CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.

Summary Monoclonal antibodies are standard therapeutics for several cancers including the anti-CD20 antibody rituximab for B cell non-Hodgkin lymphoma (NHL). Rituximab and other antibodies are not curative, and must be combined with cytotoxic chemotherapy for clinical benefit. Here we report the eradication of human NHL solely with a monoclonal antibody therapy combining rituximab with a blocking anti-CD47 antibody. We identified increased expression of CD47 on human NHL cells, and determined that higher CD47 expression independently predicted adverse clinical outcomes in multiple NHL subtypes. Blocking anti-CD47 antibodies preferentially enabled phagocytosis of NHL cells and synergized with rituximab. Treatment of human NHL-engrafted mice with anti-CD47 antibody reduced lymphoma burden and improved survival, while combination treatment with rituximab led to elimination of lymphoma and cure. These antibodies synergized through a mechanism combining Fc receptor (FcR)-dependent and FcR-independent stimulation of phagocytosis that might be applicable to many other cancers.

Summary Background Retrospective evidence indicates that disease progression after first-line chemotherapy for metastatic non-small cell lung cancer (NSCLC) occurs most often at sites of disease known to exist at baseline. However, the potential benefit of aggressive local consolidative therapy (LCT) on progression-free survival (PFS) for patients with oligometastatic NSCLC is unknown. Methods We conducted a multicenter randomized study (NCT01725165; currently ongoing but not recruiting participants) to assess the effect of LCT on progression-free survival ((PFS). Eligible patients hadwere (1) histologic confirmation of (2) stage IV NSCLC, (3) ≤3 disease sites after systemic therapy, and (4) no disease progression before randomization. Front line therapy was ≥4 cycles of platinum doublet therapy or ≥3 months of inhibitors of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) for patients with EGFR mutations or ALK rearrangements. Patients were randomized to either LCT ([chemo]radiation or resection of all lesions) +/− maintenance therapy versus maintenance therapy/observation only. Maintenance therapy was recommended based on a list of approved regimens, and observation was defined as close surveillance without cytotoxic therapy. Randomization was not masked and was balanced dynamically on five factors: number of metastases, response to initial therapy, central nervous system metastases, intrathoracic nodal status, and EGFR/ALK status. The primary endpoint was PFS, powered to detect an increase from 4 months to 7 months (hazard ratio [HR}=0.57) using intent-to-treat analysis. The plan was to study 94 randomized patients, with an interim analysis at 44 events. PFS, overall survival (OS), and time to develop a new lesion were compared between arms with log-rank tests. Results The study was terminated early after treatment of 49 patients (25 LCT, 24 control), when at a median follow-up time for PFS of 18.7 months, the median PFS time in the LCT group was 11.9 months (90% confidence interval [CI] 5.72 ,20.90) versus 3.9 months (90% CI 2.30, 6.64) in the maintenance group (HR=0.35, 90% CI 0.18,0.66, log rank p=0.005). Toxicity was similar between groups, with no grade 4–5 events. Grade 3 or higher adverse events in the maintenance therapy arm were fatigue (n=1) and anemia (n=1). In the LCT arm, Grade 3 events were: esophagitis (n=2), anemia (n=1), pneumothorax (n=1), and abdominal pain (n=1). Overall survival data are immature, with only 14 deaths recorded. Interpretation LCT +/− maintenance therapy for patients with ≤3 metastases from NSCLC that did not progress after initial systemic therapy improved PFS relative to maintenance therapy alone. These findings imply that aggressive local therapy should be further explored in phase III trials as a standard treatment option in this clinical scenario.

PURPOSE Our previously published findings reported that local consolidative therapy (LCT) with radiotherapy or surgery improved progression-free survival (PFS) and delayed new disease in patients with oligometastatic non–small-cell lung cancer (NSCLC) that did not progress after front-line systemic therapy. Herein, we present the longer-term overall survival (OS) results accompanied by additional secondary end points. PATIENTS AND METHODS This multicenter, randomized, phase II trial enrolled patients with stage IV NSCLC, three or fewer metastases, and no progression at 3 or more months after front-line systemic therapy. Patients were randomly assigned (1:1) to maintenance therapy or observation (MT/O) or to LCT to all active disease sites. The primary end point was PFS; secondary end points were OS, toxicity, and the appearance of new lesions. All analyses were two sided, and P values less than .10 were deemed significant. RESULTS The Data Safety and Monitoring Board recommended early trial closure after 49 patients were randomly assigned because of a significant PFS benefit in the LCT arm. With an updated median follow-up time of 38.8 months (range, 28.3 to 61.4 months), the PFS benefit was durable (median, 14.2 months [95% CI, 7.4 to 23.1 months] with LCT v 4.4 months [95% CI, 2.2 to 8.3 months] with MT/O; P = .022). We also found an OS benefit in the LCT arm (median, 41.2 months [95% CI, 18.9 months to not reached] with LCT v 17.0 months [95% CI, 10.1 to 39.8 months] with MT/O; P = .017). No additional grade 3 or greater toxicities were observed. Survival after progression was longer in the LCT group (37.6 months with LCT v 9.4 months with MT/O; P = .034). Of the 20 patients who experienced progression in the MT/O arm, nine received LCT to all lesions after progression, and the median OS was 17 months (95% CI, 7.8 months to not reached). CONCLUSION In patients with oligometastatic NSCLC that did not progress after front-line systemic therapy, LCT prolonged PFS and OS relative to MT/O.

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