Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy
| Autor: | Huong T. Vu, Elisabeth Seja, Denise K. Oseguera, Saral N. Amarnani, William H. McBride, N. Simon Tchekmedyian, Yohan Lee, Vivian B. Dissette, Antoni Ribas, James S. Economou, Lisa H. Butterfield, Begonya Comin-Anduix, John A. Glaspy, Jennifer A. Wargo |
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| Rok vydání: | 2004 |
| Předmět: |
Adult
Male Cancer Research Isoantigens medicine.medical_treatment T-Lymphocytes Immunology Enzyme-Linked Immunosorbent Assay Cancer Vaccines Epitopes Immune system Cancer immunotherapy Antigen Antigens CD Blocking antibody Immunology and Allergy Medicine Humans CTLA-4 Antigen Antigen-presenting cell Antibodies Blocking Melanoma Aged Pharmacology biology business.industry Dendritic cell Immunotherapy Dendritic Cells Middle Aged Antigens Differentiation Peptide Fragments Phenotype Treatment Outcome biology.protein Cytokines Female Antibody business Biomarkers |
| Zdroj: | Journal of immunotherapy (Hagerstown, Md. : 1997). 27(5) |
| ISSN: | 1524-9557 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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