Workshop on immunotherapy combinations. Society for immunotherapy of cancer annual meeting Bethesda, November 3, 2011

Although recent FDA approvals on ipilimumab and sipuleucel-T represent major milestones, the ultimate success of immunotherapy approaches will likely benefit from appropriate combinations with other immunotherapeutic and/or non-immunotherapeutic approaches. However, implementation of ideal combinations in the clinic may still face formidable challenges in regulatory, drug-availability and intellectual property aspects. The 2011 SITC annual meeting hosted a workshop on combination immunotherapy to discuss: 1) the most promising combinations found in the laboratory; 2) early success of combination immunotherapy in clinical trials; 3) industry perspectives on combination approaches, and 4) relevant regulatory issues. The integrated theme was how to accelerate the implementation of efficacious combined immunotherapies for cancer patients. Rodent animal models are providing many examples of synergistic combinations that typically include more than two agents. However, mouse and human immunology differ in a significant number of mechanisms and hence we might be missing opportunities peculiar to humans. Nonetheless, incisive animal experimentation with deep mechanistic insight remains the best compass that we can use to guide our paths in combinatorial immunotherapy. Combination immunotherapy clinical trials are already in progress and preliminary results are extremely promising. As a key to translate promising combinations into clinic, real and “perceived” business and regulatory hurdles were debated. A formidable step forward would be to be able to test combinations of investigational agents prior to individual approval. Taking together the FDA and the industrial perspective on combinatorial immunotherapy, the audience was left with the clear message that this is by no means an impossible task. The general perception is that the road ahead of us is full of combination clinical trials which hopefully will bring clinical benefit to our cancer patients at a fast pace

Does the Immunocompetent Status of Cancer Patients Have an Impact on Therapeutic DC Vaccination Strategies?

Although different types of therapeutic vaccines against established cancerous lesions in various indications have been developed since the 1990s, their clinical benefit is still very limited. This observed lack of effectiveness in cancer eradication may be partially due to the often deficient immunocompetent status of cancer patients, which may facilitate tumor development by different mechanisms, including immune evasion. The most frequently used cellular vehicle in clinical trials are dendritic cells (DCs), thanks to their crucial role in initiating and directing immune responses. Viable vaccination options using DCs are available, with a positive toxicity profile. For these reasons, despite their limited therapeutic outcomes, DC vaccination is currently considered an additional immunotherapeutic option that still needs to be further explored. In this review, we propose potential actions aimed at improving DC vaccine efficacy by counteracting the detrimental mechanisms recognized to date and implicated in establishing a poor immunocompetent status in cancer patients

Clinical guidelines in mental health: their knowledge, appreciation and implementation in the metropolitan area of Buenos Aires

El presente estudio evalúa en qué medida los profesionales del área metropolitana de Buenos Aires conocen las guías clínicas (G.C.), cuál es su actitud hacia las mismas y el impacto que tienen en su práctica clínica. Se encuestó a 173 profesionales que pertenecen al área metropolitana. Resultados: el 81,7% no conoce las guías clínicas. De los 32 profesionales que sí las conocen, el 71,8% tuvo una opinión favorable, aunque muchos de estos confundieron G.C. con sistemas diagnósticos operativos, manuales de tratamiento y/o escalas de evaluación. Sólo el 25% de quienes dijeron conocerlas (4,5% de la muestra total) hizo una referencia correcta de las G.C. y las instituciones a las que pertenecen (mayoritariamente de la American Psychiatric Association). Se destaca la necesidad de una política de difusión de las guías clínicas en nuestro medio.This study evaluates the knowledge of clinical guidelines (C.G.) by the professionals in the metropolitan area of Buenos Aires, which is their attitude to them and the impact on their clinical practice. We surveyed 173 professionals from the metropolitan area. 81.7% of the sample did not know about clinical guidelines. Among the 32 professionals did know them, 71.8% had a positive opinion, although many of them took operative diagnosis systems, treatment manuals and / or evaluation scales for C.G. Only 25% of those who affirmed to know them (4.5% of the total sample) could give a correct reference about the C.G. and the institutions they belong to (mainly the American Psychiatric Association). The authors emphasize the need of a policy for the diffusion of the C.G. in our field.Fil: Garay, Cristian Javier. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Etenberg, Mariano. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Hornes, Alan. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Martini, Sabrina. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Korman, Guido Pablo. Universidad de Buenos Aires. Facultad de Psicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Clinical guidelines in mental health: their knowledge, appreciation and implementation in the metropolitan area of Buenos Aires

