To address resistance that occurs in the majority of advanced HER2+ breast cancer following trastuzumab therapy, Upton et al. evaluated trastuzumab combined with macrophage checkpoint immunotherapy. Inhibition of CD47, which functions as a “don’t eat me” signal and is expressed in many malignancies, by Hu5F9-G4 (magrolimab) stimulated antibody-dependent cellular phagocytosis (ADCP) by macrophages. A trastuzumab and magrolimab combination was evaluated in trastuzumab-resistant, ADCC-tolerant Her2+ tumor models, resulting in Fc-dependent macrophage phagocytosis, superior efficacy, and increased survival.
Contributed by Katherine Turner
ABSTRACT: Trastuzumab, a targeted anti-human epidermal-growth-factor receptor-2 (HER2) monoclonal antibody, represents a mainstay in the treatment of HER2-positive (HER2(+)) breast cancer. Although trastuzumab treatment is highly efficacious for early-stage HER2(+) breast cancer, the majority of advanced-stage HER2(+) breast cancer patients who initially respond to trastuzumab acquire resistance to treatment and relapse, despite persistence of HER2 gene amplification/overexpression. Here, we sought to leverage HER2 overexpression to engage antibody-dependent cellular phagocytosis (ADCP) through a combination of trastuzumab and anti-CD47 macrophage checkpoint immunotherapy. We have previously shown that blockade of CD47, a surface protein expressed by many malignancies (including HER2(+) breast cancer), is an effective anticancer therapy. CD47 functions as a "don't eat me" signal through its interaction with signal regulatory protein-_ (SIRP_) on macrophages to inhibit phagocytosis. Hu5F9-G4 (magrolimab), a humanized monoclonal antibody against CD47, blocks CD47's "don't eat me" signal, thereby facilitating macrophage-mediated phagocytosis. Preclinical studies have shown that combining Hu5F9-G4 with tumor-targeting antibodies, such as rituximab, further enhances Hu5F9-G4's anticancer effects via ADCP. Clinical trials have additionally demonstrated that Hu5F9-G4, in combination with rituximab, produced objective responses in patients whose diffuse large B cell lymphomas had developed resistance to rituximab and chemotherapy. These studies led us to hypothesize that combining Hu5F9-G4 with trastuzumab would produce an anticancer effect in antibody-dependent cellular cytotoxicity (ADCC)-tolerant HER2(+) breast cancer. This combination significantly suppressed the growth of ADCC-tolerant HER2(+) breast cancers via Fc-dependent ADCP. Our study demonstrates that combining trastuzumab and Hu5F9-G4 represents a potential new treatment option for HER2(+) breast cancer patients, even for patients whose tumors have progressed after trastuzumab.
Author Info: (1) Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research, Stanford University, Stanford, CA 94305. (2) Institute for Stem Cell Bio
Author Info: (1) Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research, Stanford University, Stanford, CA 94305. (2) Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research, Stanford University, Stanford, CA 94305. (3) Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research, Stanford University, Stanford, CA 94305. (4) Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research, Stanford University, Stanford, CA 94305. (5) Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research, Stanford University, Stanford, CA 94305. (6) Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research, Stanford University, Stanford, CA 94305. (7) Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research, Stanford University, Stanford, CA 94305. (8) Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research, Stanford University, Stanford, CA 94305. (9) The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Regenerative Medicine and Stem Cell Research Center, Ben Gurion University of the Negev, 84105 Beer Sheva, Israel. (10) Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research, Stanford University, Stanford, CA 94305. (11) Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research, Stanford University, Stanford, CA 94305. (12) Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research, Stanford University, Stanford, CA 94305. (13) Department of Medicine-Med/Oncology, Stanford Cancer Institute, Stanford University, Stanford, CA 94305 mpegram@stanford.edu irv@stanford.edu. (14) Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research, Stanford University, Stanford, CA 94305; mpegram@stanford.edu irv@stanford.edu.
