We reviewed 66 women with poor-risk metastatic breast cancer from 15 centers to describe the efficacy of allogeneic hematopoietic cell transplantation (HCT). Median follow-up for survivors was 40 months (range, 3-64). A total of 39 patients (59%) received myeloablative and 27 (41%) reduced-intensity conditioning (RIC) regimens. More patients in the RIC group had poor pretransplant performance status (63 vs 26%, P=0.002). RIC group developed less chronic GVHD (8 vs 36% at 1 year, P=0.003). Treatment-related mortality rates were lower with RIC (7 vs 29% at 100 days...

Allogeneic transplantation of hematopoietic cells from an HLA-compatible donor has been used to treat hematologic malignancies. Allogeneic transplantation not only replaces the marrow affected by the disease, but exerts an immune graft-versus-tumor (GVT) effect mediated by donor lymphocytes. The development of nonmyeloablative conditioning regimens before allogeneic transplantation has allowed this therapy to be used in elderly and disabled patients. An allogeneic GVT effect is observed in a proportion of patients with renal, breast, colorectal, ovarian, and panc...

MHC-class I tetramers technology enabled the characterization of peptide-specific T cells at the single cell level in a variety of studies. Several laboratories have also developed MHC-class II multimers to characterize Ag-specific CD4+ T cells. However, the generation and use of MHC-class II multimers seems more problematic than that of MHC-I multimers. We have generated HLA-DR*1101 tetramers in a versatile empty form, which can be loaded after purification with peptides of interest. We discuss the impact of critical biological and structural parameters for the ...

Little is known about the repertoire of MAGE-A3 CD4(+) T-cell epitopes recognized in vivo by neoplastic patients and how antigen processing influences epitope formation. Here, we first show that MAGE-A3-specific CD4(+) T cells are present in the blood of advanced melanoma patients. MAGE-A3(111-125), MAGE-A3(191-205), and MAGE-A3(281-300) were recognized by 7, 6, and 5 of the 11 patients tested, respectively. MAGE-A3(146-160) and MAGE-A3(171-185) were also recognized in two and one cases, whereas no recognition of MAGE-A3(161-175) and MAGE-A3(243-258) was observed...

Pancreatic carcinoma is a very aggressive disease with dismal prognosis. Although evidences for tumor-specific T cell immunity exist, factors related to tumor microenvironment and the presence of immunosuppressive cytokines in patients' sera have been related to its aggressive behavior. Carcinoembryonic Ag (CEA) is overexpressed in 80-90% of pancreatic carcinomas and contains epitopes recognized by CD4(+) T cells. The aim of this study was to evaluate the extent of cancer-immune surveillance and immune suppression in pancreatic carcinoma patients by comparing the...

Lung cancer represents one of the malignancies in which the 3 elements of conventional therapy (ie, surgery, radiotherapy, and chemotherapy) have limited effectiveness in curbing progressive disease. In this context, there is burgeoning interest in the use of vaccine therapy as a nontoxic adjunct to increase the treatment success rates over those obtained with traditional regimens alone. Several clinical trials using a variety of vaccination strategies have been reported or are ongoing. In this review, we have provided an overview of these trials, with a special ...

Clinical trials have demonstrated from time to time that cancer vaccines can elicit effective antitumour cellular immunity that may translate to clinical benefit for cancer patients. Additionally, several monoclonal antibodies currently used for treating cancer patients mediate their effects through mechanisms like antibody-dependent cellular cytotoxicity (ADCC) and therefore rely on an effective immune system. Patients with advanced tumours, however, are known to have aberrations in their immune function. Improving the clinical effectiveness of immunotherapy the...

Evidence for the existence of CLL-specific antigens recognized by the immune system can be gathered from the observation that many patients display monoclonal or oligoclonal expansions and skewed repertoire of T cells. In vitro functional studies have shown that tumor-specific T-cells are able to lyse the leukemic cells. Antileukemic cellular immunity may be boosted in vivo using dendritic cell-based immunotherapy. Our preclinical studies provide evidence that DC that had endocytosed apoptotic CLL cells (Apo-DC) were superior to fusion hybrids, tumor lysate or RN...

