Background

CD47 interaction with SIRPɑ acts as a “do not eat me” signal, which is exploited by cancer cells to downregulate immune surveillance. Given mounting evidence regarding the pivotal role of this axis in bridging the innate and adaptive immunity, there has been intense interest to develop a mechanism of blockade for therapeutic purposes. Preliminary data from clinical trials are now being reported, and we aimed to summarize and analyze these findings.

Methods

We performed a comprehensive systematic review of relevant databases and conference abstracts. Eligible studies included clinical trials using CD47 and/or SIRPɑ inhibitors in cancer treatment reporting oncologic outcome or toxicity data. Nonlinear mixed models were applied for comparison of response, with study as a random effect.

Results

We retrieved 317 articles, 24 of which were eligible. These included a total of 771 response-evaluable patients with hematologic (47.1%) and solid tumors (52.9%). Of these, 6.4% experienced complete response, 10.4% partial response, and 26.1% stable disease for a 16.7% objective response rate (ORR), 42.8% disease control rate (DCR), and 4.8-month median duration of response (table 1). ORR was significantly higher for hematologic cancers (25.3%) than solid cancers (9.1%, p=0.042). Seven CD47 inhibitors and six SIRPɑ inhibitors were given alone or combined with checkpoint inhibitors, targeted therapy, and/or chemotherapy. In solid cancers, SIRPɑ inhibitors had a higher ORR (16.2%) than CD47 inhibitors (2.8%, p=0.079). This was particularly true for combination therapies using SIRPɑ inhibitors (ORR 28.3% vs 3.0% in CD47 inhibitors, p=0.010). Response was seen in head and neck, colorectal, endometrial, ovarian, hepatocellular, non-small cell lung, and HER2+ gastroesophageal cancers. Dose-limiting toxicity (DLT) was seen in 3.3% of patients (5.4% CD47 inhibitors, 1.4% SIRPɑ inhibitors; p=0.01). The frequency of treatment-related adverse events(TRAEs) ≥ grade 3 was 18.0% and was similar between the two groups (p=0.082) and mostly laboratory abnormalities. For CD47 inhibitors, the most common toxicities included grade 1-2 fatigue (27.2%), headache (21.0%), anemia (20.5%), and infusion-related reaction (IRR, 17.6%). For SIRPɑ inhibitors, these included grade 1-2 IRR (23.1%), and fatigue (15.8%). CD47 inhibitors were significantly more likely than SIRPɑ inhibitors to cause grade 1-2 fever, chills, nausea/vomiting, headache, and anemia.

Conclusions

CD47-SIRPɑ inhibition shows promise in cancer therapy. SIRPɑ inhibitor combination therapies have higher response rates in solid tumors than CD47 inhibitor combination therapies. Hematologic changes were the main TRAEs, and SIRPɑ inhibitors seemed to have a better grade 1-2 toxicity profile. Overall, treatment was well-tolerated with minimal DLTs.