El presente estudio evalúa en qué medida los profesionales del área metropolitana de Buenos Aires conocen las guías clínicas (G.C.), cuál es su actitud hacia las mismas y el impacto que tienen en su práctica clínica. Se encuestó a 173 profesionales que pertenecen al área metropolitana. Resultados: el 81,7% no conoce las guías clínicas. De los 32 profesionales que sí las conocen, el 71,8% tuvo una opinión favorable, aunque muchos de estos confundieron G.C. con sistemas diagnósticos operativos, manuales de tratamiento y/o escalas de evaluación. Sólo el 25% de quienes dijeron conocerlas (4,5% de la muestra total) hizo una referencia correcta de las G.C. y las instituciones a las que pertenecen (mayoritariamente de la American Psychiatric Association). Se destaca la necesidad de una política de difusión de las guías clínicas en nuestro medio.This study evaluates the knowledge of clinical guidelines (C.G.) by the professionals in the metropolitan area of Buenos Aires, which is their attitude to them and the impact on their clinical practice. We surveyed 173 professionals from the metropolitan area. 81.7% of the sample did not know about clinical guidelines. Among the 32 professionals did know them, 71.8% had a positive opinion, although many of them took operative diagnosis systems, treatment manuals and / or evaluation scales for C.G. Only 25% of those who affirmed to know them (4.5% of the total sample) could give a correct reference about the C.G. and the institutions they belong to (mainly the American Psychiatric Association). The authors emphasize the need of a policy for the diffusion of the C.G. in our field.Fil: Garay, Cristian Javier. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Etenberg, Mariano. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Hornes, Alan. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Martini, Sabrina. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Korman, Guido Pablo. Universidad de Buenos Aires. Facultad de Psicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection.

HIV infection induces phenotypic and functional changes to CD8+ T cells defined by the coordinated upregulation of a series of negative checkpoint receptors that eventually result in T cell exhaustion and failure to control viral replication. We report that effector CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue exhibit higher levels of the negative checkpoint receptor TIGIT. Increased frequencies of TIGIT+ and TIGIT+ PD-1+ CD8+ T cells correlated with parameters of HIV and SIV disease progression. TIGIT remained elevated despite viral suppression in those with either pharmacological antiretroviral control or immunologically in elite controllers. HIV and SIV-specific CD8+ T cells were dysfunctional and expressed high levels of TIGIT and PD-1. Ex-vivo single or combinational antibody blockade of TIGIT and/or PD-L1 restored viral-specific CD8+ T cell effector responses. The frequency of TIGIT+ CD4+ T cells correlated with the CD4+ T cell total HIV DNA. These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells and suggest TIGIT along with other checkpoint receptors may be novel curative HIV targets to reverse T cell exhaustion

