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MSA2 affinity-enhanced biotin-binding CAR T cells for universal tumor targeting.

ABSTRACT: Chimeric antigen receptor T cells (CAR-Ts) are promising cancer therapeutics. However, since cancer cells can lose the CAR-targeted antigen and avoid destruction, targeting multiple antigens with multiple CARs has been proposed. We illustrate here a less cumbersome alternative, anti-tag CARs (AT-CARs) that bind to tags on tumor-targeting antibodies. We have created novel AT-CARs, using the affinity-enhanced monomeric streptavidin 2 (mSA2) biotin-binding domain that when expressed on T cells can target cancer cells coated with biotinylated antibodies. Human T cells expressing mSA2 CARs with CD28-CD3? and 4-1BB-CD3? signaling domains were activated by plate-immobilized biotin and by tumor cells coated with biotinylated antibodies against the tumor-associated antigens CD19 and CD20. Furthermore, mSA2 CAR T cells were capable of mediating cancer cell lysis and IFN? production in an antibody dose-dependent manner. The mSA2 CAR is a universal AT-CAR that can be combined with biotinylated tumor-specific antibodies to potentially target many different tumor types.

SUBMITTER: Lohmueller JJ

PROVIDER: S-EPMC5739565 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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mSA2 affinity-enhanced biotin-binding CAR T cells for universal tumor targeting.

Lohmueller Jason J JJ Ham James D JD Kvorjak Michael M Finn Olivera J OJ

Oncoimmunology 20171026 1

Chimeric antigen receptor T cells (CAR-Ts) are promising cancer therapeutics. However, since cancer cells can lose the CAR-targeted antigen and avoid destruction, targeting multiple antigens with multiple CARs has been proposed. We illustrate here a less cumbersome alternative, anti-tag CARs (AT-CARs) that bind to tags on tumor-targeting antibodies. We have created novel AT-CARs, using the affinity-enhanced monomeric streptavidin 2 (mSA2) biotin-binding domain that when expressed on T cells can ...[more]

PMID: 29296519

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Project description:Adoptive cell therapy based on chimeric antigen receptor (CAR)-engineered T-cells has proven to be lifesaving for many cancer patients. However, its therapeutic efficacy has so far been restricted to only a few malignancies, with solid tumors proving to be especially recalcitrant to efficient therapy. Poor intra-tumor infiltration by T cells and T cell dysfunction due to a desmoplastic, immunosuppressive microenvironment are key barriers for CAR T-cell success against solid tumors. Cancer-associated fibroblasts (CAFs) are critical components of the tumor stroma, evolving specifically within the tumor microenvironment (TME) in response to tumor cell cues. The CAF secretome is a significant contributor to the extracellular matrix and a plethora of cytokines and growth factors that induce immune suppression. Together they form a physical and chemical barrier which induces a T cell-excluding 'cold' TME. CAF depletion in stroma rich solid tumors can thus provide an opportunity to convert immune evasive tumors susceptible to tumor-antigen CAR T-cell cytotoxicity. Using our TALEN-based gene editing platform we engineered non-alloreactive, immune evasive CAR T-cells (termed UCAR T-cells) targeting the unique CAF marker Fibroblast Activation Protein, alpha (FAP). In an orthotopic mouse model of triple-negative breast cancer (TNBC) composed of patient derived-CAFs and tumor cells, we demonstrate the efficacy of our engineered FAP UCAR T-cells in CAF depletion, reduction of desmoplasia and successful tumor infiltration. Furthermore, while previously resistant, pre-treatment with FAP UCAR T-cells now sensitized these tumors to Mesothelin (Meso) UCAR T-cell infiltration and anti-tumor cytotoxicity. Combination therapy of FAP UCAR, Meso UCAR T cells and the checkpoint inhibitor anti-PD-1 significantly reduced tumor burden and prolonged mice survival. Our study thus proposes a novel treatment paradigm for successful CAR T-cell immunotherapy against stroma-rich solid tumors.

Dataset Information

MSA2 affinity-enhanced biotin-binding CAR T cells for universal tumor targeting.

Publications

mSA2 affinity-enhanced biotin-binding CAR T cells for universal tumor targeting.

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