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A phase I trial of SD-9427 (progenipoietin) with a multipeptide vaccine for resected metastatic melanoma.

AbstractPURPOSE:
The melanoma tumor antigen epitope peptides MART-1(26-35 (27L)), gp100(209-217 (210M)),and tyrosinase(368-376 (370D)) were emulsified with incomplete Freund's adjuvant and administered with SD-9427 (progenipoietin), an agonist of granulocyte colony-stimulating factor and the FLT-3 receptor, to evaluate the toxicities of and immune responses to this regimen as primary end points and time to relapse and survival as secondary end points.
EXPERIMENTAL DESIGN:
Fifteen patients with high-risk resected stage III and IV melanoma were enrolled. Each patient received peptides + incomplete Freund's adjuvant with SD-9427 at doses of either 10, 20, or 40 microg/kg s.c. for 3 days before and 7 days after each vaccination. Immunizations were administered every month for 6 months and then administered once 6 months later. A leukapheresis to obtain peripheral blood mononuclear cells for immune analyses as well as skin testing with peptides and recall antigens was performed before and after vaccination. IFN- gamma release assay, ELISPOT, and MHC-peptide tetramer analysis were performed using peripheral blood mononuclear cells collected before and after vaccination to evaluate peptide-specific cytotoxic T-cell responses.
RESULTS:
Local pain and granuloma formation and fatigue of grade I or II were the most common side effects. One patient developed antibody-mediated leukopenia and transient grade III neutropenia that resolved after stopping SD-9427. Six of 12 patients tested developed a positive skin test response to one or more of the peptides. Seven of 10 patients tested demonstrated an immune response to at least one peptide when evaluated by IFN-gamma release assay and ELISPOT assay after vaccination, as did 11 of 12 patients analyzed by MHC-peptide tetramer assay. Four of 15 patients have relapsed with a median follow-up of 20 months, and 1 patient in this high-risk group has died of disease.
CONCLUSIONS:
SD-9427 with a multipeptide vaccine was generally well tolerated, although one patient developed reversible antibody-mediated neutropenia. These data suggest that the majority of patients with resected melanoma mount an antigen-specific immune response against a multipeptide vaccine administered with SD-9427.
AuthorsVinod Pullarkat, Peter P Lee, Ronaldo Scotland, Valerie Rubio, Susan Groshen, Conway Gee, Roy Lau, Jolie Snively, Shirley Sian, Susan L Woulfe, Richard A Wolfe, Jeffrey S Weber
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 4 Pg. 1301-12 (Apr 2003) ISSN: 1078-0432 [Print] United States
PMID12684398 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antigens, Neoplasm
  • Cancer Vaccines
  • Colony-Stimulating Factors
  • Cytokines
  • Epitopes
  • MART-1 Antigen
  • MLANA protein, human
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • PMEL protein, human
  • Peptides
  • Recombinant Proteins
  • Vaccines
  • Vaccines, Subunit
  • gp100 Melanoma Antigen
  • progenipoietin-1
  • Monophenol Monooxygenase
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, Neoplasm
  • Cancer Vaccines (metabolism)
  • Colony-Stimulating Factors (pharmacology, therapeutic use)
  • Cytokines (metabolism)
  • Dendritic Cells (metabolism)
  • Epitopes
  • Female
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Leukapheresis
  • MART-1 Antigen
  • Male
  • Melanoma (drug therapy, metabolism, surgery)
  • Membrane Glycoproteins (biosynthesis)
  • Middle Aged
  • Monophenol Monooxygenase (biosynthesis)
  • Neoplasm Proteins (biosynthesis)
  • Peptides (chemistry)
  • Recombinant Proteins
  • Time Factors
  • Treatment Outcome
  • Vaccines (metabolism)
  • Vaccines, Subunit (metabolism)
  • gp100 Melanoma Antigen

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