Prostate Cancer Adenocarcinoma in Situ Clinical Trial
Official title:
A Neoadjuvant Immunologic Study of Androgen Deprivation Therapy Combined With a Granulocytemacrophage-colony Stimulating Factor F-secreting Allogeneic Prostate Cancer Vaccine and Low-dose Cyclophosphamide in Men With High-risk Localized Prostate Cancer Undergoing Radical Prostatectomy
This research is being done to see if an investigational prostate cancer vaccine, called GVAX, can safely be given together with a single intravenous injection of a drug called cyclophosphamide to men that will undergo surgery to remove their cancerous prostate glands who have also received standard hormonal therapy.
Cancer immunotherapy refers broadly to approaches which attempt to treat cancer by activating
immune responses directed against malignant tissue. Prostate GVAX is an allogeneic cell-based
prostate cancer vaccine composed of two irradiated cell lines (PC3 and LNCaP) that have been
genetically modified to secrete granulocyte-macrophage colony-stimulating factor
(granulocytemacrophage-colony stimulating factor). The release of
granulocytemacrophage-colony stimulating factor by these modified tumor cells serves to
recruit dendritic cells which then present tumor antigens to T-cells, thus initiating
antitumor immune responses.
However, abundant preclinical data show that, when used alone, cell-based immunotherapy is
unable to break specific T-cell tolerance in tumor-bearing hosts. Studies in an autochthonous
prostate cancer mouse model have shown that giving low-dose cyclophosphamide prior to a
cell-based granulocytemacrophage-colony stimulating factor-secreting vaccine abrogates immune
tolerance through augmentation of CD8+ T cell infiltration in the prostate, transient
depletion of regulatory T cells (Tregs), and increased expression of dendritic cell
maturation markers. Enhancement of antitumor immunity has also been observed in other
preclinical models where cyclophosphamide was given in sequence with
granulocytemacrophage-colony stimulating factor-secreting immunotherapy for the treatment of
breast and pancreatic cancers. These preclinical data are supported by early-phase clinical
trials combining GVAX with low-dose cyclophosphamide in pancreatic and breast cancers.
Furthermore, emerging evidence suggests that androgen deprivation therapy (ADT) itself has
profound effects on the host immune system, resulting in thymic regeneration and enhancement
of antitumor immunity. In addition, preclinical and clinical studies demonstrate that ADT
augments prostate cancer-specific immune responses induced by immunotherapy, suggesting that
ADT may act synergistically with immunotherapy. Based on data from mouse models as well as
human clinical trials, it has been suggested that prostate cancer immunotherapy may be most
effective when administered in the setting of an androgen-suppressed environment.
Building on these findings, investigators have designed a study to assess the use of ADT
given alone or administered following immunization with low-dose cyclophosphamide and
prostate GVAX, in patients undergoing radical prostatectomy. Investigators aim (1) to
determine whether ADT is immunogenic in men with localized prostate cancer by evaluating
T-cell infiltration in harvested prostate glands; (2) to determine whether administering ADT
after low-dose cyclophosphamide and prostate GVAX augments immune infiltration into the
prostate gland; and (3) to investigate whether this combinatorial immuno-hormonal approach is
safe and feasible. Investigators hypothesize that the combination of ADT and
cyclophosphamide/GVAX will produce significantly greater antitumor immune responses than
would ADT used alone.
;