Galectin-3 inhibition using novel inhibitor GR-MD-02 improves survival and immune function while reducing tumor vasculature

Abstract

Abstract Immunosuppression and reduced cytotoxic function of tumor-infiltrating lymphocytes (TIL) are major obstacles to creating effective therapies for patients. It is known that Galectin-3 (Gal3), a lectin family member, is expressed and secreted by numerous cancers and immune cell subsets. Serum Gal3 expression is higher in patients with metastatic versus non-metastatic disease, and is associated with reduced survival in metastatic melanoma. Furthermore, Gal3 has been implicated in disease progression via the promotion of angiogenesis and metastasis, the inhibition of TIL function, and promoting M2 polarization of macrophages and mobilization of myeloid cells from the bone marrow to promote a metastatic niche within the tumor. We hypothesized that Gal3 inhibition would improve TIL function while inhibiting the growth and metastasis of tumors. Through collaboration with Galectin Therapeutics, we tested Gal3 inhibition using the novel Gal3 inhibitor, GR-MD-02, with agonist anti-OX40 therapy. We observed that Gal3 inhibition/OX40 agonism improved survival in the MCA-205 sarcoma and 4T-1 mammary carcinoma models, and prolonged survival in the TRAMP-C1 prostate cancer model. Importantly, Gal3 inhibition/OX40 agonism reduced lung metastases in the 4T-1 model. Within the tumor, we observed an increase in the number of proliferating and IFNg-producing TIL. Gal3 inhibition/OX40 agonism was also associated with a decrease in tumor vasculature, as determined by CD31 staining by IHC within the tumors. These studies, along with clinical data from a liver fibrosis trial, supported testing GR-MD-02 in combination with additional immunotherapies to augment T cell function in patients with metastatic melanoma.