Supramolecular peptide hydrogel epitope vaccine functionalized with CAR-T cells for the treatment of solid tumors

Chimeric antigen receptor T-cell (CAR-T) therapy, which benefits from the perfect combination of gene editing techniques and antibody engineering, has shown outstanding clinical efficacy in hematological malignancies. Solid tumors present the next challenge due to their extremely complicated microenvironment and structural characteristics. Targeting efficiency and persistence are currently bottleneck issues in the clinical treatment of CAR-T. Beyond drugs and cytokines, biomaterials can modulate the immune response, assisting adoptive CAR-T cells in exerting their function. In this study, a supramolecular peptide hydrogel epitope vaccine was designed to serve as both a preparation medium and a reservoir for CAR-T cells. The self-assembling peptide formed a nanofiber scaffold through non-covalent interactions of amphiphilic amino acids and ion stabilizers. Firstly, the complementary peptide conjugated vaccine epitopes and CAR-T target sites were derived from different extracellular domains of the HER2 protein, and the combination treatment improved tumor antigen spreading and targeting efficiency. The epitope hydrogel promoted CAR-T cell proliferation, cytotoxic activity, and lymphocyte subpopulation transformation. Furthermore, the supramolecular peptide epitope vaccine encapsulated CAR-T (SPEV-CAR-T) induced endogenous humoral and cellular immune responses through a sustained release of the hydrogel and CAR-T cells, demonstrating superior anti-tumor effects in an in vivo mouse model. Most importantly, SPEV-CAR-T induced central memory cells in systemic immune tissues, addressing the poor persistence of single CAR-T therapy. The integration and complementation of active and passive immune responses in this all-in-one hydrogel epitope vaccine and CAR-T system facilitated a sequential succession of endogenous and exogenous immune responses, promoting persistent and specific tumor attack. SPEV-CAR-T showed superior therapeutic effects in solid tumors.