Search

Non-Hodgkin lymphoma (NHL) presents as both localized and disseminated disease with spread to secondary sites carrying a worse prognosis. Although pathways driving NHL dissemination have been identified, there are few therapies capable of inhibiting them. Here, we report a novel role for the immunomodulatory protein CD47 in NHL dissemination, and we demonstrate that therapeutic targeting of CD47 can prevent such spread. We developed 2 in vivo lymphoma metastasis models using Raji cells, a human NHL cell line, and primary cells from a lymphoma patient. CD47 expression was required for Raji cell dissemination to the liver in mouse xenotransplants. Targeting of CD47 with a blocking antibody inhibited Raji cell dissemination to major organs, including the central nervous system, and inhibited hematogenous dissemination of primary lymphoma cells. We hypothesized that anti-CD47 antibody-mediated elimination of circulating tumor cells occurred through phagocytosis, a previously described mechanism for blocking anti-CD47 antibodies. As predicted, inhibition of dissemination by anti-CD47 antibodies was dependent on blockade of phagocyte SIRPa and required macrophage effector cells. These results demonstrate that CD47 is required for NHL dissemination, which can be therapeutically targeted with a blocking anti-CD47 antibody. Ultimately, these findings are potentially applicable to the dissemination and metastasis of other solid tumors. [ABSTRACT FROM AUTHOR]

PURPOSE: Increasingly limited resources mandate the careful allocation of assets for cancer research. Slow-accruing clinical trials delay the translation of biomedical research, contribute to increasing healthcare costs, and often languish unfinished. We analyzed The University of Texas MD Anderson Cancer Center (MDACC) experience for factors that predict slow participant accrual to phase I–III trials. MATERIALS AND METHODS: Clinical Oncology Research system (CORe) is a prospectively maintained institutional database that tracks all clinical studies at MDACC. We evaluated studies that met the following inclusion criteria: activated phase I–III trials, maximum projected accrual ≥ 10 participants, and activation prior to March 2011. The primary outcome was slow accrual, defined as an accrual rate of < 2 participants per year. Correlations of trial characteristics and development variables with slow accrual were assessed with univariate and multivariate logistic regression. Additional slow accrual cutpoints and a Bonferroni-adjusted significance threshold of P < .003 were utilized to ensure robust associations. RESULTS: A total of 4,269 clinical trials met the inclusion criteria. Trials were activated between 1981 and 2011, with 145,214 participants enrolled. Median total enrollment was 17 (interquartile range [IQR]: 6–38), with an average rate of 8.7 participants/year (IQR: 3.3–17.7). There were 755 (18%) trials classified as slow-accruing. On multivariate analysis, slow accrual exhibited robust associations with national cooperative group trials (odds ratio [OR], 4.16; P < .0001 vs industry-sponsored) and time from trial activation to first enrollment (OR, 1.13 per month; P < .0001). Factors that were not robustly associated with slow accrual included the number of concurrent trials activated within the same department, year of trial activation, and trial phase. Slow-accruing trials led to a lower rate of peer-reviewed publication (14%) than non–slow-accruing trials (69%). CONCLUSIONS: We present demographics and factors associated with slow trial accrual at MDACC. We believe that this analysis serves as a baseline and highlights areas of weakness to aid in the development of evidence-based trial guidelines. [ABSTRACT FROM AUTHOR]