IMMU-07. TUMOR STROMA–TARGETING ANTIBODY-CYTOKINE CONJUGATES TO CONVERT THE IMMUNOLOGICALLY COLD GLIOMA MICROENVIRONMENT INTO A HOT ONE

Abstract

Abstract Glioblastoma is an immunological “desert”. The administration of pro-inflammatory cytokines could shift the balance between tumor-associated immune suppression and anti-tumor immunity but the systemic administration of therapeutically active doses of pro-inflammatory cytokines is hampered by toxic side effects. We investigated different antibody-cytokine fusion products that enable a targeted delivery of interleukin (IL-) 2, IL-12 or tumor-necrosis factor (TNF)α to the tumor site upon systemic administration by binding to a tumor-specific epitope of fibronectin. We confirmed the target antigen expression in ex vivo sections of orthotopic syngeneic glioma mouse models and human glioblastoma samples and characterized the distribution of these antibody-conjugates in glioma-bearing mice upon systemic administration using in vivo imaging. Subsequently, we demonstrated potent anti-tumor activity of these antibody-fusion proteins in fully immunocompetent orthotopic mouse glioma models and characterized their mode of action. We also translated this immunotherapeutic strategy to treat patients with recurrent glioblastoma systemically with an antibody-fusion protein that enables the targeted delivery of TNFα to the tumor site. This was well tolerated, led to a treatment-associated tumor necrosis and increased the number of tumor-infiltrating T cells. This work builds a basis for future studies with antibody-cytokine fusion proteins as a promising treatment strategy for central nervous system tumors.