Inmunoterapia en cáncer: Perspectivas actuales, desafíos y nuevos horizontes / Immunotherapy in cancer. Current prospects, challenges and new horizons

La activación del sistema inmunológico en pacientes con cáncer ha sido un objetivo histórico en el campo de la oncología. En las últimas décadas, nuestro entendimiento de la respuesta inmunológica antitumoral ha promovido el desarrollo de novedosas estrategias terapéuticas dando como resultado un cambio de paradigma en el tratamiento del cáncer. La utilización de agentes bloqueantes de puntos de chequeo del sistema inmunológico como PD-1/PD-L1 y CTLA-4, de agonistas de moléculas co-estimuladoras como CD137 y OX-40 y la transferencia adoptiva de células T antitumorales modificadas genéticamente han generado importantes beneficios clínicos, reflejados en respuestas objetivas y durader as, en enfermos sin tratamientos convencionales disponibles. Sin embargo, un gran número de pacientes no responde a dichas terapias generando resistencia o sufriendo recaídas de la enfermedad debido a la aparición de circuitos inhibitorios o compensatorios. La combinación racional de estrategias terapéuticas permite eliminar mecanismos de resistencia, mientras que la identificación de biomarcadores predictivos facilita la selección de pacientes respondedores a dichos tratamientos. Recientes ensayos clínicos y estudios pre-clínicos permiten vislumbrar un escenario optimista con importantes desafíos en la implementación de estrategias de inmunoterapia en cáncer.

Recent under-standing of the mechanisms that control immune system homeostasis and orchestrate antitumor responses has prompted the development of novel immunotherapeutic modalities. These include antibodies that target immune checkpoints such as PD-1/PD-L1 and CTLA-4, agonistic antibodies of costimulatory molecules such as CD137 and OX-40 and the adoptive transfer of genetically-modified antitumor T cells. However, a large number of patients do not respond to these therapies and develop resistance as a result of activation of compensatory circuits. Rational combination of immunotherapeutic modalities will help overcome resistance and will increase the number of patients who will benefit from these treatments. Moreover, identification of predictive biomarkers will allow selection of patients responding to these treatments. Emerging clinical trials and pre-clinical studies have shown exciting results anticipating new horizons in the design and implementation of cancer immunotherapeutic modalities.

Radiotherapy and immune response: the systemic effects of a local treatment

Technological developments have allowed improvements in radiotherapy delivery, with higher precision and better sparing of normal tissue. For many years, it has been well known that ionizing radiation has not only local action but also systemic effects by triggering many molecular signaling pathways. There is still a lack of knowledge of this issue. This review focuses on the current literature about the effects of ionizing radiation on the immune system, either suppressing or stimulating the host reactions against the tumor, and the factors that interact with these responses, such as the radiation dose and dose / fraction effects in the tumor microenvironment and vasculature. In addition, some implications of these effects in cancer treatment, mainly in combined strategies, are addressed from the perspective of their interactions with the more advanced technology currently available, such as heavy ion therapy and nanotechnology.

An update on clinical oncology for the non-oncologist / Avanços em oncologia para o não oncologista

ABSTRACT Recent advances in the understanding of tumor driver mutations, signaling pathways that lead to tumor progression, and the better understanding of the interaction between tumor cells and the immune system are revolutionizing cancer treatment. The pace at which new treatments are approved and the prices at which they are set have made it even more difficult to offer these treatments in countries like Brazil. In this review we present for the non-oncologist these new treatments and compare their availability in Brazilian public health system and private health system with that of developed countries.

RESUMO Avanços recentes na compreensão de mutações promotoras de desenvolvimento do câncer, sinalização que leva à progressão de tumores, e o avanço no entendimento da interação entre as células tumorais e o sistema imunológico estão revolucionando o tratamento do câncer. A velocidade com que novos tratamentos são aprovados e o alto custo das medicações dificultam a disponibilização de terapêuticas em países como o Brasil. Nesta revisão, apresentamos ao não oncologista esses novos tratamentos e comparamos sua disponibilidade nos sistemas público e privado de saúde no Brasil com os países desenvolvidos.

One target, different effects: a comparison of distinct therapeutic antibodies against the same targets

To date, more than 30 antibodies have been approved worldwide for therapeutic use. While the monoclonal antibody market is rapidly growing, the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders. Moreover, antibodies against only five targets (TNF-alpha, HER2, CD20, EGFR, and VEGF) account for more than 80 percent of the worldwide market of therapeutic antibodies. The shortage of novel, clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets, based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another. For example, four antibodies against TNF-alpha have been approved by the FDA -- infliximab, adalimumab, golimumab, and certolizumab pegol -- with many more in clinical and preclinical development. The situation is similar for HER2, CD20, EGFR, and VEGF, each having one or more approved antibodies and many more under development. This review discusses the different binding characteristics, mechanisms of action, and biological and clinical activities of multiple monoclonal antibodies against TNF-alpha, HER-2, CD20, and EGFR and provides insights into the development of therapeutic antibodies.

