DSpace Repository :: Browsing by Author "Escors Murugarren, David"

Browsing by Author "Escors Murugarren, David"

Now showing 1 - 20 of 28

Open Access
CHL1 hypermethylation as a potential biomarker of poor prognosis in breast cancer
(Impact Journals, 2017) Martín Sánchez, Esperanza; Mendaza Lainez, Saioa; Ulazia Garmendia, Ane; Monreal Santesteban, Iñaki; Blanco Luquin, Idoia; Córdoba Iturriagagoitia, Alicia; Vicente García, Francisco; Pérez Janices, Noemi; Escors Murugarren, David; Megías, Diego; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
The CHL1 gene encodes a cell-adhesion molecule proposed as being a putative tumour-suppressor gene in breast cancer (BC). However, neither the underlying molecular mechanisms nor the clinical value of CHL1 downregulation in BC has been explored. The methylation status of three CpG sites in the CHL1 promoter was analysed by pyrosequencing in neoplastic biopsies from 142 patients with invasive BC and compared with that of non-neoplastic tissues. We found higher CHL1 methylation levels in breast tumours than in non-neoplastic tissues, either from mammoplasties or adjacent-to-tumour, which correlated with lower levels of protein expression in tumours measured by immunohistochemistry. A panel of five BC cell lines was treated with two epigenetic drugs, and restoration of CHL1 expression was observed, indicating in vitro dynamic epigenetic regulation. CHL1 was silenced by shRNA in immortalized but non-neoplastic mammary cells, and enhanced cell proliferation and migration, but not invasion, were found by real-time cell analysis. The prognostic value of CHL1 hypermethylation was assessed by the log-rank test and fitted in a Cox regression model. Importantly, CHL1 hypermethylation was very significantly associated with shorter progression-free survival in our BC patient series, independent of age and stage (p = 0.001). In conclusion, our results indicate that CHL1 is downregulated by hypermethylation and that this epigenetic alteration is an independent prognostic factor in BC.
Open Access
Circulating low density neutrophils are associated with resistance to anti-PD1 immunotherapy in squamous head and neck cancer
(Wiley, 2023) Arrazubi, Virginia; Goñi Irigoyen, Saioa; González Borja, Iranzu; Hernández García, Irene; Arasanz Esteban, Hugo; Pérez Sanz, Jairo; Bocanegra Gondán, Ana Isabel; Kochan, Grazyna; Escors Murugarren, David; Ruiz de Azúa, Yerani; Elizalde, Jesús María; Viúdez, Antonio; Vera García, Ruth; Ciencias de la Salud; Osasun Zientziak
Background: Identification of predictive biomarkers to Immune checkpoint inhibitors (ICIs) in head and neck cancer (HNSCC) is an unmet need. Methods: This was a prospective observational study including 25 patients with HNSCC treated with immunotherapy or chemotherapy after a prior platinum-based regimen. Low density neutrophils (LDNs) and serum markers were analyzed. Results: In the immunotherapy cohort, patients with high LDN levels had a shorter progression free survival (PFS) (1.8 months vs. 10.9 months; *p = 0.034). Also, progressors showed higher percentage of LDNs compared to non-progressors although significance was not reached (mean 20.68% vs. 4.095%, p = 0.0875). These findings were not replicated in patients treated with chemotherapy. High levels of interleukin-7 (IL7) were correlated with a significantly longer overall survival (OS) (13.47 months 3.51 vs. months, *p = 0.013). Conclusions: High baseline circulating LDNs and low IL7 could identify a subset of patients intrinsically refractory to ICIs as monotherapy in HNSCC.
