Gradalis® Mode Of Action


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.

Here is how the therapy works:   

  • A patient’s tumor is removed by a surgeon 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 and up to 12 doses of therapy are produced. The genetic modifications are achieved through the introduction of a proprietary gene plasmid, carrying the instructions for two genetic modifications, into the cells via electroporation. 
    • The first modification involves the introduction of a bi-functional shRNAi targeted to the enzyme furin.  This interfering RNA silences the production of furin very effectively through a duel mechanism.  One of the functions of the furin enzyme is to activate TGFβ1 and TGFβ2.  Thus, inhibiting this enzyme in the patient’s cancer cells results in nearly complete reduction in the expression of TGFβ1 and TGFβ2 in these cells.
    • The second 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 dendritic cells.
    • Before shipping the doses are irradiated to inhibit the ability of the cells to replicate.
  • The modified cancer cells are then injected into the patient’s upper arm on a one-dose-per-month dosing schedule, for up to 12 doses.
  • When the cells are injected into the patient’s arm, the two modifications are designed to work in tandem to help 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 dendritic cells.
  • The dendritic cells then follow the standard immune response by sampling the tumor cell surface antigens, and migrating to local lymph nodes where they educate and activate T-cells against those antigens recognized from the patient’s tumor cells. The immune system is now activated against the antigens of that patient’s cancer.
  • T-cells expand and then mobilize throughout the body to recognize and kill cancer cells expressing those unique antigens. Because they are now activated, these T-cells are impervious to the immunosuppressing effects of TGFβ1 and TGFβ2 that may be secreted by remaining cancer cells.

The activation of T-cells can be monitored and assessed with our Immune Activation Assay. Thus, we can demonstrate if the patient is 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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