One target, different effects: a comparison of distinct therapeutic antibodies against the same targets

To date, more than 30 antibodies have been approved worldwide for therapeutic use. While the monoclonal antibody market is rapidly growing, the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders. Moreover, antibodies against only five targets (TNF-alpha, HER2, CD20, EGFR, and VEGF) account for more than 80 percent of the worldwide market of therapeutic antibodies. The shortage of novel, clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets, based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another. For example, four antibodies against TNF-alpha have been approved by the FDA -- infliximab, adalimumab, golimumab, and certolizumab pegol -- with many more in clinical and preclinical development. The situation is similar for HER2, CD20, EGFR, and VEGF, each having one or more approved antibodies and many more under development. This review discusses the different binding characteristics, mechanisms of action, and biological and clinical activities of multiple monoclonal antibodies against TNF-alpha, HER-2, CD20, and EGFR and provides insights into the development of therapeutic antibodies.

Biological response modifiers: Current use and future prospects in cancer therapy.

Over the past few decades, considerable success has been achieved in the field of cancer treatment with biological response modifiers (BRM), which are agents that improve the body's ability to fight cancer by immunostimulation. Biological agents, such as interferons and interleukins, provide nonspecific active immunity, whereas the monoclonal antibodies provide passive immunity. Apart from this, other biological agents, such as antiangiogenic agents, matrix metalloprotease inhibitors, tyrosine kinase inhibitors, and tumor vaccines, are also increasingly being used in cancer treatment. Hematopoietic factors, such as granulocyte colony-stimulating factor, are used to increase the general immunity and prevent opportunistic infection. BRM are basically used alone or as adjuvants to cancer chemotherapeutic agents. This review sheds light on the current use and the future development of cancer immunotherapy. Search strategy included Pubmed, using the terms "Biological response modifiers in cancer" citations relevant to the topic were screened.

La inmunología clínica actual: una perspectiva genética y molecular / Present time clinical immunology: a genetic and molecular perspective

During the last few decades, basic scientists and clinicians have gained a deeper insight of the cellular and molecular physiology of the immune system. The widespread application of molecular biology and genetic techniques has advanced our understanding of states of health and disease, bringing forth renewed hopes concerning the advent of a more ÒspecificÓ therapeutic era of clinical immunology. The precise structural and genetic characterization of molecular complexes such as B and T-cell receptors, the Major Histocompatibility Complex (MHC), cytokines, chemokines, cellular receptors and co-receptors has produced a wealth of information open to both diagnostic and therapeutic purposes. We herein review several recent advances in the molecular and genetic characterization of immune deficiency states, autoimmunity and the induction of antigen specific immune unresponsiveness or tolerance, together with the therapeutic implications of these findings

El equilibrio T1/T2: posibilidades de inmunomodulación para el tratamiento de las enfermedades infecciosas

Proposito: Refisar los datos básicos de la respuesta de las citoquinas durante las infecciones por tuberculosis, lepra, leishmaniasis y toxoplasmosis así como los estudios clínicos que utilizan citoquinas como terapia principal o coadyuvante. Fuentes de obtención de datos: Bases de datos Medline (1966-1999). Selección de los estudios: Se seleccionaron los estudios básicos que mostraban datos releavntes sobre el papel de citoquinas para cada infección tanto en estudios in vitro, modelos animales o células humanas. Para los ensayos clínicos se analizaron todos los datos publicados encontrados en medline. Extracción y síntesis de datos: Se hicieron resúmenes detallados y se discutieron y contrastaron los resultados de los trabajos básicos. Los ensayos clínicos se resumieron y clasificaron en nivel de evidencia I a IV y de recomendación clínica. Resultados: Se revisaron y sintetizaron datos de 84 artículos que describen las citoquinas expresadas durante cada uno de los procesos infecciosos escogidos para análisis. Se encontraron dos ensayos clínicos en tuberculosis, dos en lepra, tres en leishmaniasis visceral, dos en leishmaniasis mucocutánea y ningún ensayo en toxoplasmosis. Conclusiones: Las citoquinas que aparecen durante una infección corresponden a los productos de células linfocitarias de perfil T1 (INFy, TNFa, IL2 e IL12) o T2 (IL4, IL6, IL10 e IL13). En esta revisión se discutieron los datos existentes sobre el papel de cada grupo de citoquinas y las experiencias clínicas con cada una de ellas. No existen estudios clínicos conclusivos para el uso de citoquinas en terapéutica humana para las enfermedades infecciosas analizadas, sin embargo el conjunto de conocimientos indica que la inmunomudulación será en el futuro un pilar fundamental en el tratamiento de las enfermedades infecciosas.

