CAR T cells targeting αβ integrin are effective against advanced cancer in preclinical models.

Objective: Integrins are heterodimeric receptors that convey cell-to-cell and cell-to-matrix interactions. Integrin αβ 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 αβ-specific chimeric antigen receptor (CAR) T-cells and analysed their antitumour function in pre-clinical models and .

Methods: αβ-CARs comprising a super-humanised hLM609 targeting domain with either high or low affinity (hLM609v7, = 3 nM vs. hLM609v11, = 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: αβ-CAR T-cells eliminated αβ-positive tumour cells rapidly and specifically, produced IFN-γ and IL-2 (CD4 > CD8) and exhibited productive proliferation. , we observed the strongest reactivity with the higher-affinity hLM609v7 αβ-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 αβ-CAR. Notably, a single administration of hLM609v11 αβ-CAR T-cells was able to induce complete elimination of melanoma lesions, leading to long-term tumour-free survival.

Conclusions: These data establish αβ 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: αβ-CAR T-cells have therapeutic potential in several prevalent solid tumours, including melanoma and triple-negative breast cancer.