GBM Immunotherapy Program

Targeting CMV as a foreign viral antigen approach to Immuno-Oncology (GBM) with a bivalent eVLP expressing two potent CMV antigens – pp65 and gB

Glioblastoma Immunotherapy (VBI-1901) Overview

VBI has applied its eVLP Platform in the development of a glioblastoma multiforme (“GBM” or “glioblastoma”) therapeutic vaccine candidate. With its novel approach, VBI intends to create a GBM immunotherapy that will stimulate the patient’s own immune system to identify and kill GBM cancer cells, with the goal of creating a commercially-viable therapy that is more effective and tolerable than current treatments. VBI has initiated a multi-center, open-label, dose-escalation Phase 1/2a study to evaluate VBI-1901 in patients with recurrent GBM.

Recent Program Milestones
  • H2 2017: Filed IND
  • H1 2018: First Patient Dosed
  • H1 2018: Positive DSMB Review
  • H2 2018: Second Positive DSMB Review
  • H2 2018: Initial Data Presented
  • H1 2019: Third Positive DSMB Review
  • H1 2019: Part A Clinical Data Presented at ASCO
  • H2 2019: First Patient Dosed in Part B Extension Phase
  • H2 2019: Announced Phase 2a Collaboration with GSK
About GBM
VBI-1901 Design
GBM Preclinical Studies

Glioblastoma Medical Need and Its Relationship to Cytomegalovirus

Glioblastoma is among the most common and aggressive malignant primary brain tumors in humans. In the U.S. alone, 12,000 new cases are diagnosed each year.1 The current standard of care for GBM is surgical resection, followed by radiation and chemotherapy. Even with aggressive treatment, GBM progresses rapidly and is exceptionally lethal, with median patient survival of less than sixteen months.2

Developing a broadly applicable GBM immunotherapy requires the identification of antigens, used to direct the immune response, that are consistently expressed on tumor cells. A growing body of research has demonstrated that GBM tumors are susceptible to infection by cytomegalovirus (“CMV”), with over 90% of GBM tumors expressing CMV antigens.3 In addition, recent research has demonstrated that an anti-CMV dendritic cell vaccination regimen can extend overall survival in patients with glioblastoma.4 Thus, effective targeting of CMV antigens may represent an attractive strategy for a GBM immunotherapy.

Glioblastoma Resources
  • Glioblastoma information from the American Brain Tumor Association. Visit resource >>
  • Brain cancer resources for patients from the National Cancer Institute. Visit resource >>
  • Primary brain and central nervous system tumors diagnosed in the U.S. in 2005–2009 from CBTRUS. Visit resource >>
  • Detection of CMV in tumors of patients diagnosed with glioblastoma. Visit resource >>

GBM Candidate Design

VBI has utilized its eVLP Platform and its expertise in anti-CMV immunity to develop VBI-1901, a polyvalent therapeutic vaccine candidate designed to direct an immune response against gB and pp65, two CMV antigens that are highly immunogenic targets during natural infection. VBI-1901 includes granulocyte-macrophage colony-stimulating factor (“GM-CSF”), an adjuvant that mobilizes dendritic function and enhances Th1-type immunity.5

Antibody Target
gB
T-Cell Targets
gB (CD4+), pp65 (CD8+)
Rationale
Targets multiple antigens, each with multiple epitopes, to promote broad immunity and delay avoid tumor selection / escape
Adjuvant
Co-administered with either GM-CSF via intradermal route or AS01B via intramuscular route

Virus-like structure stimulates innate immunity and promotes uptake by Antigen Presenting Cells (APCs)

Preclinical Highlights

In recently published preclinical studies, VBI demonstrated that its vaccine candidate stimulated immune responses critical to efficacious anti-tumor immunity.

