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CD47 is an anti-phagocytic cell surface protein mediating cancer cell evasion of phagocytosis by the innate immune system. Preclinical data suggest that CD47 is appears to be an indispensable means by which many cancer cells, including cancer stem cells, overcome intrinsic expression of their pro-phagocytic “eat me” signals. Blockade of CD47 with mAbs enables phagocytosis of cancer cells in vitro and in vivo. We have developed a novel humanized mAb (huCD47-Ab) that specifically binds CD47 and blocks it from interacting with its ligand, signal regulatory protein–α; (SIRPα), on phagocytic cells, resulting in the phagocytosis and elimination of cancer cells through their “eat me” signals. Normal cells generally do not express eat me signals, and are unaffected by CD47 blocking mAb. We observed expression of CD47 on aggressive pediatric tumors, including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), Ewing's sarcoma, neuroblastoma, and several cancers of the central nervous system (CNS), including atypical tetroid rhabdoid tumor (ATRT), primitive neuroectodermal tumor (PNET), medulloblastoma (MB), and pediatric high-grade glioma (pHGG). In-vitro phagocytosis assays, of primary patient samples shows significant engulfment by human peripheral blood derived macrophages upon incubation with the HuCD47-Ab antibody as compared to control. Furthermore we observe potent anti-tumor efficacy and survival benefit in MB, pHGG, ATRT and PNET orthotopic xenografts models establishing the ability of the huCD47 antibody to across the blood brain barrier by the CD47 blocking antibody. Using a novel human neural stem cell/brain tumor co-engraftment orthotopic xenograft model we show specificity of the HuCD47 antibody to only tumor cells and not normal human cells. We further observe potent anti-tumor efficacy in non-CNS tumor (ALL, AML and Osteosarcoma) xenograft models as well. Furthermore we demonstrate that HuCD47-Ab can be administered safely to non-human primates at therapeutic serum levels. Pre-IND and IMPD meetings with the FDA in the US and the MHRA in the UK, have been held, and the clinical trials for adult patients with advanced stage malignancies will start in early 2014. After determining safety in these phase I trials, we initiate protocols for adult CNS tumors as part of expansion cohorts, and subsequently extend the trials to pediatric cancer patients, given manageable toxicity and signs of efficacy in the adult patients. This abstract is also presented as Poster A86. Citation Format: Siddhartha S. Mitra, Sharareh Gholamin, Jens-Peter Volkmer, Abdullah Feroze, Jie Liu, Achal Achrol, Lijuan Wang, Leanne Sayles, Michael Zhang, Kathleen Sakamoto, Michelle Monje-Deisseroth, Yoon-Jae Cho, Alejandro Sweet-Cordero, Ravi Majeti, Samuel Cheshier, Irving Weissman. Overcoming immune evasion in pediatric hematologic and solid tumor malignancies: A preclinical study using a humanized anti-CD47 antibody. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr PR12.

Introduction: Extensive molecular characterization of Brain tumors done in recent years has proven valuable for tumor classification, risk stratification and outcome prediction for current treatment modalities. However the current standard of care has not improved the prognosis and carries an increased risk of cognitive impairments for children with brain tumors. A characteristic feature of tumor progression and recurrence is its ability to evade the immune system. Our hypothesis is that by modulating the innate immune system we can enhance the ability of macrophages to ‘eat and kill’ brain cancer cells. Recent data suggests that the interaction between the cell surface antigen CD47 and its binding partner SIRPα is a mechanism by which non-solid and solid tumors can evade the innate immune system. To see if anti-CD47 therapy is a potential therapy in malignant pediatric brain tumors we first looked at CD47 expression in freshly isolated patient and postmortem samples from 4 different tumor types; Diffused Intrinsic Pontine Glioma, Medulloblastoma, Ependymoma and ATRTs. We tested the hypothesis that blocking CD47- SIRPα interaction induced phagocytosis in an in-vitro phagocytosis assay. We next established orthotopic xenografts models in immune compromised mice and treated them with anti-CD47 humanized antibody, which is currently being developed for clinical trials in hematopoietic and non-CNS malignancies. Result: CD47 expression was upregulated in all tumor types and was present in >90% of the cells in high grade tumors. Increased CD47 expression was observed in CD15+ and CD133+ putative cancer stem cell population. Blocking the CD47- SIRPα interaction increases tumor phagocytosis by macrophages in-vitro. Systemic treatment with anti-CD47 antibody significantly reduced tumor burden in an orthotopic xenograft setting. Conclusion: Anti-CD47 therapy is a viable and effective treatment modality for pediatric high grade brain tumors. Citation Format: Sharareh Gholamin, Siddhartha S. Mitra, Chase Elliott Richard, Achal Achrol, Doosik Kong, Jun Jae Shin, Michelle Monje-Deisseroth, Yoon-Jae Cho, Irving Weissman, Samuel H. Cheshier. Development of Anti-CD47 therapy for pediatric brain tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5218. doi:10.1158/1538-7445.AM2013-5218