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 DCsReportar como inadecuado




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 - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal of Translational Medicine

, 7:18

First Online: 19 March 2009Received: 17 January 2009Accepted: 19 March 2009DOI: 10.1186-1479-5876-7-18

Cite this article as: Aloysius, M.M., Mc Kechnie, A.J., Robins, R.A. et al. J Transl Med 2009 7: 18. doi:10.1186-1479-5876-7-18

Abstract

BackgroundOptimal 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.

MethodsAutologous 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.

Resultsi 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.

ConclusionAddition 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.

Electronic supplementary materialThe online version of this article doi:10.1186-1479-5876-7-18 contains supplementary material, which is available to authorized users.

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