Challenges and optimal strategies of CAR T therapy for hematological malignancies

Abstract

Remarkable improvement relative to traditional approaches in the treatment of hematological malignancies by chimeric antigen receptor (CAR) T-cell therapy has promoted sequential approvals of eight commercial CAR T products within last 5 years. Although CAR T cells’ productization is now rapidly boosting their extensive clinical application in real-world patients, the limitation of their clinical efficacy and related toxicities inspire further optimization of CAR structure and substantial development of innovative trials in various scenarios. Herein, we first summarized the current status and major progress in CAR T therapy for hematological malignancies, then described crucial factors which possibly compromise the clinical efficacies of CAR T cells, such as CAR T cell exhaustion and loss of antigen, and finally, we discussed the potential optimization strategies to tackle the challenges in the field of CAR T therapy.

Chimeric antigen receptor-immune cells against solid tumors: Structures, mechanisms, recent advances, and future developments

“…Although some problems exist, there is no doubt that CAR-T cells are successful in hematological tumors, and seven new FDA-approved drugs have been put on the market. [ 107 ] However, in the treatment of solid tumors, CAR-T cells still face many intractable challenges [Figure 3 ]. To some extent, the emergence of CAR-NK cells and CAR-M partially makes up for the limitations of CAR-T cells in the treatment of solid tumors.…”

Targeting metabolism to improve CAR-T cells therapeutic efficacy

“…[1] Currently, ten CAR-T cell therapy products have been approved by the U.S. Food and Drug Administration (FDA) and National Medical Products Administration (NMPA) in China respectively, for treating incurable hematological tumors. [2][3][4] Although CAR-T cell therapy has achieved great strides and has shown some clinical ef cacy in patients with hematologic tumors and a subset of solid tumors, many obstacles remain in the eld of tumor therapy, [5][6][7][8] such as tumor antigen heterogeneity, poor immune cell in ltration ability, immunosuppressive microenvironment, metabolic microenvironment disturbance, and T-cell depletion, which have limited further improvement in solid tumor therapy. The effectiveness of CAR-T cells therapy in solid tumor can be improved by searching for new antigens, designing multitarget CARs, overexpressing chemokine receptors and cytokines, knocking down inhibitory signaling molecules, enhancing the metabolic capacity of T cells, combining with immune checkpoint inhibitors, and epigenetic modi cations.…”

CAR-T Cells Immunotherapies for the Treatment of Acute Myeloid Leukemia—Recent Advances

“…Thanks to genetic engineering methods, T cells, previously isolated from the patient's circulation, were obtained, expressing the chimeric antigen receptor (CAR) on their surface [6]. In contrast to the T cell receptor (TCR), CAR enables the recognition of antigens present on cancer cells, independently of major histocompatibility complex (MHC) molecules, thus preventing cancer cells from escaping from the surveillance of the immune system due to the reduced expression of MHC on their surface [7][8][9]. The CAR is composed of four regions, namely: the extracellular antigen-binding domain usually made of a single-chain variable fragment (scFv), the hinge (the spacer region), which increases flexibility and allows the CAR to be properly matched to the target antigen, the transmembrane domain, and the intracellular signaling domain [4,6,8].…”