Preclinical Research Highlights
  • Ex vivo studies demonstrate the vaccine candidate’s ability to induce desired anti-tumor immunity in peripheral blood mononuclear cells (“PBMCs”) harvested from healthy subjects and patients with GBM;7 GBM patient samples were provided by Columbia University’s Brain Tumor Center.
  • The vaccine candidate stimulated both CD4+ and CD8+ T cell responses, characterized by secretion of IFN-g and CCL3, key biomarkers associated with positive clinical outcomes.8
  • In vivo data confirm the vaccine candidate’s ability to induce desired CD4+ and CD8+ T cell responses in mice;9 additional animal studies are planned to determine optimal dosing and formulation properties.
GBM Patient PBMCs Respond to Bivalent CMV eVLP and GM-CSF Stimulation

Bivalent gB/pp65 eVLPs were used to stimulate frozen/thawed PBMCs from four healthy subjects and four primary GBM patients. CCL3 secretion after stimulation with empty eVLPs has been subtracted from all values.

Phase I/IIa Clinical Program

The Phase I/IIa multi-center, open-label, two-part study will enroll up to 38 patients and is designed to evaluate safety, tolerability, and the optimal therapeutic dose level of VBI-1901 in the treatment of recurrent glioblastoma multiforme (“rGBM”)

View Trial Details at ClinicalTrials.gov

Study Design

VBI-1901 is administered intradermally when adjuvanted with granulocyte-macrophage colony-stimulating factor (GM-CSF), and will be administered intramuscularly when adjuvanted with GSK’s proprietary AS01B adjuvant system. Patients in both phases of the study will receive the vaccine immunotherapeutic every four weeks until clinical progression.

  • Part A:
    • Dose-escalation phase that defined the safety, tolerability, and optimal dose level of VBI-1901 in recurrent GBM patients with any number of prior recurrences
    • This phase enrolled 18 recurrent GBM patients across three dose cohorts of VBI-1901: 0.4 µg, 2.0 µg, and 10.0µg
    • Enrollment completed December 2018
  • Part B:
    • Subsequent extension of the optimal dose level, 10.0 µg, as defined in the Part A dose escalation phase
    • This phase will be a two-arm study, enrolling 10 patients in each arm, assessing VBI-1901 in combination with either GM-CSF or AS01B as immunomodulatory adjuvants
    • Part B will enroll first-recurrent GBM patients only

References

  1. Dolecek TA, Propp JM, Stroup NE, et al. (2012) CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol 14(suppl 5):v1–v49.
  2. Johnson DR, O’neill BP. Glioblastoma survival in the United States before and during the temozolomide era. J Neurooncol. 2012;107(2):359-64.
  3. Mitchell DA, Xie W, Schmittling R, et al. Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro-oncology. 2008;10(1):10-8.
  4. Mitchell DA, Batich KA, Gunn MD, et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature. 2015;519(7543):366-9.
  5. DE Anderson. Therapeutic Vaccination against Glioblastoma Multiforme Using CMV gB/pp65 eVLPs Formulated with GM-CSF. Poster presented at: The European Society for Medical Oncology Symposium on Immuno-Oncology 2015; November 2015; Lausanne, Switzerland.
  6. Arellano M, Lonial S. Clinical uses of GM-CSF, a critical appraisal and update. Biologics. 2008;2(1):13-27.
  7. DE Anderson. Therapeutic Vaccination against Glioblastoma Multiforme Using CMV gB/pp65 eVLPs Formulated with GM-CSF. Poster presented at: The European Society for Medical Oncology Symposium on Immuno-Oncology 2015; November 2015; Lausanne, Switzerland.
  8. DE Anderson. Therapeutic Vaccination against Glioblastoma Multiforme Using CMV gB/pp65 eVLPs Formulated with GM-CSF. Poster presented at: The European Society for Medical Oncology Symposium on Immuno-Oncology 2015; November 2015; Lausanne, Switzerland.
  9. DE Anderson. Therapeutic Vaccination against Glioblastoma Multiforme Using CMV gB/pp65 eVLPs Formulated with GM-CSF. Poster presented at: The European Society for Medical Oncology Symposium on Immuno-Oncology 2015; November 2015; Lausanne, Switzerland.

Recent GBM Program News and Insights