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.
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Authors | Antoni 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 |
Journal | Journal of immunotherapy (Hagerstown, Md. : 1997)
(J Immunother)
2004 Sep-Oct
Vol. 27
Issue 5
Pg. 354-67
ISSN: 1524-9557 [Print] United States |
PMID | 15314544
(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.)
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Copyright | Copyright 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
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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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