Gradalis® Mode Of Action

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Vigil® is intended to stimulate and enhance the body’s natural mechanism for recognizing and killing cancer cells. It utilizes the patient’s own cancer cells to create a fully personalized cancer immunotherapy.

Patient’s tumor tissue is removed surgically as part of the standard of care for most advanced cancers. A portion of the tumor is shipped on ice to our cGMP manufacturing facility where, in a two-day process, the patient’s cancer cells are genetically modified. Up to 12 doses of Vigil® immunotherapy are produced for each patient.

The genetic modifications are achieved through the introduction of a proprietary gene plasmid, carrying the vectors of two genetic modifications by electroporation of the patient’s cancer cells.

The first gene sequence involves the introduction of a bi-functional shRNA targeted to the enzyme furin with the effect of knock-down of furin production.  One of the functions of the furin enzyme is to activate immunosuppressive isoforms of TGFβ1 and TGFβ2.  Thus, inhibiting furin production in the patient’s cancer cells results in nearly complete reduction in the expression of TGFβ1 and TGFβ2 in these cells.

The second gene modification involves the introduction of a gene sequence to express Granulocyte Macrophage Colony Stimulating Factor, or GM-CSF, a potent stimulator of the immune system.  It has been demonstrated that GM-CSF enhances surface antigen expression, making the cancer cells more visible to the patient’s immune system.  GM-CSF also further stimulates the patient’s immune system by actively recruiting and maturing antigen-presenting cells, such as dendritic cells.

After introduction of the plasmid and incubation over night for expression of both the bi-shRNA vector and GM-CSF, all doses are irradiated to inhibit the ability of the tumor cells to replicate.

Vigil immunotherapy is then shipped for treatment into the patient’s upper extremities once per month, for up to 12 doses.

When the cells are injected into the patient’s arm, the two modifications are designed to activate the immune system. GM-CSF expression enhances cell surface antigen expression and recruits dendritic cells to the injection site; while the inhibition of TGFβ1 and TGFβ2 secretion allows cancer cells to now be “visible” to the patients antigen-presenting cells (APCs).

Antigen-presenting cells (APCs) then follow the natural immune response by sampling the tumor cell surface antigens, and migrating to local lymph nodes where they educate and activate T-cells against those cancer neoantigens recognized from the patient’s tumor cells. Circulating T-cells now are activated and enabled to fight the patient’s cancer.

The activation of T-cells can be monitored and assessed with our Immune Activation Assay. Thus, we can demonstrate if the patient’s T cells are biochemically responding, which may help predict a clinical response.

The following references are key publications:

Senzer N, Barve M, Nemunaitis J, Kuhn J, Melnyk A, et al. (2013) Long Term Follow Up:

Phase I Trial of “bi-shRNA furin/GMCSF DNA/Autologous Tumor Cell” Immunotherapy (Vigil™) in Advanced Cancer.
J Vaccines Vaccin 4: 209. doi: 10.4172/2157-7560.1000209

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Senzer N, Barve M, Kuhn J, Melnyk A, Beitsch P, Lazar M, Lifshitz S, Magee M, Oh J, Mill SW, Bedell C, Higgs C, Kumar P, Yu Y, Norvell F, Phalon C, Taquet N, Rao DD, Wang Z, Jay CM, Pappen BO, Wallraven G, Brunicardi FC, Shanahan DM, Maples PB, Nemunaitis J:

Phase I Trial of “bi-shRNAifurin/GMCSF DNA/Autologous Tumor Cell” Vaccine (Vigil™) in Advanced Cancer
Molecular Therapy 2012; 20(3):679-686.

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Maples PB, Kumar P, Yu Y, Wang Z, Jay CM, Pappen BO, Rao DD, Kuhn J, Nemunaitis J, Senzer N: 

Vigil Vaccine: Autologous Tumor Cell Vaccine Genetically Modified to Express GM-CSF and Block Production of Furin.
BioProcessing Journal 2010; 8(4):4-14.

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