CD47 and PD-1 blockade: a new cutting edge COMBI approach to simultaneously stimulate macrophages and re-activate T cell-mediated destruction of highly aggressive metastatic breast tumors

Immune checkpoint-based cancer immunotherapy (ICBCI) revolution has just started. Despite the exciting and encouraging clinical responses, the majority of the ICBCI treated patients have partial objective responses. ICBCI’s are still in its infancy for breast cancer. PD-1/PD-L1 inhibitors induce response rates of 19% in triple-negative breast cancer (TNBC) patients heavily pretreated, developed chemotherapy resistant and dysplayed PD-L1–positive phenotype. This weak response rate clearly indicates that the majority of TNBC patients (81%) with PD-L1-positive expression are completely refractory to ICBCI’s most likely due to tumor adaptation to both innate and adaptive immunity, thus circumventing both macrophage and T lymphocyte-mediated recognition and eradication. Very recently, we reported that EMT activated breast cancer cells escape both innate (macrophage- and DC-mediated) and adaptive (CTL-mediated)immune surveillance and elimination due to up regulated CD47 and PD-L1 respectively. Hence, in addition to promoting immune evasion and immune suppression, we believe that EMT also contributes to fostering resistance to ICBCI’s (both CD47 and PD-1). During this project, we will develop a novel cutting edge preclinical combination immunotherapy (COMBI) based on simultaneous CD47 and PD-1 blockade to boost ICBCI. Combination therapy with anti-CD47 represents a rational candidate approach to extend the clinical benefit of the CTLA-4, PD-1, or PD-L1 blockades as single agents. Such a COMBI will simultaneously reactivate both innate (macrophage checkpoint CD47) and adaptive immunity (T-lymphocyte checkpoint PD-1) and ultimately provide more frequent and long lasting durable responses in breast cancer patients with highly aggressive, mesenchymal, and metastatic tumors.