SUN-292 - IGF1R-specific natural killer cell directed therapeutic strategy kills hormone receptor positive breast cancers in vivo.

Patients with hormone receptor-positive (HR+) breast cancers recur with metastases 5-20 years after diagnosis and completion of chemotherapy or prolonged endocrine therapy. 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 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. The type I IGF receptor (IGF1R), a cell surface receptor tyrosine, is expressed on HR+ breast cancers and its expression is tightly related to estrogen receptor (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 a humanized single domain antibody (sd) sequence of a CD16 nanobody to engage NK cells, a humanized sd sequence of a nanobody against IGF1R to target HR+ cells, and an IL-15 molecule between to drive NK expansion and survival. We previously showed that the IGF1R TriKE degranulated NK cells against multiple IGF1R+ HR+ breast cancer cell lines (MCF-7L, T47D and ZR-75-1).

Herein, we investigated the effect of IGF1R TriKE on tumor growth of estrogen-stimulated proliferating and quiescence tumors . Female NSG mice bearing MCF-7L tumors supplemented with 17-beta-estradiol (E2) were randomized to the following cohorts: control with no human NK (huNK) cells, 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 (p < 0.0001) 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 the TriKE cohort by huCD45 staining. The TriKE also inhibited growth of IGF1R+ patient-derived xenografts (PDX UCD4] but did not affect growth of IGF1R negative PDX tumor (HCI-003) in vivo. To test the effect in a quiescent model, 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 a week later mice were randomized to the same treatment groups as above. IGF1R TriKE significantly killed quiescent tumor cells compared to control (p < 0.0001) and IL-15 groups. Further Ki67 positivity in tumors treated with the TriKE was significantly lower than the control group.

Our data suggest that the IGF1R TriKE kills rapidly proliferating and quiescent breast cancers and could be a potential approach to eliminate slow growing cells in HR+ patients.

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