Background: DSP107 is a bi-functional fusion protein composed of sequences from the extracellular domain of SIRPα and 4-1BB ligand (4-1BBL). The SIRPα arm targets CD47 overexpressed on tumor cells, blocking the “don’t eat me” checkpoint and anchoring trimeric 4-1BBL to the tumor, which interacts with 4-1BB expressed on activated immune cells. This results in proliferation and conditional activation of effector cytotoxic T-cells in the tumor microenvironment. Thereby, DSP107 triggers both innate and adaptive immune responses. Phase 1 monotherapy dose escalation data demonstrated an excellent safety profile with no binding to red blood cells and no dose limiting toxicities (DLTs), hematological or hepato-toxicities. Here we describe data from the completed DSP107 plus atezolizumab combination dose escalation portion of study NCT04440735. Methods: Adult patients with advanced solid tumors were treated with weekly intravenous DSP107 infusions (1, 3 or 10 mg/kg; N = 6-7 patients/dose cohort) and atezolizumab (1200 mg) Q3W during 3-week treatment cycles. The primary objective was to determine the safety and tolerability of DSP107 in combination with atezolizumab. Restaging imaging was performed every two months and evaluated by RECIST v1.1 criteria. Results: In 19 patients, DSP107 with atezolizumab was well tolerated with no DLTs. Grade 1-2 treatment related adverse events (AEs) were observed in 68% of patients (13/19). The most frequent AEs included diarrhea (21%), fatigue (21%), infusion related reaction (IRR; 16%), nausea, decreased appetite, arthralgia, myalgia and Grade 1 anemia (11% each). IRRs were managed during subsequent infusions by reducing the infusion rate and administering IV fluids. Stable disease (SD) as best response was observed in 8/19 (42%) patients with treatment duration currently up to 10.5 months. At the highest dose of DSP107 (10 mg/kg), 3/7 patients had SD (1 microsatellite stable-colorectal cancer (MSS-CRC) patient with KRAS mutation had 16% target lesion shrinkage and no progression for 7 months). An additional 2 patients with advanced MSS-CRC (with BRAF and KRAS mutations, respectively) demonstrated deep and durable responses (-73 and -76% reduction in target lesions) including disappearance of pulmonary and hepatic target lesions in one patient. These patients currently continue to receive treatment after > 8 and > 6 months, respectively. Conclusions: DSP107 is a novel, CD47 and 4-1BB targeting fusion protein with a differentiated safety, binding and pharmacodynamic profile compared to other CD47 and 4-1BB targeting agents. These Phase 1 data suggest that the combination of DSP107 with PD(L)1 blockade may have anti-tumor activity in cold tumors such as MSS-CRC. Clinical trial information: NCT04440735.