[Article in Swedish]

NK cells are promising effectors for tumor adoptive immunotherapy, particularly when considering the targeting of MHC class I low or negative tumors. Yet, NK cells cannot respond to many tumors, which is particularly the case for nonhematopoietic tumors such as carcinomas or melanoma even when these cells lose MHC class I surface expression. Therefore, we targeted primary human NK cells by gene transfer of an activating chimeric receptor specific for HER-2, which is frequently overexpressed on carcinomas. We found that these targeted NK cells were specifically ac...

Comment in: Mol Ecol. 2008 Jun;17(12):2793-5. Gene-expression variation in natural populations is widespread, and its phenotypic effects can be acted upon by natural selection. Only a few naturally segregating genetic differences associated with expression variation have been identified at the molecular level. We have identified a single nucleotide insertion in a vineyard isolate of Saccharomyces cerevisiae that has cascading effects through the gene-expression network. This allele is responsible for about 45% (103/230) of the genes that show differential ...

Human T lymphocytes can be redirected with a new defined specificity by expression of a chimeric T-cell receptor (immunoreceptor) for the use in adoptive immunotherapy of cancer. Whereas standard procedures use retroviral gene transduction to constitutively express immunoreceptors in T cells, we here explored for the first time mRNA electroporation to achieve transient immunoreceptor expression, and thereby minimizing the risk of persistence of potential autoaggression. CD4(+) and CD8(+) T cells were efficiently transfected with immunoreceptors specific for ErbB2...

The incorporation of RANTES or IL-23 into DNA vaccines may improve their immunogenicity by the recruitment and activation of dendritic cells. This may also select for a TH1 response counteracting the TH2 response which can predominate when a DNA vaccine is delivered by gene gun. We have immunized mice with various DNA constructs encoding APR/8/34 influenza virus hemagglutinin (HA), either fused to or separate from, IL-23 or RANTES using a gene gun. Those immunized with IL-23/HA fusion constructs and challenged with influenza 27 weeks post-vaccination, tended to h...

IMMUNOLOGICAL MONITORING (Protocol SK-MEL24) Patient Identification number: 1st Infusion Date: Response to KLH, NTP, SK-Mel 24 and to the autologous tumor 3H-incorporation PBMC KLH No / Yes NTP No / Yes Cytokines release PBMC KLH No / Yes CD4+ T cells KLH No / Yes NTP No / Yes Autologous tumor (if available) No / Yes (if available) CD8+ T cells KLH No / Yes NTP No / Yes SK-Mel 24 No / Yes Autologous tumor (if available) No / Yes ELISPOT analysis PBMC KLH No / Yes CD4+ T cells KLH No / Yes NTP No / Yes Autologous tumor (...

There is a growing interest in using dendritic cells (DC) for vaccine approaches in the treatment of cancer and infectious diseases. This requires a reproducible method for the generation of large numbers of DC in a closed culture system suitable for clinical use and conforming to the current guidelines of good manufacturing practices. We designed a system in which the DC were generated in a closed system from adherent monocytes using Cell Factories (DC-CF). Monocytes were enriched from apheresis products by adherence and then cultured in the presence of AB serum...

BACKGROUND: Dendritic cells (DC) are the professional antigen-presenting cells of the immune system, fully equipped to prime naive T cells and thus essential components for cancer immunotherapy. METHODS: We tested the influence of several elements (cPPT, trip, WPRE, SIN) on the transduction efficiency of human DC. Human and murine DC were transduced with tNGFR-encoding lentiviruses to assess the effect of transduction on phenotype and function. Human DC were transduced with lentiviruses encoding huIi80MAGE-A3 and murine DC with huIi80tOVA to test antigen presenta...

Antigens encoded by MAGE genes are of particular interest for cancer immunotherapy because they are tumor specific and shared by tumors of different histological types. Several clinical trials are in progress with MAGE peptides, proteins, recombinant poxviruses, and dendritic cells (DC) pulsed with peptides or proteins. The use of gene-modified DC would offer the major advantage of a long-lasting expression of the transgene and a large array of antigenic peptides that fit into the different HLA molecules of the patient. In this study, we tested the ability of gen...

AIMS/HYPOTHESIS: In the human pancreas, a close topographic relationship exists between duct cells and beta cells. This explains the high proportion of duct cells in isolated human islet preparations. We investigated whether human duct cells are a source of TNFalpha-mediated interactions with beta cells and immune cells. This cytokine has been implicated in the development of autoimmune diabetes in mice. METHODS: Human duct cells were isolated from donor pancreases and examined for their ability to produce TNFalpha following a stress-signalling pathway. Duct-cell...