CAR T cells targeting αvβ3 integrin are effective against advanced cancer in preclinical models. Issue 2 (10th July 2018)

• Record Type: Journal Article
• Authors: Wallstabe, Lars; Mades, Andreas; Frenz, Silke; Einsele, Hermann; Rader, Christoph; Hudecek, Michael
• Is Part Of: Advances in cell and gene therapy. Volume 1:Issue 2(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-07-10
• Subjects: cancer immunotherapy -- chimeric antigen receptor (CAR) -- hLM609 -- integrin αvβ3 -- melanoma; Cellular therapy -- Periodicals; Gene therapy -- Periodicals; Immunotherapy -- Periodicals; Cancer -- Treatment -- Periodicals; Bone marrow -- Diseases -- Treatment -- Periodicals; Blood -- Diseases -- Treatment -- Periodicals; 615.5
• DOI: 10.1002/acg2.11
• Languages: English
• ISSNs: 2573-8461

Abstract

Abstract: Integrins are heterodimeric receptors that convey cell‐to‐cell and cell‐to‐matrix interactions. Integrin αv β3 is expressed in several tumor entities including melanoma, glioblastoma, breast, pancreatic, and prostate cancer, where it promotes tumor cell survival and metastasis. Here, we generated αv β3 ‐specific chimeric antigen receptor (CAR) T cells and analyzed their antitumor function in preclinical models in vitro and in vivo. αv β3 ‐CARs comprising a super‐humanized 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. αv β3 ‐CAR T cells eliminated αv β3 ‐positive tumor cells rapidly and specifically, produced IFN‐γ and IL‐2 (CD4 + > CD8 + ) and exhibited productive proliferation. In vitro, we observed the strongest reactivity with the higher affinity hLM609v7 αv β3 ‐CAR in the short spacer configuration, consistent with the tumor membrane‐distal localization of the hLM609 epitope. In a murine xenograft model of metastatic A‐375 melanoma, the strongest antitumor effect was mediated by the lower affinity hLM609v11 αv β3 ‐CAR. Notably, a single administration of hLM609v11 αv β3 ‐CAR T cells was able to induce complete elimination of melanoma lesions, leading to long‐term tumor‐free survival. These data establish αv β3 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. αv β3 ‐CAR T cells have therapeutic potential in several prevalent solid tumors, including melanoma and triple‐negative breast cancer.