CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges

Abstract

Chimeric antigen receptor T (CAR-T) cell therapy represents a major breakthrough in cancer treatment, and it has achieved unprecedented success in hematological malignancies, especially in relapsed/refractory (R/R) B cell malignancies. At present, CD19 and BCMA are the most common targets in CAR-T cell therapy, and numerous novel therapeutic targets are being explored. However, the adverse events related to CAR-T cell therapy might be serious or even life-threatening, such as cytokine release syndrome (CRS), CAR-T-cell-related encephalopathy syndrome (CRES), infections, cytopenia, and CRS-related coagulopathy. In addition, due to antigen escape, the limited CAR-T cell persistence, and immunosuppressive tumor microenvironment, a considerable proportion of patients relapse after CAR-T cell therapy. Thus, in this review, we focus on the progress and challenges of CAR-T cell therapy in hematological malignancies, such as attractive therapeutic targets, CAR-T related toxicities, and resistance to CAR-T cell therapy, and provide some practical recommendations.

Keywords: CAR-T cell; CAR-T related toxicities; antigen escape; combinatorial therapy; hematological malignancies; immunosuppressive tumor microenvironment.

Figure 1

Four generations of CAR constructs. The first-generation of CAR consists of the antigen recognition domain scFv and an intracellular T cell activation domain CD3ζ. The second-generation CAR adds a costimulatory molecule, such as CD28, 4-1BB, OX40 or ICOS, which enables the T cells to obtain a superior proliferative capacity and secrete large amounts of cytokines. The third-generation CAR contains two distinct costimulatory domains, such as CD28 and 4-1BB. The fourth-generation of CAR, also known as TRUCK or armored CAR, is additionally equipped with safety switches or engineered to secrete cytokines in order to regulate the persistence or the function of CAR-T cells, such as iCaspase-9, IL-7, IL-15, IL-21.

Figure 2

Potential therapeutic targets in hematological malignancies. A variety of attractive targets for CAR-T cell therapy in hematological malignancies, including T and B cell leukemia/lymphoma, HL, AML, and MM.

Figure 3

The mechanisms of CRS. After the recognition of target antigens, CAR T-cells rapidly proliferate and release multiple cytotoxic molecules, such as granzyme, perforin, IFN-γ, and TNF-α, and upregulate the expression of CD40L and Fas ligand (FasL), and eventually induce pyroptosis and apoptosis of tumor cells. Besides, the CD40/CD40L interactions between tumor cells and CAR T-cells promote Fas-mediated apoptosis. Then the lysed tumor cells release large amounts of DAMPs, such as HMGB1, which could activate innate immune cells, including macrophages and dendritic cells, further amplifying inflammatory responses. In addition, the CD40/CD40L interactions participate in the activation of various immune cells, including T cells, B cells, macrophages, dendritic cells, and conditional innate immune cells such as endothelial cells. The activated CAR-T cells with the increased expression of CD40L could activate macrophages and endothelial cells and promote their production of pro-inflammatory cytokines in a CD40-dependent manner. The cytokines released from activated immune cells could bind to their receptors on endothelial cells and then mediate endothelial dysfunction, resulting in capillary leakage and the release of procoagulant factors.

Figure 4

The mechanisms of CRS-related coagulopathy. The CD40/CD40L interactions also play an essential role in CRS-related coagulopathy. The activated CAR-T cells with high CD40L expression mediate platelet activation in a CD40-independent manner. Then the activated platelets express high levels of CD40L. It could stimulate endothelial cell activation, and induce the expression of TF in monocytes and endothelial cells through direct interaction with CD40. Then TF triggers the extrinsic coagulation cascade. In addition, the CD40/CD40L interactions stimulate the excessive release of cytokines, such as IL-1β, TNF-α, and IL-6. High levels of cytokines further mediate endothelial injury and promote the release of TF and Weibel-Palade bodies (WPBs). The WPBs contains von Willebrand factor (VWF) which plays an essential role in platelet adhesion and aggregation. Due to endothelial injury, collagen fibers are exposed and activate intrinsic coagulation pathway.