Open Access
Clinical landscape of LAG-3-targeted therapy
(Elsevier, 2022) Chocarro de Erauso, Luisa; Blanco, Ester; Arasanz Esteban, Hugo; Fernández Rubio, Leticia; Bocanegra Gondán, Ana Isabel; Echaide Górriz, Míriam; Garnica, Maider; Ramos, Pablo; Fernández Hinojal, Gonzalo; Vera García, Ruth; Kochan, Grazyna; Escors Murugarren, David; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
Lymphocyte-activated gene 3 (LAG-3) is a cell surface inhibitory receptor and a key regulator of immune homeostasis with multiple biological activities related to T-cell functions. LAG-3 is considered a next-generation immune checkpoint of clinical importance, right next to programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). Indeed, it is the third inhibitory receptor to be exploited in human anticancer immunotherapies. Several LAG-3-antagonistic immunotherapies are being evaluated at various stages of preclinical and clinical development. In addition, combination therapies blocking LAG-3 together with other immune checkpoints are also being evaluated at preclinical and clinical levels. Indeed, the co-blockade of LAG-3 with PD-1 is demonstrating encouraging results. A new generation of bispecific PD-1/LAG-3-blocking agents have also shown strong capacities to specifically target PD-1+ LAG-3+ highly dysfunctional T cells and enhance their proliferation and effector activities. Here we identify and classify preclinical and clinical trials conducted involving LAG-3 as a target through an extensive bibliographic research. The current understanding of LAG-3 clinical applications is summarized, and most of the publically available data up to date regarding LAG-3-targeted therapy preclinical and clinical research and development are reviewed and discussed.
Open Access
Contribution of systemic T cell immunity to clinical efficacy of anti-PD-L1/PD-1 immunotherapies in lung cancer
(2020) Zuazo Ibarra, Miren; Escors Murugarren, David; Ciencias de la Salud; Osasun Zientziak; Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa; Gobierno de Navarra / Nafarroako Gobernua
Un alto porcentaje de pacientes con cáncer de pulmón resistentes a terapias convencionales son refractarios a la inmunoterapia con anticuerpos bloqueadores de la interacción PD-L1/PD-1. En la presente tesis doctoral se ha demostrado que la cuantificación de la proporción de linfocitos T CD4 altamente diferenciados (THD) en sangre periférica antes de comenzar el tratamiento identifica a potenciales respondedores a la inmunoterapia anti-PD-L1/PD-1. En efecto, una alta proporción de CD4 THD (>40%) pretratamiento es un indicador de la funcionalidad sistémica CD4 que resulta ser un factor diferencial para obtener respuestas clínicas. En estos pacientes, las células T CD4 son funcionales a nivel de capacidades proliferativas y presentan una baja co-expresión de PD-1/LAG-3 bajo estimulación, además de ser receptivos al bloqueo de PD-1 ex vivo e in vivo. Además, la cuantificación de los linfocitos T CD4 altamente diferenciados en combinación con la expresión positiva de PD-L1 tumoral identifica a un grupo de pacientes con una tasa de respuesta alrededor del 70%. En cambio, los pacientes con porcentajes bajos de CD4 THD (<40%) antes de comenzar el tratamiento no respondieron al bloqueo anti-PD-L1/PD-1, a pesar de presentar linfocitos T específicos de cáncer de pulmón. Aunque las células T CD4 en estos pacientes son competentes a la hora de producir de citoquinas, son disfuncionales a nivel de proliferación, co-expresan altos niveles de PD-1/LAG-3 y son refractarios al monobloqueo de PD-1. Así, la inmunidad sistémica CD8 solo pudo ser revertida a través del bloqueo de PD-L1/PD-1 en aquellos pacientes que presentaban una inmunidad CD4 basal funcional. En cambio, la disfuncionalidad proliferativa observada en las células T de pacientes refractarios a la inmunoterapia anti-PD-L1/PD-1 pudo revertirse a través del doble bloqueo de PD-1/LAG‐3. De esta manera, mediante los presentes datos se ha confirmado que la co-expresión de PD-1/LAG-3 contribuye a la disfuncionalidad de las células T en pacientes con cáncer de pulmón resistentes a terapias convencionales. Estos resultados proporcionan el fundamento experimental para la combinación de las terapias bloqueadoras de PD-L1/PD-1 y LAG-3 en pacientes que manifiestan una inmunidad CD4 basal disfuncional.
Open Access
Cutting-edge CAR engineering: beyond T cells
(MDPI, 2022) Chocarro de Erauso, Luisa; Blanco, Ester; Fernández Rubio, Leticia; Arasanz Esteban, Hugo; Bocanegra Gondán, Ana Isabel; Echaide Górriz, Míriam; Garnica, Maider; Ramos, Pablo; Piñeiro Hermida, Sergio; Vera García, Ruth; Kochan, Grazyna; Escors Murugarren, David; Ciencias de la Salud; Osasun Zientziak
Chimeric antigen receptor (CAR)-T adoptive cell therapy is one of the most promising advanced therapies for the treatment of cancer, with unprecedented outcomes in haematological malignancies. However, it still lacks efficacy in solid tumours, possibly because engineered T cells become inactive within the immunosuppressive tumour microenvironment (TME). In the TME, cells of the myeloid lineage (M) are among the immunosuppressive cell types with the highest tumour infiltration rate. These cells interact with other immune cells, mediating immunosuppression and promoting angiogenesis. Recently, the development of CAR-M cell therapies has been put forward as a new candidate immunotherapy with good efficacy potential. This alternative CAR strategy may increase the efficacy, survival, persistence, and safety of CAR treatments in solid tumours. This remains a critical frontier in cancer research and opens up a new possibility for next-generation personalised medicine to overcome TME resistance. However, the exact mechanisms of action of CAR-M and their effect on the TME remain poorly understood. Here, we summarise the basic, translational, and clinical results of CAR-innate immune cells and CAR-M cell immunotherapies, from their engineering and mechanistic studies to preclinical and clinical development.
