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Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy.

Abstract
MART-1(27-35)-peptide-pulsed immature dendritic cells (DCs) resulted in immunologic and clinical activity in a prior phase 1 trial. A phase 2 cohort expansion was initiated to further characterize the phenotype and cytokine milieu of the DC vaccines and their immunologic activity in vitro and to further examine a possible link between clinical activity and determinant spreading. In an open-label phase 2 trial, 10(7) autologous ex vivo generated DCs pulsed with the HLA-A*0201 immunodominant peptide MART-1(27-35) were administered to 10 subjects with stage II-IV melanoma. The experimental vaccines were administered intradermally in a biweekly schedule for a total of three injections, and blood for immunologic assays was obtained before each administration and at three time points after. DC vaccine preparations had wide intra- and interpatient variability in terms of cell surface markers and preferential cytokine milieu, but they did not correlate with the levels of antigen-specific T cells after vaccination. Of four patients with measurable disease, one had stable disease for 6 months and another has a continued complete response for over 2 years, which is confounded by receiving a closely sequenced CTLA4 blocking antibody. The DC vaccines induced determinant spreading in this subject, and CTLA4 blockade reactivated T cells with prior antigen exposure. The DC phenotype and cytokine profile do not correlate with the ability to induce antigen-specific T cells, while determinant spreading after DC immunization may be a marker of an efficient antitumor response. Sequential CTLA4 blockade may enhance the immune activity of DC-based immunotherapy.
AuthorsAntoni Ribas, John A Glaspy, Yohan Lee, Vivian B Dissette, Elisabeth Seja, Huong T Vu, N Simon Tchekmedyian, Denise Oseguera, Begonya Comin-Anduix, Jennifer A Wargo, Saral N Amarnani, William H McBride, James S Economou, Lisa H Butterfield
JournalJournal of immunotherapy (Hagerstown, Md. : 1997) (J Immunother) 2004 Sep-Oct Vol. 27 Issue 5 Pg. 354-67 ISSN: 1524-9557 [Print] United States
PMID15314544 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
CopyrightCopyright 2004 Lippincott Williams & Wilkins
Chemical References
  • Antibodies, Blocking
  • Antigens, CD
  • Antigens, Differentiation
  • Biomarkers
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cancer Vaccines
  • Cytokines
  • Epitopes
  • Isoantigens
  • MART-1 antigen (27-35), Leu(28)-beta-HIle(30)-
  • Peptide Fragments
Topics
  • Adult
  • Aged
  • Antibodies, Blocking (therapeutic use)
  • Antigens, CD
  • Antigens, Differentiation (immunology)
  • Biomarkers (analysis)
  • CTLA-4 Antigen
  • Cancer Vaccines (therapeutic use)
  • Cytokines (immunology)
  • Dendritic Cells (immunology)
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes (immunology)
  • Female
  • Humans
  • Immunotherapy
  • Isoantigens (immunology)
  • Male
  • Melanoma (immunology, therapy)
  • Middle Aged
  • Peptide Fragments (immunology)
  • Phenotype
  • T-Lymphocytes (immunology)
  • Treatment Outcome

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