Abstract LB231: IGF1R targeted NK cell engager kills proliferating and quiescent hormone receptor positive breast cancers

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Abstract Patients with hormone receptor-positive (HR+) breast cancers frequently recur with metastatic disease 5-20 years after initial diagnosis and completion of chemotherapy and prolonged hormonal therapy treatment. A potential mechanism of resistance in HR+ patients is the presence of slow dividing or dormant well-differentiated cancer cells that result in clinically detectable metastases after a prolonged latency. One way to eliminate these is immunotherapy. The objective of this study is to target HR+ breast cancers using a natural killer (NK) cell based approach that targets cell surface receptors in HR+ breast cancer. The type I IGF receptor (IGF1R) is expressed on HR+ breast cancers and its expression is tightly related to ER function. We hypothesized that a drug targeting NK cells to IGF1R expressing HR+ breast cancer cells will be effective in killing them. We generated IGF1R specific Tri specific Killer Engagers (TriKE) that leverages expression of IGF1R on HR+ cells to cause NK cell directed cell death. The IGF1R TriKE consists of humanized single domain antibody (VHH) sequence of a CD16 nanobody to engage and activate NK cells, a humanized VHH sequence of a nanobody against IGF1R to target HR+ breast cancer cells, and an IL-15 molecule between them to drive NK cell expansion and survival. The IGF1R TriKE did not bind embryonal fibroblasts from IGF1R knock out mice (R- cells) but bound R-/IGF1R cells (R- cells engineered to express human IGF1R) and to IGF1R+ MCF-7 & T47D breast cancer cells indicating specific binding to IGF1R on cells. It did not cause downregulation of IGF1R levels or inhibit signaling via IGF1R in multiple HR+ breast cancer cells. It specifically induced human NK cell degranulation, measured by surface CD107a expression and intracellular IFNγ production, against IGF1R+ target breast cancer cells (MCF-7, T-47D, ZR-75-1) in a functional assay compared to the anti-IGF1R nanobody. It did not induce degranulation of NK cells against IGF1R negative cells suggesting that the functionality was specific for IGF1R positive targets. The TriKE enhanced cell killing of HR+ breast cancer cells as measured by cytotoxicity assays. We next investigated the effect of IGF1R TriKE on tumor growth of estrogen stimulated proliferating tumors and in a quiescence model of breast cancer. Female NSG mice bearing MCF-7L tumors supplemented with 17-β-estradiol (E2) were randomized to these cohorts: control with no human NK (huNK) cells, huNK cells+IL-15 and huNK cells+TriKE treatments. huNK cells were infused iv weekly and IL-15 or IGF1R TriKE thrice a week for 4 weeks. IGF1R TriKE inhibited estrogen-stimulated tumor growth in 3 independent experiments. Further, CD56+ huNK in blood of mice treated with the TriKE persisted for 3 weeks compared to IL-15 cohort and were also detected in tumor sections of TriKE cohort by huCD45 staining. To test the effect in a model of quiescence, female ovariectomized NSG mice were implanted with MCF-7L cells and given 17-beta-E2. When tumors were 150mm3, E2 was withdrawn to allow cells to become quiescent and two weeks later mice were randomized to same treatment groups as above. IGF1R TriKE significantly killed quiescent tumor cells compared to control and IL-15 groups. Our data suggest that IGF1R TriKE kills both proliferating and quiescent HR+ breast cancers and could be a potential approach to eliminate slow growing cells in HR+ patients. Citation Format: Courtney Baar, Emily Chiu, Yvette Soignier, Jeffrey Miller, Martin Felices, Deepali Sachdev. IGF1R targeted NK cell engager kills proliferating and quiescent hormone receptor positive breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB231.

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