These include (1) virus-associated safety concerns (2) limited payload capacity of viral vectors (3) low expansion capacity and low percentage of CAR + T cells following transduction (4) low CAR-T cell persistence and (5) high cost of manufacturing virally-produced CAR-T cells.Ī virus-free system can overcome most if not all of these hurdles, but electroporation-associated damages in virus-free systems present a critical challenge. However, CAR-T cells generated virally have several limitations. Viral vector has been widely used for the development of CAR-T cell therapy due to its high efficiency in gene delivery and integration, resulting in stable long-term gene expression. A technological breakthrough needs to be developed to overcome these hurdles. differentiation, exhaustion, senescence, and survival). Consistent with these desired therapeutic properties, it has been clinically demonstrated that high levels of CAR-T SCM cells lead to better clinical outcomes.ĬAR-T cell therapy faces several challenges in the context of solid tumor, including (1) lack of CAR-T cell trafficking to the tumor (2) antigen heterogeneity of solid tumors and (3) immunosuppressive tumor microenvironment (TME) which can adversely affect T cell fitness (e.g. Furthermore, T SCM cells have the highest therapeutic efficacy due to enhanced metabolic fitness and low level of senescence and exhaustion ( Figure 1). T SCM are characterized by stem-like properties with high capacity for self-renewal, resulting in long-term persistence. Therefore, the potency and persistence of CAR-T cells are key to a successful CAR-T cell therapy. However, the widespread application of CAR-T cell therapy for the treatment of cancer has encountered several challenges, including (1) the potential for on-target/off-tumor toxicity and/or cytokine release syndrome (CRS) (2) relapses due to: (i) antigen escape and/or antigen heterogeneity of solid tumor, resulting in outgrowth of non-targeted tumor cells and/or (ii) a lack of CAR-T cell persistence (3) lack of potency for the treatment of solid tumors and (4) the high cost associated with CAR-T cell manufacturing. The development of chimeric antigen receptor T (CAR-T) cell therapy is a major breakthrough in cancer therapy due to the remarkable clinical responses observed in certain hematological cancer patients infused with cancer-targeting CAR-T cells.
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