Avances y promesas en la inmunoterapia de sepsis neonatal / Advances and promises in immunotherpy for neonatal sepsis

La sepsis neonatal es una infección sistémica en el primer mes de vida que, según su gravedad, presenta las 4 fases del síndrome de respuesta inflamatoria sistémica (SRIS) que caracteriza a esta enfermedad en los adultos. El uso de antibióticos sigue siendo el pilar en su tratamiento; sin embargo, la morbi-letalidad de la sepsis neonatal no ha disminuido significativamente y la aparición de cepas resistentes es alarmante, lo cual plantea la necesidad de alternativas terapéuticas. En esta búsqueda, se pretende regular la respuesta inflamatoria a la infección a través de 3 grandes grupos de citocinas: interleucinas, interferones y los factores de crecimiento, algunas de las cuales se comportan como pro-inflamatorias, y otras como anti-inflamatorias al neutralizar, bloquear o inhibir a las pro-inflamatorias. Hasta ahora, los 2 mayores avances en la terapia auxiliar de sepsis neonatales son la inmunoglobulina para uso intravenoso (IgIV), que tiene su principal indicación en los neonatos prematuros y de bajo peso, y los factores estimulantes de colonias de granulocitos y de macrófagos (G-CSF y GM-CSF), indicados en neonatos pretérmino o a término con neutropenia por sepsis. Una actitud de extrema reserva entre muchos médicos ha postergado de manera poco justificable su aplicación clínica. En fases preliminares de investigación se encuentran los antagonistas naturales de la endotoxina bacteriana, como la BPI, proteína producida por los granulocitos, y las inmunoadhesinas, moléculas híbridas de inmunoglubulina y un receptor específico que bloquean la unión de citocinas pro-inflamatorias con sus receptores celulares, modulando así la respuesta inflamatoria a la infección

A imunoterapia para doenças alérgicas no Brasil / Immunotherapy for allergic diseases in Brazil

Com o objetivo de se conhecer e avaliar a prática de IT em nosso país, foram enviados 1105 questionários a alergistas filiados à SBAI, divididos em duas partes; a primeira, referente à prática clínica e a segunda, à remuneraçäo e análise crítica do capítulo da alergia na THAMB (Tabela de Honorários Médicos da AMB). Os dados foram analisados atravÚs do programa EPI-INFO. Dos 29,2 por cento questionários respondidos, 93 por cento declararam utilizar a IT, dos quais 56,9 por cento a prescrevem para menos de 40 por cento, e 32,9 por cento para 40 a 80 por cento dos pacientes. Quanto à segunda parte, 96,3 por cento declararam atender através de convênios e 92,3 por cento manifestaram insatisfaçäo com a THAMB. Concluiu-se pela necessidade, manifesta pelos alergistas, de educaçäo continuada estimulada pela SBAI e regionais, nos aspectos clínico-científicos da IT, em busca de parâmetros nacionais para estabelecimento de normas possibilitando a prática segura e avaliaçäo de sua eficácia, ao lado da necessidade de reformulaçäo do capítulo de alergia da THAMB e da sistemática de contratos com as empresas de seguro-saúde.

Sistema inmune e inmunoterapia en el recién nacido: II inmunoterapia / Immune system and immunotherapy in the newbron infant:II immunotherapy

En esta segunda parte se revisan las diversas modalidades de inmunoterapia e inmunoprofilaxis utilizadas en el periodo neonatal, experimentales y clínicas. Se hace especial énfasis en la utilidad de las preparaciones de inmunoglobulinas intravenosas, la transfusión de neutrófilos, citocinas, anticuerpos monoclonales, nutrientes, etc., como adyuvantes en el manejo de sepsis neonatal

Sistema inmune e inmunoterapia en el recién nacido I: El recién nacido como hospedero inmunocomprometido / Immune system and immunoteraphy in the newborn I newborn as a immunocompromises host

A pesar de grandes avences para el apoyo del recién nacido grave, incluyendo la introducción de surfacteante, nuevos y más potentes antibióticos, mejores ventiladores, etc., la mortalidad asociada a sepsis continua siendo muy alta. Esto puede ser debido a la inexperiencia e inmadurez del sistema inmunológico del recién nacido. En esta primera parte se resumen los aspectos de la inmunidad, no específica (PMN), específica (células B y T) y mixta (monocitos/macrófagos, células NK), que señalan al recién nacido como un hospedero inmunocomprometido. También se hacen algunas consideraciones con respecto a otras condiciones que hacen al neonato susceptible a infecciones

Vacinaçäo em hanseníase: tendências atuais / Present situation of vaccination in leprosy

Realizou-se revisäo bibliográfica sobre vacinaçäo em Hanseníase, procurando-se conhecer as tendências atuais das pesquisas realizadas nesta área. Verificou-se que essas podem ser divididas em dois grupos: aquelas que se limitam a buscar efeito imunoprofilático e aquelas que buscam também efeito imunoterapêutico, sendo que esta última vertente vem ganhando crédito. Dentre as vacinas em experimentaçäo, destacam-se: BCG, BCG associado ao M. leprae, ICRC e MW