CAR T cells targeting ?v?3 integrin are effective against advanced cancer in preclinical models.

ABSTRACT: Objective:Integrins are heterodimeric receptors that convey cell-to-cell and cell-to-matrix interactions. Integrin ?v?3 is expressed in several tumour entities including melanoma, glioblastoma, breast, pancreatic and prostate cancer, where it promotes tumour cell survival and metastasis. Here, we generated ?v?3-specific chimeric antigen receptor (CAR) T-cells and analysed their antitumour function in pre-clinical models in vitro and in vivo. Methods:?v?3-CARs comprising a super-humanised hLM609 targeting domain with either high or low affinity (hLM609v7, K d = 3 nM vs. hLM609v11, K d = 160 nM) and equipped with either a long or a short IgG4-Fc extracellular spacer (229 vs. 12 amino acids) were expressed in CD8+ and CD4+ T-cells through lentiviral transduction. Results:?v?3-CAR T-cells eliminated ?v?3-positive tumour cells rapidly and specifically, produced IFN-? and IL-2 (CD4+ > CD8+) and exhibited productive proliferation. In vitro, we observed the strongest reactivity with the higher-affinity hLM609v7 ?v?3-CAR in the short spacer configuration, consistent with the tumour membrane-distal localization of the hLM609 epitope. In a murine xenograft model of metastatic A-375 melanoma, the strongest antitumour effect was mediated by the lower-affinity hLM609v11 ?v?3-CAR. Notably, a single administration of hLM609v11 ?v?3-CAR T-cells was able to induce complete elimination of melanoma lesions, leading to long-term tumour-free survival. Conclusions:These data establish ?v?3 integrin as a novel target for CAR T-cell immunotherapy, and affirm our previous notion that binding domain affinity and spacer length can be calibrated to augment CAR reactivity. Clinical implications:?v?3-CAR T-cells have therapeutic potential in several prevalent solid tumours, including melanoma and triple-negative breast cancer.

SUBMITTER: Wallstabe L 

PROVIDER: S-EPMC6226260 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature