Combining CD47 blockade with trastuzumab eliminates HER2-positive breast cancer cells and overcomes trastuzumab tolerance
Rosalynd Upton, Allison Banuelos, Dongdong Feng, Tanuka Biswas, Kevin S. Kao, Kelly M. McKenna, Stephen B. Willingham, Po Y. Ho, Benyamin Rosental, Michal Caspi Tal, Tal Raveh, Jens-Peter Volkmer, Mark D. Pegram, Irving L. Weissman
Abstract
Significance This study demonstrates the efficacy of combining macrophage-checkpoint inhibition with tumor-specific antibodies for cancer immunotherapy. The combination of anti-CD47 (magrolimab) and anti-HER2 (trastuzumab) antibodies eliminated HER2 + breast cancer cells with increased efficacy due to the enhancement of antibody-dependent cellular phagocytosis by macrophages, even when the cancer cells were tolerant to trastuzumab-induced antibody-dependent cellular cytotoxicity by natural killer cells. We believe these findings present a promising therapeutic approach for treating HER2 + breast cancer patients whose tumors are either sensitive or resistant to trastuzumab treatment, as long as the cells harbor the HER2 trastuzumab-binding epitope. This study supports the notion that combining CD47 blockade with existing macrophage FcR-engaging tumor-specific antibodies may be an effective approach for treating a wide range of cancers.