Abstract B122: Development of a new immunotherapy treatment for glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) is the most frequently occurring primary brain tumor; it is a debilitating disease that is associated with poor prognosis, short median patient survival and a limited response to current therapies. As a result, there is a dire need for novel therapeutic interventions that are curative, or at the very least extend patient survival. Immunotherapy is an attractive option for the treatment of GBM due to its high specificity and minimal systemic toxicity. Peripherally activated immune cells have been shown to efficiently penetrate the brain parenchyma and access intracranial tumors, overcoming the blood-brain barrier, which hinders many molecularly targeted therapies. Two antigens, TRP-2 and WT-1, were found to be significantly expressed in GBM tissue sections while being absent from the normal brain. Peptide sequences known to be immunogenic were chosen from both TRP-2 and WT-1 antigens. The DNA sequences corresponding to these peptide sequences were then inserted into the complementarity determining regions of a DNA plasmid encoding an antibody known as ImmunoBody®; this vaccine has been shown to generate a higher avidity response than both peptide and peptide-pulsed dendritic cell vaccinations. As a result of the highly promising preclinical results shown, the ImmunoBody® vaccination is currently being studied in a phase I/II clinical trial for melanoma. As a result the ImmunoBody® DNA vaccine has been selected as our method of vaccination. Syngeneic C57BL/6 mice and humanized C57BL/6 HHDII/DR1 mice were used to assess the TRP-2 and WT-1 directed ImmunoBody® vaccines. Mice were vaccinated biolistically with the ImmmunoBody® plasmid coated onto gold particles using a gene gun. An initial priming dose was given on day 0 followed by a boost on days 7 and 14. Mice were vaccinated with either a TRP-2-ImmunoBody®, a WT-1-ImmunoBody® or a combination of the two. The immune response generated was determined by ex vivo IFN-γ ELISpot using splenocytes derived from the spleen of immunized animals. Results from these dual vaccination experiments reveal that it is possible to use both of these vaccines in tandem without losing the specificity towards each vaccine-containing peptide. High level of peptide-specific IFN-γ-releasing cells were detected directly ex vivo and the ability of these IFN-γ-releasing cells to recognize targeT-cells that naturally express the WT-1 and TRP-2 antigens is being investigated. The efficacy of TRP-2-ImmunoBody® with or without PD-1 at treating syngeneic orthotopic GL-261Luc2 tumors implanted in C57BL/6 mice is also currently being assessed. The combination of the two vaccines will also be assessed in the humanized HHDII/DR1 mice using a humanized B16 cell line that has had murine Beta-2m knocked out and HHDII and HLA-DR1 knocked in. Anti-PD-1 checkpoint blockade will also be incorporated into this vaccination regime with the aim of boosting the antitumor immune response. Citation Format: Joshua R. D. Pearson, Lindy G. Durrant, Victoria A. Brentville, Graham Pockley, Stephanie E.B. McArdle. Development of a new immunotherapy treatment for glioblastoma multiforme [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B122.