• Johns, Terrance
• Lesterhuis, Joost
• Abbas, Zahra
• Endersby, Raelene
• Hii, Hilary
• Gottardo, Nicholas
• Buck, Jessica
• Johnson, Iley
• Byrne, Jacob
• Elaskalani, Omar
• George, Courtney
• Arias, Clara Andradas
• Howlett, Meegan
• Kuchibhotla, Mani

Abstract

<jats:title>Abstract</jats:title><jats:p>Stagnation in clinical outcomes as well as severe side-effects of current treatment approaches for Group 3 medulloblastoma have prompted the search for novel therapies. To date, immunotherapies have not demonstrated success in medulloblastoma. Due to the highly aggressive nature of relapsed medulloblastoma, we suggest that it would be advantageous to introduce new immunotherapies first-line, alongside conventional therapies. To design immunotherapeutic strategies that are compatible in combination with standard therapies, we first determined the effect of standard-of-care craniospinal irradiation (CSI) and chemotherapy on the immunology of these tumours in immune competent and deficient murine models. We show that standard treatment approaches deplete adaptive immune cells, while macrophage and brain-resident microglia are not depleted. Furthermore, medulloblastomas are myeloid dominant tumors, and blocking the anti-phagocytic CD47-SIRPa interaction has shown preclinical efficacy. Therefore, we tested the combination of anti-CD47 immunotherapy with radiotherapy in a patient-derived xenograft model of Group 3 medulloblastoma. We found that anti-CD47 monotherapy had limited efficacy, while CSI results in only a temporary reduction in tumor size. In the cerebellum of relapsed tumors post-CSI, flow cytometry revealed increased peripheral myeloid populations. Remarkably, the combination of anti-CD47 and CSI was effective in clearing tumors and maintaining long-term tumor-free survival. Using RNA sequencing and immunohistochemistry, we found that the combination therapy results in enhanced cytokine signalling and phagocytic myeloid cell infiltration into the tumors compared to the monotherapies. We have also developed and characterized novel age-appropriate preclinical models for medulloblastoma and have observed altered myeloid cell phenotypes in these age-appropriate models. We are now testing this novel combination therapy in our new neonatal murine models to determine efficacy in age-appropriate hosts.</jats:p>

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