Abstract
In recent decades, great advances have been made in the field of tumor treatment. Especially, cell-based therapy targeting tumor associated antigen (TAA) has developed tremendously. T cells were engineered to have the ability to attack tumor cells by generating CAR constructs consisting of genes encoding scFv, a co-stimulatory domain (CD28 or TNFRSF9), and CD247 signaling domains for T cell proliferation and activation. Principally, CAR-T cells are activated by recognizing TAA by scFv on the T cell surface, and then signaling domains inside cells connected by scFv are subsequently activated to induce downstream signaling pathways involving T cell proliferation, activation, and production of cytokines. Many efforts have been made to increase the efficacy and persistence and also to decrease T cell exhaustion. Overall, allogeneic and universal CAR-T generation has attracted much attention because of their wide and prompt usage for patients. In this review, we summarized the current techniques for generation of allogeneic and universal CAR-T cells along with their disadvantages and limitations that still need to be overcome.
Highlights
Known as a living drug, CAR-T cell therapy has been intensively performed over the past decade
IL12 released from activated CAR-T is deposited around the target tumor lesion before attracting innate immune cells such as natural killer cell and macrophages that can kill the tumor cells that are invisible to CAR-T cells [31,32]
To generate CAR-T cells targeting a specific antigen, the endogenous T cell receptor (TR) locus was replaced with a CAR construct using homing endonuclease and an Adeno-associated virus (AAV) donor template that allowed for the expression of CAR under the endogenous TR promoter [58]
Summary
Known as a living drug, CAR-T cell therapy has been intensively performed over the past decade. To minimize GvHD, chemotherapy regimens including immunosuppressive combinations of Fludarabine and Cyclophosphamide, and serotherapy using Alemtuzumab (anti-CD52 mAb) could be administered ahead of allogeneic CAR-T treatment [3]. Another advantage of TR depleted CAR-T cells is that they can be used off-the-shelf. Since the curative effect of CAR-T cells stem mainly from various released cytokines, common side-effects are often associated with uncontrolled cytokine release and could be very harmful; for instance, some cytokines can penetrate the blood brain barrier (BBB) and cause neurotoxicity [6] To prevent this problem, various safety switches have been developed such as the incorporation of suicide genes, expression of known target genes for therapeutic antibodies, and the addition of molecular switch proteins between CAR and tumor cells. We summarized the techniques used to generate allogeneic and universal CAR-T cells and discuss their advantages and considerations for their wide use
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