Cutaneous Melanoma: A Test Field for Immunotherapy and a Medical Challenge

Cutaneous melanoma (CM) is the fourth tumor in frequency, and that whose incidence increases faster. In half of the cases, CM arises from pre-existing nevi. CM is a highly heterogeneous tumor, whose degree of differentiation varies among different hosts, and such heterogeneity is probably based on the accumulation of mutations that determine transitions from normal melanocytic stem cells mutated benign melanocytic stem cells malignant melanocytic stem cells clonogenic melanocytic cells. These populations may express different antigens and would therefore trigger the proliferation of different T and B cell clones. Early diagnosis is the clue for the cure of CM; when visceral metastatic disease is established, the prognosis is somber. This is especially so since CM is quite resistant to chemotherapy, and some of the reasons for such resistance will be discussed here. However, CM has proved to be sensitive to immunological effectors, although the mechanism of such sensitivity is still being investigated. These effectors range from therapeutic vaccines, in vitro expanded cytotoxic lymphocytes, cytokines, and monoclonal antibodies. Finally, we will discuss new therapeutic approaches that include the combination of immune modulators and vaccines which are being assayed in light of recent tumor immunology research.Fil: Aris, Mariana. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Barrio, Maria Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Mordoh, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentin

Vacuna terapéutica CSF-470 para melanoma cutáneo

El melanoma cutáneo es la patología tumoral con mayor incidencia de crecimiento. Una vez que hace metástasis, es resistente a los tratamientos convencionales, con pronóstico reservado. Recientemente han surgido nuevas estrategias terapéuticas con resultados alentadores, incluyendo la inmunoterapia. En esta nota nos centraremos en el uso de vacunas, en particular en la vacuna alogeneica irradiada CSF-470, coadyuvada con BCG y Molgramostim (GM-CSF), para el tratamiento adyuvante de pacientes con melanoma cutáneo estadios IIB, IIC o III post-cirugía. Describiremos los resultados del estudio clínico de fase I y el diseño del estudio actual de fase II-III activoFil: Aris, Mariana. Fundacion Cancer. Centro de Investigaciones Oncologicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barrio, Maria Marcela. Fundacion Cancer. Centro de Investigaciones Oncologicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mordoh, Jose. Fundacion Cancer. Centro de Investigaciones Oncologicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Cetuximab and IL-15 Promote NK and Dendritic Cell Activation In Vitro in Triple Negative Breast Cancer

Triple Negative Breast Cancer (TNBC) treatment is still challenging, and immunotherapy is a potential approach in this tumor subtype. Cetuximab is an IgG1 monoclonal antibody (mAb) directed against Epidermic Growth Factor Receptor (EGFR), a protein overexpressed in a subgroup of TNBC patients and associated with poor prognosis. Previously, we demonstrated in vitro that Cetuximab triggers Ab-dependent cell cytotoxicity against TNBC cells. In this study, using co-cultures including TNBC cells, and NK and Dendritic Cells (DCs) from healthy donors, we studied the effect of Cetuximab-activated NK cells on DC function. Given that we already demonstrated that TNBC has an immunosuppressive effect on NK cells, we also tested Cetuximab combination with IL-15. We determined that Cetuximab opsonization of TNBC cells increased IFN-γ and TNF-α production by NK cells co-cultured with DCs. Moreover, we showed that NK cells activated by TNBC cells opsonized with Cetuximab promoted tumor material uptake and maturation of DCs, as well as their ability to produce IL-12. Furthermore, the stimulation with IL-15 increased the activation of NK cells and the maturation of DCs. These results suggest that IL-15 may enhance the efficacy of Cetuximab in the treatment of TNBC by promoting activation of both NK cells and DCs.Fil: Juliá, Estefanía Paula. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mordoh, Jose. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Fundación Instituto Leloir; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Levy, Estrella Mariel. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Monocyte chemoattractant protein correlates with angiogenesis in metastatic melanoma

