Abstract
Recently we published the effect of a humanized anti-CD47 antibody, on five aggressive and etiologically distinct pediatric brain tumors: Group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrates therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Disabling the inhibitory signals transduced by SIRPa by blocking anti- CD47 antibodies we promote phagocytic response driven by tumor-specific antibodies. These phagocytic innate cells are also professional antigen-presenting cells (APC), providing a link from innate to adaptive antitumor immunity. Consequently, we tested a number of approaches to augment immune checkpoint immunotherapy. We hypothesized that by activating immunogenic phagocytosis we could kickstart the cancer immunity cycle and hence augment adaptive checkpoint inhibitors against cold tumors such as medulloblastoma and pediatric glioma. RESULTS: To determine the in vivo efficacy of combinatorial anti-CD47 and anti-PD1 therapies, spontaneous SHH medulloblastoma mouse models were treated by, i.p. injections with either PBS (control), anti-CD47, anti-PD1 or in combination. To test the cancer immunity hypothesis combination treatment was carried out either in sequence or simultaneously. Mice receiving anti-CD47 anti-PD1 duotherapy demonstrated increased survival when treated sequentially as compared to both monotherapies and control cohorts. Immunohistochemical and Flowcytometry analysis with the macrophage marker F4/80 and T-cell subset immune panel demonstrated varying patterns of macrophage and T-cell infiltration. Addition of anti-CTLA4 mAb did not enhance the efficacy of this effect suggesting the lack of infiltrating T-regulatory cells.