Open Access
Cutting-edge: preclinical and clinical development of the first approved LAG-3 inhibitor
(MDPI, 2022) Chocarro de Erauso, Luisa; Bocanegra Gondán, Ana Isabel; Blanco, Ester; Fernández Rubio, Leticia; Arasanz Esteban, Hugo; Echaide Górriz, Míriam; Garnica, Maider; Ramos, Pablo; Piñeiro Hermida, Sergio; Vera García, Ruth; Escors Murugarren, David; Kochan, Grazyna; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
Immune checkpoint inhibitors (ICIs) have revolutionized medical practice in oncology since the FDA approval of the first ICI 11 years ago. In light of this, Lymphocyte-Activation Gene 3 (LAG-3) is one of the most important next-generation immune checkpoint molecules, playing a similar role as Programmed cell Death protein 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4). 19 LAG-3 targeting molecules are being evaluated at 108 clinical trials which are demonstrating positive results, including promising bispecific molecules targeting LAG-3 simultaneously with other ICIs. Recently, a new dual anti-PD-1 (Nivolumab) and anti-LAG-3 (Relatimab) treatment developed by Bristol Myers Squibb (Opdualag), was approved by the Food and Drug Administration (FDA) as the first LAG-3 blocking antibody combination for unresectable or metastatic melanoma. This novel immunotherapy combination more than doubled median progression-free survival (PFS) when compared to nivolumab monotherapy (10.1 months versus 4.6 months). Here, we analyze the large clinical trial responsible for this historical approval (RELATIVITY-047), and discuss the preclinical and clinical developments that led to its jump into clinical practice. We will also summarize results achieved by other LAG-3 targeting molecules with promising anti-tumor activities currently under clinical development in phases I, I/II, II, and III. Opdualag will boost the entry of more LAG-3 targeting molecules into clinical practice, supporting the accumulating evidence highlighting the pivotal role of LAG-3 in cancer.
Open Access
Descubrimiento de nuevas dianas terapéuticas mediante un sistema de selección racional de líneas tumorales de cáncer de páncreas adaptadas a la inhibición de rutas de señalización
(2020) Arasanz Esteban, Hugo; Escors Murugarren, David; Kochan, Grazyna; Ciencias de la Salud; Osasun Zientziak
Los objetivos de esta tesis son los siguientes: - Evaluar in vitro los efectos de una inhibición diferencial de cada una de las isoformas de AKT en una línea celular de adenocarcinoma de páncreas metastásico. - Caracterizar mediante proteomica cuantitativa diferencial los mecanismos de escape y adaptación de dichas células al silenciamiento individual de las isoformas de AKT. - Estudiar tanto in vitro como in vivo la posible sinergia entre la inhibición de AKT y terapias dirigidas frente a las principales rutas de escape detectadas por los estudios de proteomica cuantitativa.
Open Access
Enzalutamida como radiopotenciador de líneas celulares de cáncer de próstata
(2021) Barrado Los Arcos, Marta; Arias de la Vega, Fernando; Escors Murugarren, David; Encío Martínez, Ignacio; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua, BMED 033-2014
En este trabajo evaluamos el papel de enzalutamida como potenciador de la radioterapia en líneas celulares de cáncer de próstata, sirviendo como experimento de apoyo de investigación básica para investigación clínica. En este proyecto, proponemos estudiar este tratamiento combinado en dos líneas celulares humanas de cáncer de próstata representativas, LNCaP y PC3. Los objetivos concretos son los siguientes: analizar el efecto del tratamiento con enzalutamida antes de la radioterapia sobre la proliferación de células tumorales prostáticas evaluando si existe un efecto sinérgico entre ambas; comprobar el grado de apoptosis conseguido tras la combinación del tratamiento; y abordar el potencial de la tecnología de monitorización en tiempo real (RTCA) para probar si el régimen terapéutico combinatorio de radioterapia con enzalutamida en las líneas celulares de cáncer de próstata puede justificar su aplicación de esta combinación en pacientes con cáncer de próstata localizado.
