Carlos Ferrada

Prolonged Survival of Dendritic Cell–Vaccinated Melanoma Patients Correlates With Tumor-Specific Delayed Type IV Hypersensitivity Response and Reduction of Tumor Growth Factor β-Expressing T Cells

PURPOSE The aim of this work was to assess immunologic response, disease progression, and post-treatment survival of melanoma patients vaccinated with autologous dendritic cells (DCs) pulsed with a novel allogeneic cell lysate (TRIMEL) derived from three melanoma cell lines. PATIENTS AND METHODS Forty-three stage IV and seven stage III patients were vaccinated four times with TRIMEL/DC vaccine. Specific delayed type IV hypersensitivity (DTH) reaction, ex vivo cytokine production, and regulatory T-cell populations were determined. Overall survival and disease progression rates were analyzed using Kaplan-Meier curves and compared with historical records. RESULTS The overall survival for stage IV patients was 15 months. More than 60% of patients showed DTH-positive reaction against the TRIMEL. Stage IV/DTH-positive patients displayed a median survival of 33 months compared with 11 months observed for DTH-negative patients (P = .0014). All stage III treated patients were DTH positive and remained alive and tumor free for a median follow-up period of 48 months (range, 33 to 64 months). DTH-positive patients showed a marked reduction in the proportion of CD4+ transforming growth factor (TGF) beta+ regulatory T cells compared to DTH-negative patients (1.54% v 5.78%; P < .0001). CONCLUSION Our findings strongly suggest that TRIMEL-pulsed DCs provide a standardized and widely applicable source of melanoma antigens, very effective in evoking antimelanoma immune response. To our knowledge, this is the first report describing a correlation between vaccine-induced reduction of CD4+TGFbeta+ regulatory T cells and in vivo antimelanoma immune response associated to improved patient survival and disease stability.

Dendritic cell immunizations alone or combined with low doses of interleukin-2 induce specific immune responses in melanoma patients.

Dendritic cell (DC)‐based therapy has proved to be effective in patients with a variety of malignancies. However, an optimal immunization protocol using DCs and the best means for delivering antigens has not yet been described. In this study, 20 patients with malignant melanoma in stages III or IV were vaccinated with autologous DCs pulsed with a melanoma cell lysate, alone (n = 13) or in combination with low doses of subcutaneous (s.c.) interleukin (IL)‐2 injections (n = 7), to assess toxicity, immunological and clinical responses. Monocyte‐derived DCs were morphological, phenotypic and functionally characterized in vitro. Peripheral blood mononuclear cells (PBMC), harvested from patients either prior to and after the treatment, were analysed using enzyme‐linked immunosorbent spot (ELISPOT). After vaccination, 50% of the patients tested (seven of 13) from the first group and (three of seven) from the second, showed an increase in interferon (IFN)‐γ production in response to allogeneic melanoma cell lines but not to controls. Four of five tested human leucocyte antigen (HLA)‐A2+ patients with anti‐melanoma activity also showed specific T cell responses against peptides derived from melanoma‐associated antigens. Delayed type IV hypersensitivity reaction (DTH) against melanoma cell lysate was observed in six of 13 patients from the group treated with DC vaccines only and four of seven from the group treated with the combination of DCs and IL‐2. Significant correlations were found between DTH‐positive responses against tumour lysate and both disease stability and post‐vaccination survival on the stage IV patients. There were no toxicities associated with the vaccines or evidence of autoimmunity including vitiligo. Furthermore, no significant enhancement was observed as a result of combining DC vaccination with IL‐2. Our data suggest that autologous DCs pulsed with tumour lysate may provide a standardized and widely applicable source of melanoma specific antigens for clinical use. It is safe and causes no significant side effects and has been demonstrated to be partially efficient at triggering effective anti‐melanoma immunity.

Incidencia de hipocalcemia pos tiroidectomía total

Postoperative hypocalcemia is one of the mostcommon complications of thyroid surgery. It is related to the type of disease (malignant orbenign), the number of identified parathyroid glands during the surgical procedure, and thesurgeon’s experience. Total thyroidectomy is the procedure of choice in our hospital for benignand malignant thyroid disease, but it can increase the incidence of complications.

