Injectable Supramolecular Hydrogels for in Situ Programming of Car-T Cells Towards Solid Tumor Immunotherapy.

Chimeric antigen receptor (CAR)-T cell immunotherapy has been approved in the treatment of hematological malignancies, but remains far from satisfaction in solid tumor treatment due to inadequate intra-tumor CAR-T cell infiltration. Herein, an injectable supramolecular hydrogel system, based on self-assembly between cationic polymer mPEG-PCL-PEI (PPP) conjugated with T cell targeting anti-CD3e f(ab')2 fragment and α-cyclodextrin (α-CD), has been designed to load plasmid CAR (pCAR) with T cell specific CD2 promoter, which successfully achieved in situ fabrication and effective accumulation of CAR-T cells at the tumor site in humanized mice models. More importantly, due to this tumor microenvironment reprogramming, secretion of cellular inflammatory cytokines (IL-2, TNF-α, and IFN-γ) or tumor killer protein granzyme B was significantly promoted, which reversed the immunosuppressive microenvironment and significantly enhanced the intra-tumor CAR-T cells and cytotoxic T cells infiltration. To the best of our knowledge, this is a pioneer report of using injectable supramolecular hydrogel for in situ reprogramming CAR-T cells, which might be beneficial for solid tumor CAR-T immunotherapy. This article is protected by copyright. All rights reserved.