Low-dose radiation followed by on-target inhibition of Galectin-3 in combination with anti-4-1BB monoclonal antibody regulates immune responses in Group 3 and Group 4 medulloblastoma mouse model
David Cachia1, Ramin Eskandari2, Daniel G McDonald3, Libby Kosnik Infinger4, William A Vandergrift III4, Abhay K. Varma4, Sunil J. Patel4, Alicia M Zukas4, Scott M. Lindhorst 4, ARABINDA DAS4
1University of Massachusetts, 2Medical University of South Carolina, 3Radiation Oncology, 4Neurosurgery, Medical University of South Carolina
Objective:
Investigation novel treatment options for Group 3 and Group 4 medulloblastoma patients
Background:
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+ T cells with agonistic anti-4-1BB (CD137) monoclonal antibody (mAb) activates CD8+ 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.
Design/Methods:
Treatment effects were assessed using western blot, flow cytometry, H&E, immunofluorescence imaging and ELISA SPOT.
Results:
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.
Conclusions:
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.