Safety and biological activity of repeated doses of recombinant human Flt3 ligand in patients with bone scan-negative hormone-refractory prostate cancer.

Abstract

PURPOSE:

The purpose of this study was to evaluate the safety, biological activity, and feasibility of repeated doses of the dendritic cell (DC)-stimulating agent Flt3 ligand (FL) in patients with bone scan-negative hormone-refractory prostate cancer.

EXPERIMENTAL DESIGN:

Thirty-one patients with hormone-refractory prostate cancer who had elevated prostate-specific antigen (PSA) levels and negative bone scans were enrolled. Six cycles (28 days each) were planned. In the first cycle, patients were randomized to FL or placebo. All patients received open-label FL during the next five courses. DC, anti-FL antibody, and PSA levels were measured every 15 days to assess biological activity.

RESULTS:

DCs increased markedly in FL-treated patients from precycle to day 15, and the increase was consistent in each cycle. Mean percentages of DCs in peripheral blood ranged from 1.4% to 1.9% precycle and from 10.1% to 13.9% on day 15, and after the first cycle, absolute counts on day 15 were approximately 29-fold higher than precycle levels. Natural killer cell counts (CD56(+)) were found to be elevated after cycle 1 (154% increase versus 2.8% decrease in placebo group at day 22). Twenty-two of 27 patients tested developed nonneutralizing anti-FL antibody. The most frequently experienced toxicity was injection site reaction, followed by asthenia, rash, and diarrhea. Although median PSA levels did not vary during any cycle, a significant slowing in velocity of PSA was observed while patients were on-study (relative velocity = 0.002) compared with prestudy PSA velocity (relative velocity = 0.007).

CONCLUSIONS:

FL was well tolerated. FL consistently produced an increase in DC count without any evidence of decreasing response with continued exposure. The expansion of DCs and the slowing of PSA velocity after administration of FL suggest potential clinical applications in the immunotherapy of prostate cancer.

• Authors: Celestia S Higano, Nicholas J Vogelzang, Jeffrey A Sosman, Anyang Feng, Dania Caron, Eric J Small
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 4 Pg. 1219-25 (Feb 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 14977818 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• CD56 Antigen
• Membrane Proteins
• Placebos
• Recombinant Proteins
• flt3 ligand protein
• Prostate-Specific Antigen

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents, Hormonal (pharmacology)
• CD56 Antigen (biosynthesis)
• Dendritic Cells (metabolism)
• Drug Resistance, Neoplasm
• Flow Cytometry
• Hematopoietic Stem Cells (metabolism)
• Humans
• Leukocytes, Mononuclear (metabolism)
• Lymphocytes (cytology, metabolism)
• Male
• Membrane Proteins (administration & dosage, metabolism)
• Middle Aged
• Monocytes (metabolism)
• Placebos
• Prostate-Specific Antigen (biosynthesis)
• Prostatic Neoplasms (drug therapy)
• Random Allocation
• Recombinant Proteins (chemistry, pharmacology)
• Time Factors