A Neoadjuvant Immunologic Study of Androgen Deprivation Therapy Combined With a GM-CSF-secreting Allogeneic Prostate Cancer Vaccine and Low-dose Cyclophosphamide in Men With High-risk Localized Prostate Cancer Undergoing Radical Prostatectomy
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 (GM-CSF). The release of GM-CSF 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 GM-CSF-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 GM-CSF-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.
Interventional
Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Intraprostatic CD8+ T cell infiltration
To quantify the extent of CD8+ T cell infiltration into the prostate from harvested prostate glands in men with localized prostate cancer receiving neoadjuvant ADT alone (2 weeks prior to surgery), or cyclophosphamide and GVAX followed by ADT, (with CY/GVAX administered 4 weeks prior to prostatectomy, and ADT administered 2 weeks prior to prostatectomy).
2 years
Yes
Emmanual Antonarakis, M.D
Principal Investigator
Johns Hopkins University
United States: Food and Drug Administration
J1265
NCT01696877
September 2012
October 2015
Name | Location |
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The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Baltimore, Maryland 21231 |