CD47-SIRPα interaction acts as a \"don\'t eat me\" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense interest to develop a mechanism of blockade, and we aimed to analyze the emerging data from early clinical trials. We performed a systematic review and meta-analysis of relevant databases and conference abstracts including clinical trials using CD47 and/or SIRPα inhibitors in cancer treatment. Nonlinear mixed models were applied for comparison of response and toxicity. We retrieved 317 articles, 24 of which were eligible. These included 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, and 4.8-month median duration of response. ORR was significantly higher for hematologic cancers (25.3%) than solid cancers (9.1%, p=0.042). Comparing by mechanism, seven CD47 monoclonal antibodies (mAbs) and six selective SIRPα blockers were given alone or combined with checkpoint inhibitors, targeted therapy, and/or chemotherapy. In solid cancers, selective SIRPα blockade showed a higher ORR (16.2%) than anti-CD47 mAbs (2.8%, p=0.079), which was significant for combination therapies (ORR 28.3% vs 3.0%, respectively, p=0.010). Responses were 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% anti-CD47 mAbs, 1.4% selective SIRPα blockers; p=0.01). The frequency of treatment-related adverse events (TRAEs) ≥grade 3 was 18.0%, similar between the two groups (p=0.082), and mostly laboratory abnormalities. For anti-CD47 mAbs, the most common toxicities included grade 1-2 fatigue (27.2%), headache (21.0%), and anemia (20.5%). For selective SIRPα blockers, these included grade 1-2 infusion reaction (23.1%) and fatigue (15.8%). Anti-CD47 mAbs were significantly more likely than selective SIRPα blockers to cause grade 1-2 fever, chills, nausea/vomiting, headache, and anemia. In conclusion, combination therapies using selective SIRPα blockade had higher response rates in solid tumors than anti-CD47 mAb combinations. Hematologic changes were the main TRAEs, and selective SIRPα blockers seemed to have a better grade 1-2 toxicity profile. Treatment was well-tolerated with minimal DLTs.

The mammalian immune system consists of two distinct arms, nonspecific innate and more specific adaptive, with the innate immune response as the first line of defense and protection, which primes and amplifies subsequent adaptive responses. On the basis of this binary immune interplay, stimulation of T cells through checkpoint inhibitors (CIs), which bypasses innate involvement, seems likely to engender suboptimal or incomplete anticancer immunity, given that the successful induction of effect or responses depends on two-way innate/adaptive coordination. Indeed, the majority of patients-70%-80%, do not respond to CIs, which is potentially problematic if access to more optimal standard therapies is withheld or delayed in favor of ineffective or only marginally effective anti-PD-1/PD-L1 treatment. Therefore, stimulation of the innate immune response in combination with CIs (or other inducers of T cell cytotoxicity) has the potential to make the immune system \"whole\" and thereby to enhance and broaden the anti-tumor activity of PD-1/PD-L1 inhibitors for example, in relatively nonimmunogenic or \"cold\" tumor types. A critical innate macrophage immune checkpoint and druggable target is the antiphagocytic and \"marker of self\" CD47-SIRPα pathway, which is co-opted by cancer cells to mediate escape from immune-mediated clearance and checkpoint inhibition. This review summarizes the status of key CD47 antagonists in clinical trials, including the biologics, Hu5F9-G4 (5F9), TTI-621, and ALX148, as well as the small molecule, RRx-001, now in a Phase 3 clinical trial, which has not been previously included in CD47-SIRPα reviews focused on biologics. Hu5F9-G4 (5F9), TTI-621, ALX148, and RRx-001 are chosen as compounds with potentially promising data that have advanced the farthest in clinical development.

Hematological malignancies express high levels of CD47 as a mechanism of immune evasion. CD47-SIRPα triggers a cascade of events that inhibit phagocytosis. Preclinical research supports several models of antibody-mediated blockade of CD47-SIRPα resulting in cell death signaling, phagocytosis of cells bearing stress signals, and priming of tumor-specific T cell responses. Four different antibody molecules designed to target the CD47-SIRPα interaction in malignancy are currently being studied in clinical trials: Hu5F9-G4, CC-90002, TTI-621, and ALX-148. Hu5F9-G4, a humanized anti-CD47 blocking antibody is currently being studied in four different Phase I trials. These studies may lay the groundwork for therapeutic bispecific antibodies. Bispecific antibody (CD20-CD47SL) fusion of anti-CD20 (Rituximab) and anti-CD47 also demonstrated a synergistic effect against lymphoma in preclinical models. This review summarizes the large body of preclinical evidence and emerging clinical data supporting the use of antibodies designed to target the CD47-SIRPα interaction in leukemia, lymphoma and multiple myeloma.

CD47 is a widely expressed cell membrane receptor belonging to the immunoglobulin (Ig) superfamily. CD47 is involved in a number of cellular processes, including proliferation, apoptosis, adhesion and migration through interacting with integrin, thrombospondins and SIRPα. CD47 also plays an important role in the immune system and homeostasis. In recent few years, numerous studies have demonstrated that targeting CD47 exhibits noticeable effects on inhibition of tumor growth and prevention of metastasis in various types of cancers, while the mechanisms is complicated. In this review, we stated three possible mechanisms of targeting CD47 for cancer treatment. First, blockade of CD47 interrupts the CD47-SIRPα pathway which helps cancer cells escape from phagocytosis by macrophages. Second, ligation of CD47 induces cancer cells apoptosis. Third, targeting CD47 improves the tumor microenvironment. We also described several prospective strategies that have been used for targeting CD47 in cancer therapy, including antibodies, miRNA/siRNA and recombinant protein, etc. In conclusion, CD47 is a promising cancer biomarker, and targeting CD47 presents an effective and potential therapeutic strategy through synthesized mechanisms.

Neutrophil-epithelial interactions were modelled using polarized T84 cells and ligands were identified through observations of beta2-integrin dependence in patients with chronic granulomatious disease. Interactions between neutrophils and the apical membrane of crypt cells were analysed using HPLC and an in vitro model with T84 monolayers colonized by Salmonella typhimurium was used to assess neutrophil movement across the epithelium. The decline in transepithelial resistance following movement of neutrophils across the epithelial monolayer may have been due to an interaction between neutrophils and ligand ICAM-1 in which the neutrophils move along the paracellular pathway of epithelial cells. Cell surface polarity may influence these neutrophil-epithelial interactions which influence Cl secretion. These studies revealed that only strains produced in vivo were able to induce neutrophil transmigration in the in vitro model and may be indicative of new progressive therapies for inflammatory bowel disease.