Blockade ofthe negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis

INTRODUCTION: Fungal sepsis is an increasingly common problem in intensive care unit patients.Mortality from fungal sepsis remains high despite antimicrobial therapy that is highly active against most fungal pathogens, a finding consistent with defective host immunity that is present in many patients with disseminated fungemia.One recently recognized immunologic defect that occurs in patients with sepsis is T cell "exhaustion" due to increased expression of programmed cell death -1 (PD-1).This study tested the ability of anti-PD-1 and anti-programmed cell death ligand -1 (anti-PD-L1) antagonistic antibodies to improve survival and reverse sepsis-induced immunosuppression in two mouse models of fungal sepsis. METHODS: Fungal sepsis was induced in mice using two different models of infection, that is, primary fungal sepsis and secondary fungal sepsis occurring after sub-lethal cecal ligation and puncture (CLP).Anti-PD-1 and anti-PD-L1 were administered 24 to 48 h after fungal infection and effects on survival, interferon gamma production, and MHC II expression were examined. RESULTS: Anti-PD-1 and anti-PD-L1 antibodies were highly effective at improving survival in primary and secondary fungal sepsis.Both antibodies reversed sepsis-induced suppression of interferon gamma and increased expression of MHC II on antigen presenting cells.Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a second negative co-stimulatory molecule that is up-regulated in sepsis and acts like PD-1 to suppress T cell function, also improved survival in fungal sepsis. CONCLUSIONS: Immuno-adjuvant therapy with anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies reverse sepsis-induced immunosuppression and improve survival in fungal sepsis.The present results are consistent with previous studies showing that blockade of PD-1 and CTLA-4 improves survival in bacterial sepsis.Thus, immuno-adjuvant therapy represents a novel approach to sepsis and may have broad applicability in the disorder.Given the relative safety of anti-PD-1 antibody in cancer clinical trials to date, therapy with anti-PD-1 in patients with life-threatening sepsis who have demonstrable immunosuppression should be strongly considered

Combined treatment and therapeutic complementary for the anxiety disorders

El presente artículo revisa la literatura científica referida a la combinación entre tratamientos farmacológicos y psicosociales en los trastornos de ansiedad. Se reseñan aquellos estudios que han realizado la evaluación empírica de la combinación de tratamientos con el mayor rigor metodológico a través de las bases de datos de PubMed y PsycINFO. A partir de los ensayos realizados, se observa que la información disponible acerca de la ventaja del tratamiento combinado por encima de algún tipo de monoterapia, parece ser bastante controvertida y no concluyente en la mayoría de los trastornos de ansiedad. Esto puede observarse en los ensayos realizados sobre el trastorno por pánico con y sin agorafobia, el trastorno de ansiedad social y el trastorno de ansiedad generalizada. Se observa un déficit de investigación en general pero particularmente en la fobia específica, para la cual no encontramos estudios comparativos. En el tratamiento del trastorno por estrés postraumático, sólo se considera la combinación cuando la psicoterapia no haya alcanzado sus objetivos, y en el abordaje del trastorno obsesivo-compulsivo es donde contamos con evidencia aunque bastante limitada acerca de la superioridad del tratamiento combinado sobre la monoterapia. Se comentan las implicaciones clínicas de estos estudios.This article reviews the scientific literature concerning to the combination of pharmacological and psychological treatments for the anxiety disorders. We include studies that evaluate the combined treatment in PubMed and PsycINFO databases and show the best methodological rigor. Based on the clinical trials, it shows that the available evidence about the superiority of the combined treatment over any type of monotherapy seems to be controverted and not conclusive for the most types of anxiety disorders. That is the case of the trials about the panic disorder, with and without agoraphobia, the social anxiety disorder and the generalised anxiety disorder. It shows a research deficit in the field, moreover in the specific phobia, where we couldn´t find any comparative trial. About the treatment of posttraumatic stress disorder, it considers combination when the psychotherapy did not achieve the goals. We found limited evidence for the treatment of obsessive-compulsive disorder and it supports the combined treatment over monotherapy. It comments the clinical consequences of the data.Fil: Garay, Cristian Javier. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Fabrissin, Javier Hernán. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Korman, Guido Pablo. Centro Argentino de Etnología Americana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Etenberg, Mariano. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Hornes, Alan. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: D´Alessandro, Fabián. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Etchevers, Martín Javier. Universidad de Buenos Aires. Facultad de Psicología; Argentin

