Checkpoint blockade meets gene therapy: Opportunities to improve response and reduce toxicity.

Immune checkpoint inhibitors (ICIs) based on monoclonal antibodies represent a breakthrough for the treatment of cancer. However, their efficacy varies among tumor types and patients, and they can lead to adverse effects due to on-target/off-tumor activity, since they are administered systemically at high doses. An alternative and attractive approach for the delivery of ICIs is the use of gene therapy vectors able to express them in vivo. This review focuses on the most recent studies using viral vectors able to express ICIs locally or systemically in preclinical models of cancer. These vectors include non-replicating viruses, oncolytic viruses able to propagate specifically in tumor cells and destroy them, and self-amplifying RNA vectors, armed with different formats of antibodies against immune checkpoints. Non-replicating vectors usually lead to long-term ICI expression, potentially eliminating the need for repeated administration. Vectors with replication capacity, although they have a shorter window of expression, can induce inflammation which enhances the antitumor effect. Finally, these engineered vectors can be used in combination with other immunostimulatory molecules or with CAR-T cells, further boosting the antitumor immune responses.

Discordant results for ALK based on immunohistochemistry versus fluorescence in situ hybridization in a cohort of patients diagnosed with lung adenocarcinoma / Discordancia de los resultados para ALK basados en inmunohistoquímica e hibridación fluorescente in situ en una cohorte de pacientes diagnosticados con adenocarcinoma de pulmón

Introduction: Anaplastic lymphoma kinase (ALK) rearrangement located on the short arm of chromosome 2, region 2 and band 3 is frequent in lung cancer patients who respond to targeted therapies with ALK inhibitors Therefore, their identification has become a standard diagnostic test in patients with advanced NSCLS, as such chromosomal alterations may lead to the activation of important signalling pathways involved in cell survival and proliferation. Methods: To investigate the ALK gene status, we performed FISH and IHC assays in 18 lung adenocarcinoma patients, 12 women and 6 men, aged between 29 and 85 years. Paraffin-embedded samples were analyzed in the Pathology Department of the Hospital Universitario San Ignacio. Results: Results between the two techniques in 5 patients showed discordant patterns, being positive for FISH and negative for IHC. The borderline to define ALK positivity was set at 15%, These results present experimental evidence that the techniques differ in specific situations. Conclusions: Our findings show that it is advisable to investigate the ALK gene status in patients with suspected lung cancer using both FISH and IHC in combination.(AU)

Introducción: La reorganización de la (anaplastic lymphoma kinase) ALK ubicada en el brazo corto del cromosoma 2, región 2 y banda 3 es frecuente en los pacientes con cáncer de pulmón que responden a terapias dirigidas con inhibidores de la ALK. Por ello, su identificación se ha establecido como una prueba diagnóstica estándar en pacientes con CPCNP, ya que dichas alteraciones cromosómicas puedan determinar la activación de importantes vías de señalización implicadas en la supervivencia y proliferación celulares. Métodos: Para determinar el estatus de gen ALK se realizaron pruebas FISH e IHC en 18 pacientes con adenocarcinoma pulmonar, 12 mujeres y 6 varones, con edades comprendidas entre 29 y 85 años. Las muestras fueron analizadas en el Departamento de Anatomía Patológica del Hospital Universitario San Ignacio. Resultados: Los resultados entre ambas técnicas mostraron patrones discordantes en 5 pacientes, con positividad de FISH y negatividad con IHC. El límite para definir la positividad de ALK se estableció en el 15%. Estos resultados muestran evidencia experimental que dichas técnicas difieren en situaciones específicas. Conclusiones: Este estudio recomienda la investigación del estatus del gen ALK en los pacientes con sospecha de cáncer de pulmón, mediante la combinación de FISH e IHC.(AU)

Local Delivery of Immunomodulatory Antibodies for Gastrointestinal Tumors.

Cancer therapy has experienced a breakthrough with the use of immune checkpoint inhibitors (ICIs) based on monoclonal antibodies (mAbs), which are able to unleash immune responses against tumors refractory to other therapies. Despite the great advancement that ICIs represent, most patients with gastrointestinal tumors have not benefited from this therapy. In addition, ICIs often induce adverse effects that are related to their systemic use. Local administration of ICIs in tumors could concentrate their effect in the malignant tissue and provide a higher safety profile. A new and attractive approach for local delivery of ICIs is the use of gene therapy vectors to express these blocking antibodies in tumor cells. Several vectors have been evaluated in preclinical models of gastrointestinal tumors to express ICIs against PD-1, PD-L1, and CTLA-4, among other immune checkpoints, with promising results. Vectors used in these settings include oncolytic viruses, self-replicating RNA vectors, and non-replicative viral and non-viral vectors. The use of viral vectors, especially when they have replication capacity, provides an additional adjuvant effect that has been shown to enhance antitumor responses. This review covers the most recent studies involving the use of gene therapy vectors to deliver ICIs to gastrointestinal tumors.

Discordant results for ALK based on immunohistochemistry versus fluorescence in situ hybridization in a cohort of patients diagnosed with lung adenocarcinoma.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) rearrangement located on the short arm of chromosome 2, region 2 and band 3 is frequent in lung cancer patients who respond to targeted therapies with ALK inhibitors Therefore, their identification has become a standard diagnostic test in patients with advanced NSCLS, as such chromosomal alterations may lead to the activation of important signalling pathways involved in cell survival and proliferation. METHODS: To investigate the ALK gene status, we performed FISH and IHC assays in 18 lung adenocarcinoma patients, 12 women and 6 men, aged between 29 and 85 years. Paraffin-embedded samples were analyzed in the Pathology Department of the Hospital Universitario San Ignacio. RESULTS: Results between the two techniques in 5 patients showed discordant patterns, being positive for FISH and negative for IHC. The borderline to define ALK positivity was set at 15%, These results present experimental evidence that the techniques differ in specific situations. CONCLUSIONS: Our findings show that it is advisable to investigate the ALK gene status in patients with suspected lung cancer using both FISH and IHC in combination.

The recognition of silicosis: labor unions and physicians in the Chilean copper industry, 1930s-1960s.

By the late 1930s, silicosis had become one of the most important occupational diseases in Chile. It was a medical and scientific problem, and a favorite topic in medical congresses; in Chile, a mining country, it also had serious political and economic implications. The recognition of silicosis did not happen in a vacuum, but was part of a national debate on the social role of the state and its responsibility toward working people's health and safety. This article traces the history of silicosis as an occupational disease from the late 1930s to the late 1960s, and argues that the recognition of the disease was the result of a medical, labor, and political struggle.

The recognition of silicosis: labor unions and physicians in the Chilean copper industry, 1930s-1960s

It traces the history of silicosis as an occupational disease from the late 1930s to the late 1960s and argues that the recognition of the disease was the result of a medical, labor and political struggle.(AU)