The FUS-activated FUS-CAR T cells demonstrated antitumor efficacies in two subcutaneous tumor models; more importantly, the FUS-CAR T cells were shown to cause significantly lower on-target off-tumor toxicity compared with standard constitutive CAR T cells
The FUS-activated FUS-CAR T cells demonstrated antitumor efficacies in two subcutaneous tumor models; more importantly, the FUS-CAR T cells were shown to cause significantly lower on-target off-tumor toxicity compared with standard constitutive CAR T cells.150 In another Hsp-based design, Miller utilized plasmic gold nanorods to convert near infrared (NIR) light to heat, activating Hsp-driven IL15 superagonist in constitutive CAR T cells. for blood tumors.1C5 CAR PTZ-343 T therapy involves genetic engineering of the patients’ T cells with the CAR molecule, which equips the T cells with redirected specificity against target tumor cells, and the subsequent infusion of the CAR T cells back into the patients for cancer treatment. As of September 2021, five CAR T products have been approved by the Food and Drug Administration (FDA) in the United States, targeting leukemia, lymphoma, and multiple myeloma. In fact, synthetic chimeric molecules composed of antibody-like variable regions PTZ-343 fused to T cell receptor (TCR)-derived constant regions were first reported approximately three decades ago.6C9 These were later referred to as the first generation CAR, typically containing an extracellular single-chain variable fragment (scFv) for antigen recognition, hinge (H), and transmembrane (TM) domains for signal transduction, and an intracellular CD3z for activation (Fig. 1). Despite the antigen-specific activation and cytotoxicity, the first generation CAR T cells showed low proliferation developed CAR T cells targeting fluorescein isothiocyanate (FITC), and used bispecific adapters consisting of FITC-conjugated folate to redirect the anti-FITC CAR T cells to tumor cells expressing folate receptors.34 Lee further characterized FITC-folate mediated CAR T cells and demonstrated their ability in mitigating CRS.35 Rodgers developed peptide-specific switchable CAR T cells (sCAR-T) recognizing peptide neo-epitopes (PNE) inserted in a tumor-antigen-specific antibody and demonstrated PNE dose-dependent activation of sCAR-T.36 Viaud further optimized sCAR-T and characterized their antitumor ability in a syngeneic murine tumor model.37 Using similar principles, Paul showed that a bispecific antibody targeting TRB5C5 and TRBV12 could specifically lyse malignant T cell lines in mouse models.38 Cho developed a split, universal, and programmable (SUPRA) CAR system composed of a universal receptor (zipCAR) expressed on T cells, where a tumor-targeting scFv adaptor (zipFv) enabled the switch of targets in tumor cells and the response to multiple antigens using different adaptors without reengineering the T cells.39 These innovations provide solutions to antigen limitations in conventional CARs. Despite the enhanced performance of bispecific CARs, for some applications, an OR-gate contributes to increased levels of on-target off-tumor toxicity leading to a lower therapeutic index. As it is difficult to identify surface antigens unique to cancer cells, CAR T cells are expected to kill normal cells expressing target antigens. For applications where such overlap in antigen expression occurs between cancerous and healthy tissues, more complex logic gates may be required. AND logic gates can require multiple antigens to be expressed on a cell before a T cell response can be triggered, and NOT logic gates can prevent CAR T activation when certain antigens are expressed on normal tissues/organs. Toward the PTZ-343 implementation of more complex logic gates, Lajoie developed a CAR that targets a non-native epitope that exists in a colocalization-dependent protein switch called Co-LOCKR [Fig. 2(d)].40 This switch can be toggled between a conformation where the epitope is exposed and another conformation where the epitope is hidden depending on co-localization of switch components. While this strategy has been shown to work to implement complex combinations of AND, OR, and NOT logic gates, such a strategy would require intravenous administration of the switch components.40 Thus, pharmacokinetics and immunogenicity of the colocalization-dependent protein switch may present future challenges for this approach. Other groups have also worked toward introducing Boolean logic gates in CAR T cells. For example, Salzer have developed an avidity-based system where T cells are transduced with multiple CARs that bind weakly to targeted antigen. Thus, on their own, an individual CAR will be insufficient to mount a significant immune response. Then, by further engineering intermolecular interactions between such low-affinity CARs, the researchers were able to develop AND logic gates by Rabbit Polyclonal to CNGA1 introducing a dimerization domain.41 The hinge and transmembrane domains CARs can also benefit from optimizations in the H/TM domains. It has been shown that different H/TM domains can affect the expression and stability of the CAR molecules as well as the efficiency of signal transmitting.42 Some H/TM domains also appear associated with neurologic toxicity in CAR T therapies. Brudno reported that the occurrence of neurologic toxicity is significantly lower.