Se analizaron biopsias de melanoma metastásico humano para elucidar la relación entre la expresión de la quimioquina MCP-1/CCL2 (monocyte chemoattractant protein-1), la angiogénesis y la agresividad del tumor. Se encontró que esta quimioquina se expresa en el 100% de los casos, con heterogeneidad en el porcentaje de células positivas dentro del tumor. Estos tumores presentaron gran cantidad de macrófagos infiltrantes, particularmente asociados a las áreas de más activa angiogénesis. Se obtuvo correlación positiva entre el porcentaje de células que expresan MCP-1 y el grado de vascularización. Asimismo, se encontró asociación entre una mayor angiogénesis y la proliferación tumoral evaluada como índice mitótico. Estos resultados sugieren que el aumento en la vascularización podría ser predictivo de metástasis más agresivas, donde la expresión de MCP-1 estaría estrechamente vinculada al desarrollo de vasos a través del reclutamiento de macrófagos.Biopsies from human metastatic melanomas were analyzed in order to elucidate the relationship between MCP-1/CCL-2 (monocyte chemoattractant protein-1) chemokine expression by tumor cells, angiogenesis and aggressiveness in tumor development. The chemokine was expressed in 100% of the cases, with heterogeneity in the percentage of positive cells within the tumor mass. Tumors presented an important infiltration of macrophages, particularly associated to areas of active angiogenesis. Microvascular development, assessed by immunohistochemistry, correlated with the high percentage of cells expressing MCP-1/CCL-2. There was also significant correlation with vascularization and mitotic index. These results suggest that vascularization could be predictive of more aggressive melanoma metastasis, where the MCP-1/CCL-2 expression would be closely associated to vessel development through macrophages recruitment.Fil: Gazzaniga, Silvina Noemí. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Bravo, Alicia Ines. Hospital Eva Perón; ArgentinaFil: Mordoh, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Wainstok, Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentin

Standardization of molecular monitoring for chronic myeloid leukemia in Latin America using locally produced secondary cellular calibrators

Residual disease in chronic myeloid leukemia (CML) patients undergoing therapy with tyrosine kinase inhibitors (TKIs) is measured by assessing the quantity of transcripts of the BCR-ABL1 fusion gene in peripheral white blood cells. This analysis is based on reverse-transcription quantitative PCR (RT–qPCR) technology; however, the wide array of methods used worldwide has led to large variation in quantitative BCR-ABL1 measurements, which hamper inter-laboratory comparative studiesFil: Ruiz, María Sol. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Medina, M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Tapia, I.. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Mordoh, Jose. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Cross, N. C. P.. Universidad de Southampton Uk; Reino UnidoFil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Bianchini, Michele. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentin

Inoculation site from a cutaneous melanoma patient treated with an allogeneic therapeutic vaccine: A case report

We have developed a therapeutic vaccine consisting of a mixture of lethally-irradiated allogeneic cutaneous melanoma cell lines with BCG and GM-CSF as adjuvants. The CSF-470 vaccine is currently being assayed in a Phase II-III trial against medium-dose IFN-a2b. All vaccinated patients immunized intradermally developed large edematous erythema reactions, which then transformed into subcutaneous nodules active for several months. However, vaccine injection sites were not routinely biopsied. We describe the case of a female patient, previously classified as stage III, but who, due to the simultaneous discovery of bone metastases only received one vaccination was withdrawn from the study, and continued her treatment elsewhere. This patient developed a post-vaccination nodule which was surgically removed 7 weeks later, and allowed to analyze the reactivity and immune profiling of the inoculation site. An inflammatory reaction with zones of fibrosis, high irrigation, and brisk lymphoid infiltration, primarily composed of CD8+ and CD20+ lymphocytes, was observed. There were no remaining BCG bacilli, and scarce CD4+ and Foxp3+ T cells were determined. MART-1 Ag was found throughout the vaccination site. CD11c+ Ag presenting cells were either dispersed or forming dense nests. Some CD11c+ cells proliferated; most of them contained intracellular MART-1 Ag, and some interacted with CD8+ lymphocytes. These observations suggest a potent, long-lasting local inflammatory response with recruitment of Ag-presenting cells that incorporate melanoma Ags, probably leading to Ag presentation to naïve T cells.Fil: Aris, Mariana. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bravo, Alicia Ines. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Barrio, Maria Marcela. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mordoh, Jose. Fundación Instituto Leloir; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Instituto Alexander Fleming.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Properties of synthetic and native liver glycogen

