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Targeting of Aberrant ?v?6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells.

ABSTRACT: Expression of the ?v?6 integrin is upregulated in several solid tumors. In contrast, physiologic expression of this epithelial-specific integrin is restricted to development and epithelial re-modeling. Here, we describe, for the first time, the development of a chimeric antigen receptor (CAR) that couples the recognition of this integrin to the delivery of potent therapeutic activity in a diverse repertoire of solid tumor models. Highly selective targeting ?v?6 was achieved using a foot and mouth disease virus-derived A20 peptide, coupled to a fused CD28+CD3 endodomain. To achieve selective expansion of CAR T cells ex vivo, an IL-4-responsive fusion gene (4??) was co-expressed, which delivers a selective mitogenic signal to engineered T cells only. In vivo efficacy was demonstrated in mice with established ovarian, breast, and pancreatic tumor xenografts, all of which express ?v?6 at intermediate to high levels. SCID beige mice were used for these studies because they are susceptible to cytokine release syndrome, unlike more immune-compromised strains. Nonetheless, although the CAR also engages mouse ?v?6, mild and reversible toxicity was only observed when supra-therapeutic doses of CAR T cells were administered parenterally. These data support the clinical evaluation of ?v?6 re-targeted CAR T cell immunotherapy in solid tumors that express this integrin.

SUBMITTER: Whilding LM

PROVIDER: S-EPMC5261028 | BioStudies | 2017-01-01

REPOSITORIES: biostudies

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