Generation in vivo of peptide-specific cytotoxic T cells and presence of regulatory T cells during vaccination with hTERT (class I and II) peptide-pulsed DCs
| Autor: | Joti Bhalla, Farzin Farzaneh, Richard A Robins, Mark M. Aloysius, Jennifer M. Eremin, Sukchai Satthaporn, Chandan Verma, M. El-Sheemy, Nagy A. Habib, Oleg Eremin, Thiagarajan Sreenivasan, Alastair J Mc Kechnie, Nicola Hardwick |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Cytotoxicity
Immunologic Telomerase medicine.medical_treatment lcsh:Medicine Research & Experimental Medicine CD8-Positive T-Lymphocytes T-Lymphocytes Regulatory Epitope Neoplasms Cytotoxic T cell Medicine(all) HLA-D Antigens PROSTATE SPECIFIC ANTIGEN TREATED PATIENTS 11 Medical And Health Sciences General Medicine medicine.anatomical_structure Medicine Research & Experimental TELOMERASE REVERSE-TRANSCRIPTASE HUMAN DENDRITIC CELLS Tumor necrosis factor alpha Life Sciences & Biomedicine STAGE MELANOMA PATIENTS T cell Immunology Cancer Vaccines General Biochemistry Genetics and Molecular Biology Dinoprostone LOW-DOSE CYCLOPHOSPHAMIDE medicine Humans Telomerase reverse transcriptase Science & Technology business.industry Biochemistry Genetics and Molecular Biology(all) Interleukin-6 Tumor Necrosis Factor-alpha Research Macrophages lcsh:R Histocompatibility Antigens Class I IFN-ALPHA Interferon-alpha Immunotherapy Peptide Fragments PBL-SCID MICE Cancer research DENILEUKIN DIFTITOX Lymph Nodes business CD8 Interleukin-1 T-Lymphocytes Cytotoxic |
| Zdroj: | Journal of Translational Medicine Journal of Translational Medicine, Vol 7, Iss 1, p 18 (2009) |
| ISSN: | 1479-5876 |
| Popis: | Background Optimal techniques for DC generation for immunotherapy in cancer are yet to be established. Study aims were to evaluate: (i) DC activation/maturation milieu (TNF-α +/- IFN-α) and its effects on CD8+ hTERT-specific T cell responses to class I epitopes (p540 or p865), (ii) CD8+ hTERT-specific T cell responses elicited by vaccination with class I alone or both class I and II epitope (p766 and p672)-pulsed DCs, prepared without IFN-α, (iii) association between circulating T regulatory cells (Tregs) and clinical responses. Methods Autologous DCs were generated from 10 patients (HLA-0201) with advanced cancer by culturing CD14+ blood monocytes in the presence of GM-CSF and IL-4 supplemented with TNF-α [DCT] or TNF-α and IFN-α [DCTI]. The capacity of the DCs to induce functional CD8+ T cell responses to hTERT HLA-0201 restricted nonapeptides was assessed by MHC tetramer binding and peptide-specific cytotoxicity. Each DC preparation (DCT or DCTI) was pulsed with only one type of hTERT peptide (p540 or p865) and both preparations were injected into separate lymph node draining regions every 2–3 weeks. This vaccination design enabled comparison of efficacy between DCT and DCTI in generating hTERT peptide specific CD8+ T cells and comparison of class I hTERT peptide (p540 or p865)-loaded DCT with or without class II cognate help (p766 and p672) in 6 patients. T regulatory cells were evaluated in 8 patients. Results (i) DCTIs and DCTs, pulsed with hTERT peptides, were comparable (p = 0.45, t-test) in inducing peptide-specific CD8+ T cell responses. (ii) Class II cognate help, significantly enhanced (p < 0.05, t-test) peptide-specific CD8+T cell responses, compared with class I pulsed DCs alone. (iii) Clinical responders had significantly lower (p < 0.05, Mann-Whitney U test) T regs, compared with non-responders. 4/16 patients experienced partial but transient clinical responses during vaccination. Vaccination was well tolerated with minimal toxicity. Conclusion Addition of IFN-α to ex vivo monocyte-derived DCs, did not significantly enhance peptide-specific T cell responses in vivo, compared with TNF-α alone. Class II cognate help significantly augments peptide-specific T cell responses. Clinically favourable responses were seen in patients with low levels of circulating T regs. |
| Databáze: | OpenAIRE |
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