CD47 Is a Therapeutic Antibody Target in Leiomyosarcoma
Badreddin Edris, Kipp Weiskopf, Jens Volkmer, Stephen Willingham, Anne Volkmer, Jonathan Fletcher, Andrew Beck, Irv Weissman, Matt van de Rijn. Stanford University School of Medicine, Stanford, CA; Harvard Medical School, Boston, MA
Background: Leiomyosarcoma (LMS) is a neoplasm of smooth muscle for which limited therapeutic options exist. Tumor-associated macrophages (TAMs) can act as promoters of cancer progression; we have shown that in LMS a high density of TAMs is associated with poor patient outcome. CD47 is a transmembrane protein that is highly expressed on tumor cells and that binds to SIRPa on macrophages. The interaction between CD47 and SIRPa prevents macrophages from phagocytosing tumor cells. Inhibition of this interaction with CD47-specific monoclonal antibodies (mcAbs) allows phagocytosis to occur and decreases tumor burden in experimental models of leukemia and lymphoma.
Design: mRNA profiling and immunofluorescence staining for CD47 was performed on normal uterus, leiomyomas, and LMS samples. In vitro phagocytosis assays using 2 human LMS cell lines and human or mouse macrophages tested the ability of anti-CD47 mcAbs to enable phagocytosis of LMS cells. Xenotransplants of 2 human LMS cell lines in mice assessed the effect of anti-CD47 mcAbs on primary tumor growth. A model for neoadjuvant treatment was developed by starting anti-CD47 treatment one week prior to resection of primary subcutaneous LMS tumors and allowing mice to develop lymph node and lung metastases; the efficacy of anti-CD47 therapy was evaluated in this model.
Results: We show that CD47 is present on LMS tumor cells at a higher level than on benign leiomyomas and normal muscle, and that anti-CD47 mcAbs enable phagocytosis of 2 human LMS cell lines by human and mouse macrophages in vitro. Treatment with anti-CD47 mcAbs significantly inhibits primary tumor growth of 2 human LMS cell lines transplanted in mice. We developed a model for neoadjuvant therapy of LMS in which mice develop lymph node and lung metastases after resection of their primary tumors. In this model, anti-CD47 treatment increases recurrence-free survival and significantly diminishes the size and incidence of lymph node and lung metastases.
Conclusions: These results demonstrate that anti-CD47 mcAb therapy may be a promising treatment for LMS and that targeting CD47 on LMS cells has the potential to change the behavior of resident TAMs to inhibit, rather than promote, tumor growth.
Category: Bone & Soft Tissue
Monday, March 19, 2012 1:00 PM
Poster Session II # 24, Monday Afternoon