Embargo
Estudio de los mecanismos inmunosupresores en cáncer
(2024) Andueza San Miguel, Ainhoa; Escors Murugarren, David; Escuela Técnica Superior de Ingeniería Agronómica y Biociencias; Nekazaritzako Ingeniaritzako eta Biozientzietako Goi Mailako Eskola Teknikoa
La inmunoterapia con bloqueadores de señalización por moléculas de control inmunitario PD-1/PD-L1 tiene como objetivo interferir con la señalización mediada por estas moléculas con el fin de potenciar y reactivar el sistema inmunitario y, así, obtener una inmunidad antitumoral. Sin embargo, algunos pacientes no responden frente a estas terapias. Esta resistencia se debe principalmente a la co-expresión de moléculas de control inmunitario adicionales, como LAG-3 en cáncer de pulmón no microcítico. Por ello, la generación de anticuerpos biespecíficos con capacidad de unión a dos dianas de forma simultánea resulta una terapia prometedora. La especificidad de unión dual permite el bloqueo simultáneo de dos vías de señalización diferentes, facilitando así la re-dirección de células inmunitarias a células tumorales. En el presente proyecto se ha generado un anticuerpo biespecífico contra los puntos de control inmunitario PD-1 y LAG-3 de ratón, con el fin de estudiar la expresión del mismo en diferentes líneas celulares. Para ello, en primer lugar, se ha diseñado y generado la construcción del anticuerpo biespecífico anti-PD-1 y anti-LAG-3 y se ha clonado en un vector de expresión lentiviral. A continuación, se han generado partículas lentivirales con la construcción mediante la transfección de células HEK 293T y se ha determinado el título por transducción de esta misma línea celular. Además, se ha establecido un sistema de visualización del anticuerpo biespecífico fusionado a GFP en las líneas celulares 3LL, MC38 y LACUN-3. Este proyecto es la base del estudio de la eficacia de los anticuerpos biespecíficos frente a las inmunoterapias actuales.
Open Access
Immune profiling uncovers memory T-cell responses with a Th17 signature in cancer patients with previous SARS-CoV-2 infection followed by mRNA vaccination
(MDPI, 2022) Echaide Górriz, Míriam; Labiano, Ibone; Delgado, Marina; Fernández de Lascoiti, Ángela; Ochoa, Patricia; Garnica, Maider; Ramos, Pablo; Chocarro de Erauso, Luisa; Fernández Rubio, Leticia; Arasanz Esteban, Hugo; Bocanegra Gondán, Ana Isabel; Blanco, Ester; Piñeiro Hermida, Sergio; Morente Sancho, Pilar; Vera García, Ruth; Alsina, María; Escors Murugarren, David; Kochan, Grazyna; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
It is unclear whether patients with cancer present inherently impaired responses to COVID-19 and vaccination due to their treatments, neoplastic diseases or both. To address this question, immune profiling was performed in three cohorts of healthy donors and oncologic patients: infected with SARS-CoV-2, BNT162b2-vaccinated, and with previous COVID-19 disease and subsequently vaccinated. Cancer patients showed good antibody responses to vaccination, but poor induction of T-cell responses towards the S protein when compared to infection. Following natural infection, the major targets for T-cells were the SARS-CoV-2 structural proteins M and S, but not the N protein. Similar to antibody titers, the T-cell responses quickly decayed after six months post-vaccination. Significant memory T-cell expansion was observed in vaccinated donors only if previously diagnosed with COVID-19 before undergoing vaccination. Oncologic patients with previous COVID-19 followed by vaccination exhibited potent IL-17+ CD4 and CD8 T-cell responses and elevated numbers of circulating neutrophils in peripheral blood. © 2022 by the authors.
