T cell immunotherapy of prostate cancer (CaP) offers the potential for less toxic, more effective outcomes. A clinical trial was conducted in 28 patients with locally advanced or metastatic CaP to determine whether an HLA-A2 binding epitope of prostate-specific antigen, PSA146-154 (PSA-peptide), can induce specific T cell immunity. Patients were vaccinated either by intradermal injection of PSA-peptide and GM-CSF or by intravenous administration of autologous dendritic cells pulsed with PSA-peptide at weeks 1, 4 and 10. Delayed-type hypersensitivity (DTH) skin testing was performed at weeks 4, 14, 26 and 52. Fifty percent of the patients developed positive DTH responses to PSA-peptide. The size of the DTH induration progressively increased over time in the majority of responding patients. Skin biopsies from seven DTH-positive patients were available and T cells that developed in situ were also characterized. The phenotype of recovered T cells demonstrated variable proportions of CD4+CD8-, CD4-CD8+ and CD4+CD8+ T cell populations. Cytokine analysis of PSA-peptide stimulated T cells per bead array assay exhibited specific IFN-gamma and TNF-alpha response in six of seven patients. Specific IL-4 response was observed in five patients, while IL-10 response was detected in one patient. Purified CD4-CD8+ T cells isolated from four patients demonstrated specific cytolytic activity per chromium release assay. In conclusion, immunization with PSA-peptide induced specific T cell immunity in one-half of the patients with locally advanced and hormone-sensitive, metastatic CaP. DTH-derived T cells exhibited PSA-peptide-specific cytolytic activity and predominantly expressed a type-1 cytokine profile.
The interferon response genes 1 and 2 have been shown to be involved in the regulation of differentiation and proliferation of cells of the myeloid series, with the former functioning as an anti-oncogene and the latter as an oncogene. In the study described here, the levels of expression of these two genes and the ratio of their expression were compared in AML and normal marrow. The ratio of gene expression was significantly less in AML marrow cells as compared to normal marrow cells [med ratio = 1.33 vs. 2.97, P = 0.003]. While the expression ratio was unaffected by the presence or absence of either ras or fms mutations, p53 mutations were associated with higher IRF1:IRF2 expression ratios that wt p53 genes [med = 1.701 vs. 1.135, P = 0.014]. Given the functional characteristics and the competitive nature of these two genes, it is possible that leukemic transformation is associated with a fall in IRF1:IRF2 ratios. Finally, the administration of IL4 can result in the normalization of the IRF1:IRF2 ratio in the marrow cells of some patients with AML.
The trafficking or homing of different lymphoid subsets to particular microenvironment is mediated by specific cell adhesion molecules (CAMs) expressed on lymphocytes and endothelial cells. B-cell chronic lymphocytic leukaemia (B-CLL) or Non-Hodgkin's lymphoma of small lymphocytic, B-cell type are monoclonal expansions of mature lymphocytes. The relative distribution of the tumor lymphocytes among various lymphoid compartments vary from patient to patient. Very few studies underlying this issue are available. To this effect, we have analysed the expression of LFA-1; VLA-4, ICAM-1; CD44H and CD44v6 (haematopoietic and variant form respectively) on freshly isolated lymphocytes obtained from bone marrow (BM), peripheral blood (PB) and lymph node (LN) by flow cytometry. Overall, we find strong expression of CD44H, low to moderate expression of LFA-1, negative to low expression of VLA-4 and lack of expression of CD44v6. ICAM-1 expression was observed only in patients with prominent lymphadenopathy. Higher expression of CD44H in PB lymphoid cells relative to that of BM lymphoid cells correlated with higher PB lymphocytosis (p < 0.001). Proliferating cell nuclear antigen expression in LN sections correlated inversely with VLA-4 expression on BM and PB lymphoid cells (p < 0.05). There was no significant correlation between expression of CAMs and bcl-2 protein.
Prostate-specific antigen (PSA) is a potentially useful antigen for targeted T-cell immunotherapy of prostate cancer (CaP). Our laboratory has identified a synthetic nonamer peptide (PSA 146-154) homologue of PSA, which binds to the prevalent human leukocyte antigen, HLA-A2, and elicits specific cytotoxic T-lymphocyte (CTL) responses from normal individuals of the HLA-A2 phenotype. In the present study, we report on the induction of CTL from peripheral blood mononuclear cells (PBMC) of patients with hormone-refractory CaP, which exhibit the same specificity. T-cell lines were established from two patients by stimulation of PBMC with PSA 146-154 peptide in vitro. The T-cell lines exhibited specific cytolytic activity against T2 cells pulsed with PSA 146-154 peptide, but not a control HLA-A2 binding peptide (HIV-RT 476-484) via chromium release assay (CRA). The T-cell lines also showed PSA 146-154 peptide-specific IL-4 responses, but no detectable interferon-gamma (IFN-gamma) responses via enzyme-linked immuno-spot assays. Magnetic immuno-selection studies of one of the T-cell lines demonstrated that both cytolytic and interleukin-4 (IL-4) responses were mediated by CD8(+), but not by CD4(+) T cells. This Tc2 line was further characterized for the ability to recognize endogenously processed PSA epitopes. The line specifically secreted IL-4 in response to HLA-A2(+) target cells transfected to express PSA and specifically lysed the PSA(+) target cells, but not control transfected cells. The results indicate that the PSA 146-154 peptide emulates a naturally processed and presented peptide epitope of PSA that is within the T-cell repertoire of HLA-A2(+)patients with CaP.
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