Activity during reduction of NO by CO over bimetallic palladium-rhodium/silica catalysts

A study of the activity of bimetallic Pd-Rh catalysts supported on silica in the reduction of NO by CO is presented. The catalysts were prepared by three different methods: (1) Pd and Rh were coimpregnated on the support, (2) Rh was impregnated first and, after calcining, the sample was impregnated with Pd, (3) the monometallic Pd and Rh catalysts were physically mixed. The results showed that the activity of the catalysts prepared by coimpregnation was much lower than that of the other two catalysts.

Avances en inmunoterapia celular contra el melanoma maligno

An alternative strategy for cancer treatment is the manipulation of the immune system, denominated cancer immunotherapy. The immunotherapeutical use of cells of the immune system, like dendritic cells (DC), is being explored in different clinical protocols. Recently, we finalized a clinical phase I protocol, for the treatment of malignant melanoma, using DCs loaded with tumor lysates. Our results indicate that the subcutaneous application of DCs do not produce adverse effects. We also observed an increase of tumor specific T lymphocytes precursors in the blood, associated to hypersensitivity reactions (DTH) in 60% of the treated patients. In most cases, an stability in the disease was observed, although without a significant association between vaccination and survival. Additionally, therapies based on Interleukin-2 (IL-2) have been used with relative success in the treatment of some kind of tumors since 1985. However, problems associated to the toxicity of IL-2 still restrict its massive use. Our direct experience with the use of IL-2, indicates that low doses and its subcutaneous application, maintains the beneficial effects for patients, eliminating the adverse effects. Based on the accumulated evidence during last the five years, we decided to implement an optimized clinical protocol, which alternatively combines dendritic cells vaccines with the use of low doses of IL-2 for the reinforcement of the immunological system (Rev Med Chile 2004; 132: 1115-26). (Key Words: Dendritic cells; Immunotherapy; Interleukin-2; Malignant melanoma)

Abstract B17: Heat shock-induced danger signals in tumor cells are crucial for a rapid differentiation of monocyte to therapeutic dendritic cells

Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that initiate a cell-mediated antitumor immune response. Recently, we showed that monocyte-derived DCs loaded with a heat-shocked melanoma cell lysate (TRIMEL®) induce melanoma-specific immune responses, thus prolonging patient survival. Here, we describe the rapid effect of TRIMEL on human monocytes differentiation to tumor-antigen presenting cells (TAPCells®). TAPCells showed a mature DC-like phenotype and effectively activated melanoma associated antigen (MAA)-specific CD4+ and CD8+ T lymphocytes. Moreover, heat shock (HS) pre-conditioning of TRIMEL composing cells increased calreticulin (CRT) cell surface translocation and released high-mobility group box 1 protein (HMGB1), which was closely associated to the induction of APC maturation and efficient MAAs cross-presentation. Finally, 26 out of 43 patients vaccinated with TAPCells showed a TRIMEL-specific delayed type hypersensitivity reaction (DTH) associated to anti-melanoma T cell recognition, reduced rates of progression and prolonged patient survival. Our results suggest that heat-shocked tumor cell lysates are optimal source of MAAs, inducing activated APCs with improved MAAs cross-presentation capacity and clinically effective immunogenicity. Citation Information: Clin Cancer Res 2010;16(7 Suppl):B17

Tumor fibroso solitario del tiroides

El tumor fibroso solitario (TFS) es una neoplasia de celulas fusadas, de muy baja frecuencia, encontrada mayormente en la pleura pero tambien descrita en sitios extrapleurales. En la literatura se han reportado 24 casos de TFS originados en el tiroides, todos con caracteristicas patologicas e inmunohistoquimicas (IHQ) similares. Reportamos el caso de un tumor tiroideo en un hombre de 30 anos. El tumor se caracterizo por ser una proliferacion de celulas fusadas dispuestas en un patron estoriforme y hemangiopericitoide, sin necrosis ni atipias, con baja actividad mitotica. El estudio IHQ presento positividad para CD34 y bcl-2 y negatividad para Desmina, Pancitokeratina y S-100, caracteristicas concordantes con un TFS. Es importante saber que esta entidad puede surgir en el tiroides y asi poder orientar el estudio para su diagnostico correcto.