Open Access
Leading edge: intratumor delivery of monoclonal antibodies for the treatment of solid tumors
(MDPI, 2023) Blanco, Ester; Chocarro de Erauso, Luisa; Fernández Rubio, Leticia; Bocanegra Gondán, Ana Isabel; Arasanz Esteban, Hugo; Echaide Górriz, Míriam; Garnica, Maider; Piñeiro Hermida, Sergio; Kochan, Grazyna; Escors Murugarren, David; Ciencias de la Salud; Osasun Zientziak
Immunotherapies based on immune checkpoint blockade have shown remarkable clinical outcomes and durable responses in patients with many tumor types. Nevertheless, these therapies lack efficacy in most cancer patients, even causing severe adverse events in a small subset of patients, such as inflammatory disorders and hyper-progressive disease. To diminish the risk of developing serious toxicities, intratumor delivery of monoclonal antibodies could be a solution. Encouraging results have been shown in both preclinical and clinical studies. Thus, intratumor immunotherapy as a new strategy may retain efficacy while increasing safety. This approach is still an exploratory frontier in cancer research and opens up new possibilities for next-generation personalized medicine. Local intratumor delivery can be achieved through many means, but an attractive approach is the use of gene therapy vectors expressing mAbs inside the tumor mass. Here, we summarize basic, translational, and clinical results of intratumor mAb delivery, together with descriptions of non-viral and viral strategies for mAb delivery in preclinical and clinical development. Currently, this is an expanding research subject that will surely play a key role in the future of oncology.
Open Access
Metabolic dyshomeostasis induced by SARS-CoV-2 structural proteins reveals immunological insights into viral olfactory interactions
(Frontiers Media, 2022) Lachén Montes, Mercedes; Mendizuri, Naroa; Ausín, Karina; Echaide Górriz, Míriam; Blanco, Ester; Chocarro de Erauso, Luisa; Toro, María de; Escors Murugarren, David; Fernández Irigoyen, Joaquín; Kochan, Grazyna; Santamaría Martínez, Enrique; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
One of the most common symptoms in COVID-19 is a sudden loss of smell. SARS-CoV-2 has been detected in the olfactory bulb (OB) from animal models and sporadically in COVID-19 patients. To decipher the specific role over the SARS-CoV-2 proteome at olfactory level, we characterized the in-depth molecular imbalance induced by the expression of GFP-tagged SARS-CoV-2 structural proteins (M, N, E, S) on mouse OB cells. Transcriptomic and proteomic trajectories uncovered a widespread metabolic remodeling commonly converging in extracellular matrix organization, lipid metabolism and signaling by receptor tyrosine kinases. The molecular singularities and specific interactome expression modules were also characterized for each viral structural factor. The intracellular molecular imbalance induced by each SARS-CoV-2 structural protein was accompanied by differential activation dynamics in survival and immunological routes in parallel with a differentiated secretion profile of chemokines in OB cells. Machine learning through a proteotranscriptomic data integration uncovered TGF-beta signaling as a confluent activation node by the SARS-CoV-2 structural proteome. Taken together, these data provide important avenues for understanding the multifunctional immunomodulatory properties of SARS-CoV-2 M, N, S and E proteins beyond their intrinsic role in virion formation, deciphering mechanistic clues to the olfactory inflammation observed in COVID-19 patients.
Open Access
Molecular mechanisms of programmed cell death-1 dependent T cell suppression: relevance for immunotherapy
(AME Publishing, 2017) Zuazo Ibarra, Miren; Gato Cañas, María; Llorente, Noelia; Ibañez Vea, María; Arasanz Esteban, Hugo; Kochan, Grazyna; Escors Murugarren, David; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
Programmed cell death-1 (PD1) has become a significant target for cancer immunotherapy. PD1 and its receptor programmed cell death 1 ligand 1 (PDL1) are key regulatory physiological immune checkpoints that maintain self-tolerance in the organism by regulating the degree of activation of T and B cells amongst other immune cell types. However, cancer cells take advantage of these immunosuppressive regulatory mechanisms to escape T and B cell-mediated immunity. PD1 engagement on T cells by PDL1 on the surface of cancer cells dramatically interferes with T cell activation and the acquisition of effector capacities. Interestingly, PD1-targeted therapies have demonstrated to be highly effective in rescuing T cell anti-tumor effector functions. Amongst these the use of anti-PD1/PDL1 monoclonal antibodies are particularly efficacious in human therapies. Furthermore, clinical findings with PD1/PDL1 blockers over several cancer types demonstrate clinical benefit. Despite the successful results, the molecular mechanisms by which PD1-targeted therapies rescue T cell functions still remain elusive. Therefore, it is a key issue to uncover the molecular pathways by which these therapies exert its function in T cells. A profound knowledge of PDL1/PD1 mechanisms will surely uncover a new array of targets susceptible of therapeutic intervention. Here, we provide an overview of the molecular events underlying PD1-dependent T cell suppression in cancer.
