Neoadjuvant GM-CSF and thalidomide in men with high-risk prostate carcinoma undergoing radical prostatectomy

Abstract

4564 Background: Granulocyte macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that stimulates dendritic cells (DC’s) and promotes uptake of tumor antigens by DC’s leading to T cell cross-priming. Thalidomide is an anti-inflammatory agent with immunomodulatory and antiangiogenic activity. Administration of GM-CSF and Thalidomide can induce PSA responses in 20–25% of patients (pts) with Hormone-Refractory Prostate Cancer (HRPC). In an effort to further evaluate this novel combination we conducted a phase II trial in pts with locally advanced PCA. Methods: High-risk PCA pts undergoing radical prostatectomy (RP) were eligible. ECOG 0–1, adequate organ function, and no prior hormonal therapy were required. All pts received GM-CSF at 250 μg administered SC three times weekly. Thalidomide was escalated to reach the study dose of 200 mg/day. Patients were assessed every 4 weeks with therapy continuing to a maximum of 8 weeks. The primary endpoints were pathologic response, rate of PSA decline and toxicity. High-throughput tissue microarrays (TMAs) were also used to assess exploratory tissue endpoints including tumor expression of PTEN, CD3, Ki-67, and CD68 by immunohistochemistry. Results: To date 22 of a total planned of 29 pts are enrolled. Median age is 59 (43–72), median PSA of 10.4 (3.6–64.8). Baseline Gleason Scores (9 pts-GS7, 10 pts-GS8, and 3 pts GS9). 19/22 pts received all 8 weeks of therapy. Three pts discontinued therapy early due to toxicity or drug intolerance. A maximum PSA decline of 15–55% was observed in 86% of pts. Grade (G) 1–2 toxicities included dizziness/paresthesias (68%), constipation (64%), injection site reactions (64%) and fatigue (50%). Only one pt developed G3 toxicity (DVT). Tumor tissue expression of PTEN, Ki-67, CD3 and CD68 was significantly higher in treated pts when compared with matched controls (PTEN p = 0.03, Ki-67 p = 0.004, CD3 p < 0.001, and CD68 p < 0.001). Conclusions: Neoadjuvant therapy with GM-CSF and Thalidomide is well tolerated, and does not appear to impact on the perioperative morbidity of RP. This combination therapy appears to induce overexpression of PTEN, Ki-67, CD3 and CD68 in PCA tissue. Ongoing tissue and serum immune studies are underway to better define the significance of these tissue findings. [Table: see text]