype-determining factors can still create room for a more effective CAR-T therapy in R/R B-ALL. Herein, we review preclinical and clinical strategies with a focus on novel studies aiming to address the mentioned hurdles and stepping further towards a milestone in CAR-T therapy of B-ALL.

CAR-T cell therapy in triple-negative breast cancer: Hunting the invisible devil

“…In the context of CAR-T therapy of hematologic malignancies, such as those targeting CD19, due to the expression of CD19 by both normal cells and malignant blasts, CAR-T therapy results in the elimination of both of these cells leading to a phenomenon known as “ B-cell aplasia ” ( 235 ). This occurrence is a marker of an efficient CAR-T therapy of hematologic malignancies, even though it makes the relative patients susceptible to opportunistic infections to tackle which the patients should undergo immunoglobulin replacement ( 235 ).…”

“…CRS is well-known CAR-T cell therapy adverse event which is more likely to occur in CAR-T therapy of hematologic malignancies ( 235 , 236 ). CRS results from the rapid activation of various immunological pathways.…”

“…Generally, antihistamines or corticosteroids are recommended for low-grade CRS management ( 236 ). However, in the case of CAR-T therapy-mediated CRS, more efficient strategies are required, especially in the case of hematologic malignancies such as B-cell acute lymphoblastic leukemia (B-ALL) ( 235 ). IL-1 and IL-6 blockade, GM-CSF blockade, antibody-based immunotherapy pretreatment, therapeutic plasma exchange, hemofiltration, and fractionated CAR-T infusion are among strategies proven to be efficient in the management of severe lethal CRS after CAR-T therapy ( 235 , 237 – 245 ).…”

Recent Advances in Solid Tumor CAR-T Cell Therapy: Driving Tumor Cells From Hero to Zero?

“…Considering the durable clinical responses in the treatment of patients with the mentioned hematological indications (which still has room for improvement), what came out as bad news was the unfavorable efficacy of CAR-T therapy against solid tumors ( 36 – 39 ). These unsuccessful outcomes are mainly due to the lack of suitable CAR-T target antigens in solid tumors and that the targeted antigens are usually found on healthy tissues leading to “on-target off-tumor” toxicities.…”

Proteomic profiling of plasma exosomes from patients with B-cell acute lymphoblastic leukemia

“…Compared with the less-common T-cell precursor lineage, the B-cell precursor lineage subtype is much more prevalent, accounting for approximately 85% of all ALL cases 3 . Despite the dramatic improvements in the overall prognosis of patients with B-cell ALL (B-ALL) promoted by the increased availability of cellular immunotherapy and targeted therapy, the outcome of some B-ALL patients remains poor because of cytokine release syndrome and tumor heterogeneity 4 . Therefore, it is imperative to identify novel biomarkers as effective therapeutic targets for better management of patients with B-ALL.…”