Open Access
Mrna vaccines against sars-cov-2: advantages and caveats
(MDPI, 2023) Echaide Górriz, Míriam; Chocarro de Erauso, Luisa; Bocanegra Gondán, Ana Isabel; Blanco, Ester; Kochan, Grazyna; Escors Murugarren, David; Ciencias de la Salud; Osasun Zientziak
The application of BNT162b2 and mRNA-1273 vaccines against SARS-CoV-2 infection has constituted a determinant resource to control the COVID-19 pandemic. Since the beginning of 2021, millions of doses have been administered in several countries of North and South America and Europe. Many studies have confirmed the efficacy of these vaccines in a wide range of ages and in vulnerable groups of people against COVID-19. Nevertheless, the emergence and selection of new variants have led to a progressive decay in vaccine efficacy. Pfizer–BioNTech and Moderna developed updated bivalent vaccines—Comirnaty and Spikevax—to improve responses against the SARS-CoV-2 Omicron variants. Frequent booster doses with monovalent or bivalent mRNA vaccines, the emergence of some rare but serious adverse events and the activation of T-helper 17 responses suggest the need for improved mRNA vaccine formulations or the use of other types of vaccines. In this review, we discuss the advantages and limitations of mRNA vaccines targeting SARS-CoV-2 focusing on the most recent, related publications.
Open Access
The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity
(Springer Nature, 2021) Edwards, Carolyn J.; Sette, Angelica; Cox, Carl; Di Fiore, Barabara; Wyre, Chris; Sydoruk, Daniela; Yadin, David; Hayes, Philip; Stelter, Szymon; Bartlett, Phillip D.; Zuazo Ibarra, Miren; García Granda, María Jesús; Benedetti, Giovanni; Fiaska, Stratonik; Birkett, Neil R.; Teng, Yumin; Enever, Carrie; Arasanz Esteban, Hugo; Bocanegra Gondán, Ana Isabel; Chocarro de Erauso, Luisa; Fernández Hinojal, Gonzalo; Vera García, Ruth; Archer, Bethan; Osuch, Isabelle; Lewandowska, Martyna; Surani, Yasmin M.; Kochan, Grazyna; Escors Murugarren, David; Legg, James; Pierce, Andrew J.; Ciencias de la Salud; Osasun Zientziak; Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa; Gobierno de Navarra / Nafarroako Gobernua
Background: improving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II. Methods: CB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked VH domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques. Results: CB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration. Conclusions: CB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control.
Open Access
Oleuropein-driven reprogramming of the myeloid cell compartment to sensitise tumours to PD-1/PD-L1 blockade strategies
(Springer Nature, 2024) Blanco, Ester; Silva-Pilipich, Noelia; Bocanegra Gondán, Ana Isabel; Chocarro de Erauso, Luisa; Procopio, Antonio; Ausín, Karina; Fernández Irigoyen, Joaquín; Fernández Rubio, Leticia; Razquin, Nerea; Igea, Ana; Garnica, Maider; Echaide Górriz, Míriam; Arasanz Esteban, Hugo; Vera García, Ruth; Escors Murugarren, David; Smerdou, Cristian; Kochan, Grazyna; Ciencias de la Salud; Osasun Zientziak
Background: Previous studies have shown that functional systemic immunity is required for the efficacy of PD-1/PD-L1 blockade immunotherapies in cancer. Hence, systemic reprogramming of immunosuppressive dysfunctional myeloid cells could overcome resistance to cancer immunotherapy. Methods: Reprogramming of tumour-associated myeloid cells with oleuropein was studied by quantitative differential proteomics, phenotypic and functional assays in mice and lung cancer patients. Combinations of oleuropein and two different delivery methods of anti-PD-1 antibodies were tested in colorectal cancer tumour models and in immunotherapy-resistant lung cancer models. Results: Oleuropein treatment reprogrammed monocytic and granulocytic myeloid-derived suppressor cells, and tumour-associated macrophages towards differentiation of immunostimulatory subsets. Oleuropein regulated major differentiation programmes associated to immune modulation in myeloid cells, which potentiated T cell responses and PD-1 blockade. PD-1 antibodies were delivered by two different strategies, either systemically or expressed within tumours using a self-amplifying RNA vector. Combination anti-PD-1 therapies with oleuropein increased tumour infiltration by immunostimulatory dendritic cells in draining lymph nodes, leading to systemic antitumour T cell responses. Potent therapeutic activities were achieved in colon cancer and lung cancer models resistant to immunotherapies, even leading to complete tumour regression. Discussion: Oleuropein significantly improves the outcome of PD-1/PD-L1 blockade immunotherapy strategies by reprogramming myeloid cells.
