The Development and Design of the MelVac platform and lead product, DC-MelVac

The sentinel discovery of the concept and technology can be traced to when Dr. Wallack began his research at the Wistar Institute in Philadelphia, PA, and developed a Cancer Vaccine against Melanoma from 1973 to 1977. This vaccine used a live vaccinia vaccine virus–augmented polyvalent melanoma cell lysates called Vaccinia Melanoma Oncolysate (VMO). The choice of vaccinia virus as an adjuvant for the preparation of VMO was made for two clinically sound reasons;

  1. Vaccinia Virus enhanced the immunogenicity of tumors.
  2. The safety profile of Vaccinia Virus was validated since it was used for mass immunizations against smallpox throughout the world.

The first cancer vaccine developed by Dr. Wallack was produced at the Institute Merieux in Lyon, France, and was tested in human melanoma clinical trials, first in Lyon, France and then in the United States. In the United States, the Phase I and Phase II trials were sponsored by the National Cancer Institute (NCI) and performed within the Southeastern Cancer Study Group (SECSG). The SECSG Phase I trial determined the limited toxicity and the effective dose of the VMO, and the SECSG Phase II trial evaluated both the immune responses and the clinical responses induced by the VMO in Stage III melanoma patients with more than five positive nodes in the draining lymph node area located near the primary tumor.

In all these trials, VMO showed minimal toxicity and no side effects.

Furthermore, in the Phase II trial, VMO treatment resulted in an increase survival of highly aggressive Stage II melanoma resected patients when compared to historic controls. As a result, the VMO was approved for a Phase III randomized trial that was funded by the National Cancer Institute (NCI) and approved by the Federal Drug Administration (FDA). This surgical adjuvant Phase III clinical trial was performed between 1988- 1992 and was the first randomized, prospective, double–blind, multi-institutional, pharma-produced cancer vaccine trial in the world. Subset analysis indicated that male patients between the ages of 44 and 57 having one to five (1-5) positive microscopic or macroscopic lymph nodes showed a 37% difference in overall survival at the five (5) year time point when compared with controls. As a result of this male subset of patients that showed a positive response, Dr. Wallack and colleagues developed the more potent melanoma vaccine platform, “MelVac” for the next generation of melanoma trials.

The MelVac Patent:
United States Patent #7,015,205 B1

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“Melanoma vaccine and methods of making and using same.”

The MelVac Platform Preparation Process:

Four Step Process for Lead Product DC-MelVac Vaccinia Virus (rIL-2VV) Seed Lot

Number 1

Propagation of rIL-2V

Melanoma rIL-2VV Oncolysate Preparation

Melanoma rIL-2VV Oncolysate Preparation

Number 3: Preparation of Patient-Derived Dendritic Cells and DC-MelVac Vaccine
Preparation of Patient-Derived Dendritic Cells and DC-MelVac Vaccine

Number 4: Immunobiologic Vaccination of Patients
Immunobiologic Vaccination of Patients

Process for Propagation of Recombinant
Vaccinia Virus (rIL-2VV) Seed Lot

  1. Infect normal lung epithelial cell line, MRC-5, with recombinant vaccinia virus ( rIL-2VV).
  2. Incubate infected cells for 24 hours
  3. Release and purify seed virus by sonication of infected cells, followed by serial centrifugations

Process of the Melanoma Viral Oncolysate Preparation

  1. Infect melanoma cell lines with rIL-2VV at a ratio of 1 PFU:10 melanoma cells
    Examples of cells – MEL-2, MEL-2, 3MM, KFM, GLM-2, autologous melanoma cells
  2. Break virus-infected melanoma cells by sonication and isolate enucleated cytosol, cell membranes, and virus particles.
  3. UV-irradiate melanoma sonicate to inactivate rIL-2-VV
    This is the Viral Melanoma Oncolysate (VMO)
  4. Pool desired number of melanoma line oncolysates at a concentration corresponding to 107 original cells/ml. Freeze l ml vials at -70°C.

Process for the Preparation of Patient-Derived Dendritic Cells and DC- MelVac

  1. 50-60 ml of blood per patient is collected to obtain Autologous Peripheral Blood Mononucleocytes (PBMCs)
  2. Differentiate adherent cells into autologous dendritic cells by culturing in the presence of 1μg/ml IL-4 and 500μg/ml GMCSF
    Acceptable yield of dendritic cells is between 0.5 x 106 and 5 x 106
  3. Incubate patient-derived DCs with either 2mg, 3mg, or 4mg of the rIL-2VMO for 4 hrs at 37oC in a total volume of 1.2 ml
    This is DC-IL2 VMO or DC-MelVac

Administration and Vaccination Schedule

  1. Intradermally inject 107 PFU of live vaccinia virus encoding IL-2 (rIL-2VV) in 4-6 sites proximal to patient’s regional lymph nodes.
  2. After 30 minutes, inject approximatley 1 million melanoma-loaded DC cells (DC-IL2 VMO) into the same sites as rIL-2VV.
  3. Repeat injections for three months at biweekly intervals (induction phase) followed by injections every 3 months for 1-2 years or until recurrence.
    Monitor clinical and immune response parameters.