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Toroidal-spiral particles as a CAR-T cell delivery device for solid tumor immunotherapy.

ABSTRACT: Chimeric antigen receptor (CAR) T cell therapy has resulted in positive effects on patients with hematologic malignancy but shows limited efficacy in solid tumor treatments due to insufficient trafficking and tumor infiltration, intensive CAR-T-related toxicities, and antigen escape. In this work, we developed and investigated a biodegradable and biocompatible polymeric toroidal-spiral particle (TSP) as a in vivo cell incubator and delivery device that can be implanted near tumor through a minimally invasive procedure or injected near or into solid tumors by using a biopsy needle. The main matrix structure of the millimeter-sized TSP is made from crosslinking of gelatin methacrylamine (GelMA) and poly (ethylene glycol) diacrylate (PEGDA) with a tunable degradation rate from a few days to months, providing appropriate mechanical properties and sustained release of co-encapsulated drugs and/or stimulation compounds. The toroidal-spiral layer of the particles, presenting an internal void volume for high-capacity cell loading and flexibility of co-encapsulating small and large molecular compounds with individually manipulated release schedules, is filled with collagen and suspended T cells. The TSPs promote cell proliferation, activation, and migration in the tumor micro-environment in a prolonged and sustained manner. In this study, the efficacy of mesothelin (MSLN) CAR-T cells released from the TSPs was tested in preclinical mouse tumor models. Compared to systemic and intratumoral injection, peritumoral delivery of MSLN CAR-T cells using the TSPs resulted in a superior antitumor effect. The TSPs made of FDA approved materials as an in vivo reactor may provide an option for efficiently local delivery of CAR-T cells to solid tumors for higher efficacy and lower toxicity, with a minimally invasive administration procedure.

SUBMITTER: Tang H

PROVIDER: S-EPMC10947521 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Toroidal-spiral particles as a CAR-T cell delivery device for solid tumor immunotherapy.

Tang Hui H Zaroudi Maryam M Zhu Yuli Y Cheng Alex A Qin Lei L Zhang Bin B Liu Ying Y

Journal of controlled release : official journal of the Controlled Release Society 20230912

Chimeric antigen receptor (CAR) T cell therapy has resulted in positive effects on patients with hematologic malignancy but shows limited efficacy in solid tumor treatments due to insufficient trafficking and tumor infiltration, intensive CAR-T-related toxicities, and antigen escape. In this work, we developed and investigated a biodegradable and biocompatible polymeric toroidal-spiral particle (TSP) as a in vivo cell incubator and delivery device that can be implanted near tumor through a minim ...[more]

PMID: 37673306

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Project description:IntroductionCAR-T cell therapy, though successful in hematologic malignancies, faces challenges in solid tumors due to limitations of autologous T cells. Cytokine-induced killer (CIK) cells can be given safely across allogeneic barriers and constitute alternative effector cells generated from healthy donors. CIK cells are a heterogenous population of predominantly T cells with a mixed natural killer (NK) phenotype and combine non-MHC-restricted cytotoxicity with potent anti-tumor capacity of the adaptive immune system. Here, we characterize and compare efficacy, phenotypic subpopulations and modes of action of CAR-CIK cells and conventional CAR-T cells from same-donor samples in ErbB2+ rhabdomyosarcoma (RMS).MethodsTo benchmark CAR-CIK against conventional CAR-T cells, effector cells were generated from same-donor samples and lentivirally transduced with a second generation CD28-CD3ζ CAR. Effector subpopulations and their dynamics upon target cell exposure were phenotypically characterized by flow cytometry. Efficacy was assessed in human ErbB2+ RMS cancer cell lines and primary patient samples in vitro and ex vivo using cytotoxicity and spheroid co-incubation assays. Modes of action were assessed by comparing cytokine secretion profiles using bead-based multiplexed flow cytometry and by liquid chromatography mass spectrometry whole cell proteomics. Finally, we used an in vivo model of RMS mimicking minimal metastatic residual disease to compare anti-tumor potency of CAR-CIK vs. CAR-T cells and to assess their target organ infiltration.ResultsIn vitro assays demonstrated superior cytotoxicity of CAR-CIK cells against RMS cell lines and primary tumor samples. Long-term co-incubation with tumor spheroids led to expansion of CAR-CIK cells and enrichment of CD3+CD56+ TNK cells. CAR-CIK cell cytokine signature showed significantly increased secretion of effector molecules like interferon-γ, perforin and granulysin, and lower secretion of Th2 cytokines IL-2, IL-4 and IL-10. Whole cell proteomics showed corresponding upregulation of chemokine signaling and NK-cytotoxicity pathways in CAR-CIK cells. In NSG mice xenografted with ErbB2+ RMS, a single injection of either CAR-effector cells strongly impeded metastatic tumor development and significantly improved survival.ConclusionOur results demonstrate that CAR-CIK cells are at least equipotent to CAR-T cells. Combined with their favorable safety profile and allogeneic applicability, these findings position CAR-CIK cells as promising immune effectors for solid tumors.

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Toroidal-spiral particles as a CAR-T cell delivery device for solid tumor immunotherapy.

Publications

Toroidal-spiral particles as a CAR-T cell delivery device for solid tumor immunotherapy.

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