PROJECT SUMMARY Immune evasion is a hallmark of cancer. Various tumor immunotherapy treatments, such as immune checkpoint blockade and cancer vaccination, have been developed to overcome cancer’s ability to avoid immune detection and destruction; however, the result of these endeavors have not been satisfactory given a number of critical barriers. One of these barriers, and a prominent mechanism by which cancer evades immune surveillance and elimination, is through the cancer cell expressed CD47 to ligate SIRPα, an ITIMs-containing inhibitory signaling receptor expressed on macrophages, which serves as a negative regulator that inhibits macrophage phagocytosis, proinflammatory response and antigen presentation. In our studies, we discovered “Phago-Act”- a proprietary reagent that downregulates SIRPα expression and empowers SIRPα-deficient macrophages (SIRPαLow MØs) to be an initiator for triggering potent innate and adaptive anti-cancer immunity. Not only do they directly phagocytose cancer cells (“liquid”/non-adherent cancer in particular), but SIRPαLow MØs are also capable of conducting immunogenic antigen presentation to robustly activate tumor-specific cytotoxic T cells (Tc) with high tumoricidal activities, leading to rapid elimination of late-stage, large-size solid tumors with distal lesions (mimic metastases). The results of SIRPαLow MØs-initiated responses, which are especially effective in solid tumors, have been vetted extensively in various pre-clinical solid tumor models including cancers of pancreatic, colorectal, lung, breasts and skin (melanoma), all of which resist advanced anti-cancer therapies including immune checkpoint inhibitors and their combinations with RT and other modalities. Moreover, SIRPαLow MØs- induced tumor elimination also leads to long-lasting anti-cancer immunity that prevents recurrence. The goal of this fast-track STTR is to leverage these important research findings and to accelerate their translation to clinical implement of scalable SIRPαLow MØ-based immunotherapy – “SIRPant Technology” – to treat a broad spectrum of cancers and prevent relapse. Our current focus is Solid Tumors. In Phase I, we will extend current studies and establish reproducible protocols for producing human SIRPαLow MØ from PBMC (Aim I-1). Phase II is to fund specific IND-enabling CMC refinement (Aim II-1) and toxicology studies (Aim II-2) needed for a Phase I clinical trial, as well as patient applicable SIRPαLow MØs delivery strategies in combined with RT or/and immune checkpoint inhibitors (Aim II-3). (These discoveries and therapeutic developments are protected by our filed patents)