Abstract
<h3>Objective:</h3> Investigation novel treatment options for Group 3 and Group 4 medulloblastoma patients <h3>Background:</h3> Group 3 and 4 medulloblastomas (MB) have a significantly worse prognosis when compared to the sonic hedgehog (SHH) or wingless (WNT) -activated subtypes and are also the most resistant to therapy. Current aggressive radiation/chemotherapy practices though improving survival, have potential long-term comorbidities with potential neurocognitive deficits impacting patients’ overall quality of life. A key factor limiting the therapeutic success of single-agent immune therapies is the poor penetration of tumor-specific immune cells into tumor microenvironments. Recent studies have demonstrated that galectin-3 (Gal-3) accelerates M2 macrophage-infiltration and restricts T cell receptor (TCR)-mediated signaling. Immunotherapy targeting CD8<sup>+</sup> T cells with agonistic anti-4-1BB (CD137) monoclonal antibody (mAb) activates CD8<sup>+</sup> T cells, promoting their survival and acquiring potent cytolytic properties. Building on these findings, we hypothesize that a novel treatment paradigm with immune-priming using sub-lethal low-dose radiation in combination with a Gal-3 inhibitor (anti-Gal-3 mAb) plus anti-4-1BB mAb will synergistically deplete tumor associated macrophages, restore CD8+ T cell migration, and promote autoimmune responses into tumor islets with resultant survival benefits in preclinical immunocompetent Group 3 and Group 4 MB mouse models. <h3>Design/Methods:</h3> Treatment effects were assessed using western blot, flow cytometry, H&E, immunofluorescence imaging and ELISA SPOT. <h3>Results:</h3> Our data demonstrated higher levels of Gal-3 expression in Group 3 and 4 patient derived tumor tissue, as compared to non-tumor tissue. We observed that Gal-3 shifted cytokine production via switching microglia polarization to the M2 subtype. Furthermore, H&E-stained tumor sections following treatment with combination low-dose radiation, Gal-3 inhibitor and anti-4-1BB mAb showed a reduction of tumor size by ~70% when compared to untreated controls. <h3>Conclusions:</h3> The results of these investigations provide critical preliminary data for further trials examining the effectiveness of immune-priming using sub-lethal low-dose radiation followed by combination treatment using a Gal-3 inhibitor plus anti-4-1BB mAb. <b>Disclosure:</b> Dr. Cachia has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for RedHill Biopharma Ltd. Dr. Cachia has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GuidePoint Global LLC. Dr. Cachia has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Dedham Group. Dr. Cachia has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Massachusetts Neurological Society. Dr. Eskandari has nothing to disclose. Mr. McDonald has nothing to disclose. Dr. Infinger has nothing to disclose. William A. Vandergrift has nothing to disclose. Abhay K. Varma has nothing to disclose. Sunil J. Patel has nothing to disclose. Dr. Zukas has nothing to disclose. Dr. Lindhorst has nothing to disclose. Dr. DAS has nothing to disclose.
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