A Neoadjuvant Study of Androgen Ablation Combined With Cyclophosphamide and GVAX Vaccine for Localized Prostate Cancer

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.

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the prostate (clinical stage T1c-T3b, N0,
M0) without involvement of lymph nodes, bone, or visceral organs

- Initial prostate biopsy is available for central pathologic review, and is confirmed
to show at least 2 positive cores and a maximum Gleason sum of ≥ 7

- Radical prostatectomy has been scheduled at Johns Hopkins Hospital

- Age ≥ 21 years

- Eastern Cooperative Oncology Group performance status 0-1, or Karnofsky score ≥ 70%

- Adequate bone marrow, hepatic, and renal function:

- White Blood Count > 3,000 cells/mm3

- Absolute neutrophil count > 1,500 cells/mm3

- Hemoglobin > 9.0 g/dL

- Platelet count > 100,000 cells/mm3

- Serum creatinine < 2.0 mg/dL

- Serum bilirubin < 2 mg/dL

- Alanine aminotransferase < 2 × upper limit of normal (ULN)

- Aspartate aminotransferase < 2 × ULN

- Alkaline phosphatase < 2 × ULN

- Willingness to provide written informed consent and HIPAA authorization for the
release of personal health information, and the ability to comply with the study
requirements (note: HIPAA authorization will be included in the informed consent)

- Willingness to use barrier contraception from the time of cyclophosphamide and/or GVAX
administration until the time of prostatectomy.

Exclusion Criteria:

- Presence of known lymph node involvement or distant metastases

- Other histologic types of prostate cancers such as ductal, sarcomatous, lymphoma,
small cell, and neuroendocrine tumors

- Prior radiation therapy, hormonal therapy, biologic therapy, or chemotherapy for
prostate cancer

- Prior immunotherapy/vaccine therapy for prostate cancer

- Previous or concurrent use of cyclophosphamide

- Concomitant treatment with other hormonal therapy or 5a-reductase inhibitors

- Current use of systemic corticosteroids or use of corticosteroids within 4 weeks of
enrollment (inhaled corticosteroids for asthma or Chronic obstructive pulmonary
disease are permitted)

- Use of experimental agents for prostate cancer within the past 3 months

- Known allergy to cyclophosphamide or G-colony stimulating factor
/granulocytemacrophage-colony stimulating factor

- Known hypersensitivity to materials of bovine origin (e.g. fetal bovine serum), or
other components of GVAX which include Dimethyl sulfoxide and hydroxyethyl starch as
well as small amounts of porcine trypsin and DNase

- History or presence of autoimmune disease requiring systemic immunosuppression
(including but not limited to: inflammatory bowel disease, systemic lupus
erythematosus, vasculitis, rheumatoid arthritis, scleroderma, multiple sclerosis,
hemolytic anemia, Sjögren syndrome, and sarcoidosis)

- Other concurrent malignancies, with the exception of non-melanoma skin cancers and
superficial bladder cancer

- Uncontrolled major active infectious, cardiovascular, pulmonary, hematologic, or
psychiatric illnesses that would make the patient a poor study candidate

- Known prior or current history of HIV and/or hepatitis B/C