Toward elucidating the mechanism of local immunotherapy for brain cancer treatment
SALAZAR U. 1
1 University of Zürich, Zürich, Switzerland
Glioblastoma (GBM) is the most common primary brain tumor in adults. Even with standard of care consisting of resection and chemoradiotherapy, GBM is associated with very poor prognosis with an average survival of 15-18 months. Various approaches try to address this unmet clinical need.
One of the main challenges with therapies for brain diseases is drug delivery through the blood-brain-barrier (BBB). Furthermore, once in the CNS, antibodies are facing FcRn mediated efflux to the circulation, limiting the exposure time in the diseased area.
To overcome these challenges, we developed “FcRn silenced” biologics, such as cytokine Fc fusion molecules, immune checkpoint inhibitors, or agonist antibodies with abrogated FcRn affinity, to allow higher exposure to the brain and abolished systemic footprint. To bypass the BBB, these compounds are delivered directly to the tumor bed through convection-enhanced-delivery (CED).
Local GBM immunotherapy faces a highly immunosuppressive microenvironment characterized by Treg infiltration, PD-L1 upregulation on tumor cells and circulating monocytes/macrophages, and PD1 upregulation on antigen experienced T cells. Yet local therapy with such modified IL-12Fc and CD40 agonists elicits robust antitumor responses in murine GBM models. Now we aim to elucidate the exact mechanism of action of such a localized treatment. This will entail a detailed characterization of the tumor microenvironment (immunophenotyping of tumor by FACS and RNAseq, characterization of tumor infiltrating exhausted T cells, and high dimensional microscopy) and functional interrogation to prioritize immunotherapies which counteract the immunosuppressive environment and restore T cell response.