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Delivery of CAR-T cells in a transient injectable stimulatory hydrogel niche improves treatment of solid tumors.

ABSTRACT: Adoptive cell therapy (ACT) has proven to be highly effective in treating blood cancers, but traditional approaches to ACT are poorly effective in treating solid tumors observed clinically. Novel delivery methods for therapeutic cells have shown promise for treatment of solid tumors when compared with standard intravenous administration methods, but the few reported approaches leverage biomaterials that are complex to manufacture and have primarily demonstrated applicability following tumor resection or in immune-privileged tissues. Here, we engineer simple-to-implement injectable hydrogels for the controlled co-delivery of CAR-T cells and stimulatory cytokines that improve treatment of solid tumors. The unique architecture of this material simultaneously inhibits passive diffusion of entrapped cytokines and permits active motility of entrapped cells to enable long-term retention, viability, and activation of CAR-T cells. The generation of a transient inflammatory niche following administration affords sustained exposure of CAR-T cells, induces a tumor-reactive CAR-T phenotype, and improves efficacy of treatment.

SUBMITTER: Grosskopf AK

PROVIDER: S-EPMC8993118 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Delivery of CAR-T cells in a transient injectable stimulatory hydrogel niche improves treatment of solid tumors.

Grosskopf Abigail K AK Labanieh Louai L Klysz Dorota D DD Roth Gillie A GA Xu Peng P Adebowale Omokolade O Gale Emily C EC Jons Carolyn K CK Klich John H JH Yan Jerry J Maikawa Caitlin L CL Correa Santiago S Ou Ben S BS d'Aquino Andrea I AI Cochran Jennifer R JR Chaudhuri Ovijit O Mackall Crystal L CL Appel Eric A EA

Science advances 20220408 14

Adoptive cell therapy (ACT) has proven to be highly effective in treating blood cancers, but traditional approaches to ACT are poorly effective in treating solid tumors observed clinically. Novel delivery methods for therapeutic cells have shown promise for treatment of solid tumors when compared with standard intravenous administration methods, but the few reported approaches leverage biomaterials that are complex to manufacture and have primarily demonstrated applicability following tumor rese ...[more]

PMID: 35394838

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Project description: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.

Dataset Information

Delivery of CAR-T cells in a transient injectable stimulatory hydrogel niche improves treatment of solid tumors.

Publications

Delivery of CAR-T cells in a transient injectable stimulatory hydrogel niche improves treatment of solid tumors.

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