MVI-118 is a unique DNA vaccine being developed by MVI. This vaccine targets the human androgen receptor ligand binding domain, the critical biological target responsible for driving prostate cancer progression and, in many cases, resistance to current therapies.
MVI views up-regulation of AR, and concurrent overexpression of AR peptide antigens on the cell surface of prostate cancer cells as an ideal environment for Th1-biased CTL killing induced by vaccination against AR.
Men with metastatic prostate cancer who have recently initiated androgen deprivation therapy (ADT).
Standard of care for men with metastatic prostate cancer is most commonly hormonal or physical castration, more recently with the addition of 2nd generation AR antagonists.
Some non-metastatic, but biochemically recurrent prostate cancer patients will also elect to begin castration therapy in advance of detectable bone metastases. Although PSA regressions are commonly achieved using these therapies, the majority of patients will develop castration-resistant disease, frequently as a result of gene amplification or high level up-regulation of the androgen receptor (AR).
MVI-118 is designed to address this primary escape mechanism by providing efficient tumor cell killing of cells overexpressing the androgen receptor.
MVI-118 completed a Phase 1 trial in men with metastatic prostate cancer who were initiating ADT. Strong safety and tolerability were observed.
A significant correlation between immune response to the AR plasmid and delayed time to disease progression over 18 months was also observed in this Phase 1 trial.
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MVI-118 is now in a Phase 2 clinical trial in combination with Keytruda™ and MVI-816 in men with mCRPC.
The androgen receptor is a steroid hormone receptor that plays a crucial role in the development of the prostate and is also important to the progression of prostate cancer. For many decades the primary treatment for recurrent prostate cancer has been androgen deprivation by surgical or pharmacological castration. However, even in the setting of castration-resistant disease the AR remains active and often over-expressed by means of gene regulation and amplification. Given the role and increased expression of AR in the progression of prostate cancer, we have evaluated it as a potential immunotherapy target of CD8+ T cells. Our concept has been that the AR is a critical molecule in prostate cancer development, and hence loss of AR expression as a means of avoiding immune detection should be uncommon. Moreover, over-expression of the AR following androgen deprivation should lead to greater presentation of AR-derived MHC-presented epitopes, permitting these tumor cells to be more readily detected by AR-specific cytolytic CD8+ T cells. Finally, while AR splice variants such as AR-V7 that lose expression of the LBD have emerged as major means of resistance to androgen depriving pharmacological therapies, expression of these variants is typically lower than continued expression of the full-length AR protein. Consequently, expression of AR-V7 or other LBD-loss splice variants may be less of a concern as a means of immunological resistance following LBD-targeted vaccination.
We have previously shown that patients with prostate cancer have CD8+ T-cells that recognize peptide epitopes derived from the AR ligand-binding domain (AR LBD) which can recognize and lyse prostate tumor cells. Furthermore, using a DNA vaccine encoding the AR LBD (pTVG-AR, aka MVI-118), or peptide epitopes derived from the AR LBD, we can elicit/amplify these peptide-specific immune responses in HLA-A2 transgenic mice, and these T-cells can recognize and lyse both human and murine prostate tumor cell lines, ultimately resulting in a lower frequency of adenocarcinoma, delayed tumor growth, and increased overall survival. We have translated these findings to a clinical trial, and demonstrated that patients with metastatic disease can be safely immunized with pTVG-AR, and that patients who develop T-cell immunity to AR appear to have a longer time to disease progression.