Combined treatment and therapeutic complementary for the anxiety disorders

El presente artículo revisa la literatura científica referida a la combinación entre tratamientos farmacológicos y psicosociales en los trastornos de ansiedad. Se reseñan aquellos estudios que han realizado la evaluación empírica de la combinación de tratamientos con el mayor rigor metodológico a través de las bases de datos de PubMed y PsycINFO. A partir de los ensayos realizados, se observa que la información disponible acerca de la ventaja del tratamiento combinado por encima de algún tipo de monoterapia, parece ser bastante controvertida y no concluyente en la mayoría de los trastornos de ansiedad. Esto puede observarse en los ensayos realizados sobre el trastorno por pánico con y sin agorafobia, el trastorno de ansiedad social y el trastorno de ansiedad generalizada. Se observa un déficit de investigación en general pero particularmente en la fobia específica, para la cual no encontramos estudios comparativos. En el tratamiento del trastorno por estrés postraumático, sólo se considera la combinación cuando la psicoterapia no haya alcanzado sus objetivos, y en el abordaje del trastorno obsesivo-compulsivo es donde contamos con evidencia aunque bastante limitada acerca de la superioridad del tratamiento combinado sobre la monoterapia. Se comentan las implicaciones clínicas de estos estudios.This article reviews the scientific literature concerning to the combination of pharmacological and psychological treatments for the anxiety disorders. We include studies that evaluate the combined treatment in PubMed and PsycINFO databases and show the best methodological rigor. Based on the clinical trials, it shows that the available evidence about the superiority of the combined treatment over any type of monotherapy seems to be controverted and not conclusive for the most types of anxiety disorders. That is the case of the trials about the panic disorder, with and without agoraphobia, the social anxiety disorder and the generalised anxiety disorder. It shows a research deficit in the field, moreover in the specific phobia, where we couldn´t find any comparative trial. About the treatment of posttraumatic stress disorder, it considers combination when the psychotherapy did not achieve the goals. We found limited evidence for the treatment of obsessive-compulsive disorder and it supports the combined treatment over monotherapy. It comments the clinical consequences of the data.Fil: Garay, Cristian Javier. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Fabrissin, Javier Hernán. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Korman, Guido Pablo. Centro Argentino de Etnología Americana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Etenberg, Mariano. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Hornes, Alan. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: D´Alessandro, Fabián. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Etchevers, Martín Javier. Universidad de Buenos Aires. Facultad de Psicología; Argentin

Workshop on immunotherapy combinations. Society for Immunotherapy of Cancer annual meeting

Abstract Although recent FDA approvals on ipilimumab and sipuleucel-T represent major milestones, the ultimate success of immunotherapy approaches will likely benefit from appropriate combinations with other immunotherapeutic and/or non-immunotherapeutic approaches. However, implementation of ideal combinations in the clinic may still face formidable challenges in regulatory, drug-availability and intellectual property aspects. The 2011 SITC annual meeting hosted a workshop on combination immunotherapy to discuss: 1) the most promising combinations found in the laboratory; 2) early success of combination immunotherapy in clinical trials; 3) industry perspectives on combination approaches, and 4) relevant regulatory issues. The integrated theme was how to accelerate the implementation of efficacious combined immunotherapies for cancer patients. Rodent animal models are providing many examples of synergistic combinations that typically include more than two agents. However, mouse and human immunology differ in a significant number of mechanisms and hence we might be missing opportunities peculiar to humans. Nonetheless, incisive animal experimentation with deep mechanistic insight remains the best compass that we can use to guide our paths in combinatorial immunotherapy. Combination immunotherapy clinical trials are already in progress and preliminary results are extremely promising. As a key to translate promising combinations into clinic, real and "perceived" business and regulatory hurdles were debated. A formidable step forward would be to be able to test combinations of investigational agents prior to individual approval. Taking together the FDA and the industrial perspective on combinatorial immunotherapy, the audience was left with the clear message that this is by no means an impossible task. The general perception is that the road ahead of us is full of combination clinical trials which hopefully will bring clinical benefit to our cancer patients at a fast pace

Memorial Service for Werner Seligmann: Distiguished Professor of Architecture

Memorial Service for Werner Seligmann (1930-1998) was held in Hendricks Chapel, Syracuse University on December 6th, 1998 at 1:30pm