Current updates on generations, approvals, and clinical trials of CAR T-cell therapy

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is a novel, customized immunotherapy that is considered a ‘living’ and self-replicating drug to treat cancer, sometimes resulting in a complete cure. CAR T-cells are manufactured through genetic engineering of T-cells by equipping them with CARs to detect and target antigen-expressing cancer cells. CAR is designed to have an ectodomain extracellularly, a transmembrane domain spanning the cell membrane, and an endodomain intracellularly. Since its first discovery, the CAR structure has evolved greatly, from the first generation to the fifth generation, to offer new therapeutic alternatives for cancer patients. This treatment has achieved long-term and curative therapeutic efficacy in multiple blood malignancies that nowadays profoundly change the treatment landscape of lymphoma, leukemia, and multiple myeloma. But CART-cell therapy is associated with several hurdles, such as limited therapeutic efficacy, little effect on solid tumors, adverse effects, expensive cost, and feasibility issues, hindering its broader implications.

The current landscape of CAR T-cell therapy for solid tumors: Mechanisms, research progress, challenges, and counterstrategies

“…A fifth generation of CARs is presently under scrutiny; they have the second generation of CARs as their basis; however, in order for the transcription factor signal transducers and activators of transcription 3 (STAT3), they encompass a truncated cytoplasmic IL-2 receptor bchain domain with a binding site. The antigen-specific activation of this receptor concomitantly ignites TCR (through the CD3z domains), co-stimulatory (CD28 domain) and cytokine (Janus kinase (JAK)-STAT3/5) signaling, culminating in the effective provision of all three synergistic signals needed physiologically to stir a thorough T-cell stimulation and multiplication (24)(25)(26).…”

Mechanisms and strategies for safe chimeric antigen receptor T‐cell activity control

“…OR‐gate CAR (1 or 2 strategy) target multiples tumor antigens (Table 1) and have been developed to increase specificity of CAR T‐cells toward tumor cells. To achieve combinatorial target antigen recognition, multiple CAR are used 117,118 . This can be performed by administering a combination of two different CAR‐transduced T‐cell populations in a specific ratio (NCT03620058) 29,30 .…”

“…In such situations, each CAR/TCR is intact and can mediate full activation upon antigen contact. Another strategy is the use of a (looped) tandem CAR, which contain two scFv domains connected by a linker in a single CAR molecule 117,118 . These CAR T‐cells can mediate cytotoxicity against tumor cells expressing either the first antigen, the second antigen or both antigens 34‐37,44 .…”

“…NOT‐gate CAR (1 not 2 strategy) inhibit OFF‐tumor CAR T‐cell activation by introducing two CAR constructs with opposing effects: a stimulatory CAR recognizing TAAs as well as an inhibitory CAR (iCAR) recognizing healthy tissue antigens, which is coupled to the signaling domain of an inhibitory co‐receptor (Table 1). 117,118 Once an iCAR is activated, it temporarily inhibits CAR T‐cells by either activating intracellular inhibitory signaling pathways or by cleaving the stimulatory CAR. The first approach relies on the incorporation of intracellular domains of cytotoxic T lymphocyte‐associated protein‐4 (CTLA‐4) or programmed cell death‐1 (PD‐1) in an iCAR, leading to a temporary and reversible inhibition of T‐cells upon iCAR activation 48 .…”

CAR T-Cell Therapy in Children with Solid Tumors

“…The third generation CAR (3G CAR) based on the 2G, differs only by an extra costimulatory molecule of CD134 or CD137. The fourth generation CAR (4G CAR) is also based on the 2G, yet it additionally expresses transgenic proteins such as interleukin 12 (IL-12) after the CAR activation [ 7 , 10 ].…”