Nanomodified Switch Induced Precise and Moderate Activation of CAR‐T Cells for Solid Tumors

Abstract

Chimeric antigen receptor (CAR)-T cell therapy is a transformative treatment against advanced malignancies. Unfortunately, once administrated in vivo, CAR-T cells become out of artificial control, and fierce response to CAR-T therapy may cause severe adverse events, represented by cytokine-release syndrome and on-target/off-tumor effects. Here, a nanomodified switch strategy is developed, leading to sustained and precise "on-tumor only" activation of CAR-T cells. Here, original gelatinase-responsive nanoparticles (NPs) are used to selectively deliver the heterodimerizing switch, which is the key component of switchable CAR with separated activation modules. The "NanoSwitch" is tumor-specific, thus inactivated switchable CAR-T cells do little harm to normal cells, even if the normal cells express the target of CAR-T. Owing to the sustained-release effect of NPs, the CAR-T cells are activated smoothly, avoiding sudden release of cytokine. These data introduce NanoSwitch as a universal and applicable solution to safety problems of CAR-T therapy regardless of the target.

Liposome‐based in situ antigen‐modification strategy for “universal” T‐cell‐receptor engineered T cell in cancer immunotherapy

“… 22 In Wang's research, gelatinase‐responsive NPs were used to create a “NanoSwitch” that can activate CAR‐T cells at the tumor site, addressing safety issues with CAR‐T therapy regardless of the target. 23 In this study, a “universal” TCR‐T‐cell therapy was developed by modifying tumor cell antigens externally. The universal TCR‐T therapy can enable tumor cells to be identified and killed by TCR‐T cells regardless of antigen expression, tumor HLA typing, or TCR‐T type.…”

“…Sun and his team were the first to develop a universal CAR‐T‐cell therapy that targets antigens, using a nanosystem that fuses with cells 22 . In Wang's research, gelatinase‐responsive NPs were used to create a “NanoSwitch” that can activate CAR‐T cells at the tumor site, addressing safety issues with CAR‐T therapy regardless of the target 23 . In this study, a “universal” TCR‐T‐cell therapy was developed by modifying tumor cell antigens externally.…”

Recent advances in biomaterial designs for assisting CAR-T cell therapy towards potential solid tumor treatment

“…Reproduced with permission. 125 Copyright 2023, John Wiley and Sons. (B) The F-AgNP modified exogenous antigens onto the tumor cell membranes, which provided sufficient targets for CAR-T cell recognition, enabling CAR-T cell to exert antitumor effects independent of tumor inherent antigen profiles.…”

“…6A). 125 Sun et al found that it is possible to load exogenous antigens onto nanoparticles (F-AgNPs). The F-AgNPs modify exogenous antigens to tumor cell membranes via membrane fusion.…”