originalFil: Parodi, Armando J.. Instituto de Investigaciones Bioquímicas Fundación Campomar; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Krisman, Clara R.. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaFil: Leloir, Luis Federico. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaFil: Mordoh, Jose. Instituto de Investigaciones Bioquímicas Fundación Campomar; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaBlanco y negro9 páginas en pdfLFL-PI-O-ART. Artículos científicosUnidad documental simpleAR-HYL-201

Comparative study of gene expression by cDNA microarray in human colorectal cancer tissues and normal mucosa

The causative molecular pathways underlying the pathogenesis of colorectal cancer (CRC) need to be better characterized. The purpose of our study was to better understand the genetic mechanism of oncogenesis for human colorectal cancer and to identify new potential tumor markers of use in clinical practice. We used cDNA microarrays to compare gene expression profiles of colorectal biopsies from 25 CRC patients and 13 normal mucosa from adjacent non-cancerous tissues. Findings were validated by real-time PCR; in addition, western blotting and immunochemistry analysis were carried out as further confirmation of differential expression at a protein level. Comparing cancerous tissues with normal colonic mucosa we identified 584 known genes differentially expressed to a significant degree (p<0.001). Many of the transcripts that were more abundant in tumors than in non-neoplastic tissues appear to reflect important events for colon carcinogenesis. For example, a significant number of these genes serve as apoptotic inhibitors (e.g. BFAR, BIRC1, BIRC6). Furthermore, we observed the simultaneous up-regulation of HLA-E and the down-regulation of beta2-microglobulin; these genes strongly support a potential tumor escape strategy from immune surveillance in colon cancer tissues. Our study provides new gene candidates in the pathogenesis of human CRC disease. From our results we hypothesize that CRC cells escape immune surveillance through a specific gene expression alteration; moreover, over-expression of several survival genes seems to confer a more anti-apoptotic phenotype. These genes are involved in pathways not previously implicated in CRC pathogenesis and they may provide new targets for therapy.Fil: Bianchini, Michele. Fundación P/la Invest.y Prevención del Cancer. Centro de Investigaciones Oncologicas; ArgentinaFil: Levy, Estrella Mariel. Fundación P/la Invest.y Prevención del Cancer. Centro de Investigaciones Oncologicas; Argentina. Universidad de Buenos Aires; ArgentinaFil: Zucchini, Cinzia. Università di Bologna; ItaliaFil: Pinski, Victor. Universidad de Buenos Aires; ArgentinaFil: Macagno, Carlo. Universidad de Buenos Aires; ArgentinaFil: De Sanctis, Paola. Università di Bologna; ItaliaFil: Valvassori, Luisa. Università di Bologna; ItaliaFil: Carinci, Paolo. Università di Bologna; ItaliaFil: Mordoh, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Fundación P/la Invest.y Prevención del Cancer. Centro de Investigaciones Oncologicas; Argentin

Action patterns of phosphorylase and glycogen synthetase on glycogen

originalFil: Parodi, Armando José A.. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaFil: Mordoh, Jose. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaFil: Krisman, Clara R.. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaFil: Leloir, Luis Federico. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaBlanco y negro9 páginas en pdfLFL-PI-O-ART. Artículos científicosUnidad documental simpleAR-HYL-201

In vitro synthesis of particulate glycogen from uridine diphosphate glucose

originalFil: Parodi, Armando José A.. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaFil: Mordoh, Jose. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Krisman, Clara R.. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaFil: Leloir, Luis Federico. Instituto de Investigaciones Bioquímicas Fundación Campomar; ArgentinaBlanco y negro6 páginas en pdfLFL-PI-O-ART. Artículos científicosUnidad documental simpleAR-HYL-201