Open Access
El ozono no consigue la desinfección de los vehículos de emergencias de virus similares al SARS-CoV-2
(SEMES, 2020) Biurrun Cía, Jorge; García Martínez, Begoña; Pérez Montero, Andrea; Kochan, Grazyna; Escors Murugarren, David; Crespo Martínez, José; Lasa Uzcudun, Íñigo; Echarri Sucunza, Alfredo; Ciencias de la Salud; Osasun Zientziak
Ante la pandemia generada por el coronavirus SARS-CoV-2, la desinfección de los vehículos de emergencias supone una cuestión crucial. No en vano, son medio de transporte de pacientes contagiados y podrían ser vector de contagio para otros pacientes. Administraciones, servicios de emergencias y empresas privadas de transporte sanitario están aplicando diversas medidas para la desinfección de los vehículos. Actualmente, el uso de cañones productores de ozono es uno de los métodos más utilizados. El ozono es un gas oxidante con demostrada actividad desinfectante en medio acuoso que se utiliza para la desinfección de aguas y alimentos1-3. Sin embargo, su eficacia como desinfectante de superficies por nebulización no ha sido suficientemente probada y el Ministerio de Sanidad no lo registra como viricida para la desinfección de superficies4.
Open Access
PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets
(EMBO Press, 2024-07-19) Chocarro de Erauso, Luisa; Blanco, Ester; Fernández-Rubio, Leticia; Garnica, Maider; Zuazo Ibarra, Miren; García Granda, María Jesús; Bocanegra Gondán, Ana Isabel; Echaide Górriz, Míriam; Johnston, Colette; Edwards, Carolyn J.; Legg, James; Pierce, Andrew J.; Arasanz Esteban, Hugo; Fernández Hinojal, Gonzalo; Vera García, Ruth; Ausín, Karina; Santamaría Martínez, Enrique; Fernández Irigoyen, Joaquín; Kochan, Grazyna; Escors Murugarren, David; Ciencias de la Salud; Osasun Zientziak
Many cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD-1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers immune infiltrates. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic, and epigenetic pathways, but especially a reinforced negative regulation of the TCR signalosome. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. A differential analysis of the proteome of PD-1/LAG-3 T-cells showed a specific enrichment in ubiquitin ligases participating in E3 ubiquitination pathways. PD-1/LAG-3 co-blockade inhibited CBL-B expression, while the use of a bispecific drug in clinical development also repressed C-CBL expression, which reverted T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD-1 blockade. The combination of CBL-B-specific small molecule inhibitors with anti-PD-1/anti-LAG-3 immunotherapies demonstrated notable therapeutic efficacy in models of lung cancer refractory to immunotherapies, overcoming PD-1/LAG-3 mediated resistance. © The Author(s) 2024.
Open Access
PD-L1 expression in systemic immune cell populations as a potential predictive biomarker of responses to PD-L1/PD-1 blockade therapy in lung cancer
(MDPI, 2019) Bocanegra Gondán, Ana Isabel; Fernández Hinojal, Gonzalo; Zuazo Ibarra, Miren; Arasanz Esteban, Hugo; García Granda, María Jesús; Hernández, Carlos; Ibañez Vea, María; Hernandez Marin, Berta; Martínez Aguillo, Maite; Lecumberri, María José; Fernández de Lascoiti, Ángela; Teijeira, Lucía; Morilla Ruiz, Idoia; Vera García, Ruth; Escors Murugarren, David; Kochan, Grazyna; Ciencias de la Salud; Osasun Zientziak; Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa
PD-L1 tumor expression is a widely used biomarker for patient stratification in PD-L1/PD-1 blockade anticancer therapies, particularly for lung cancer. However, the reliability of this marker is still under debate. Moreover, PD-L1 is widely expressed by many immune cell types, and little is known on the relevance of systemic PD-L1+ cells for responses to immune checkpoint blockade. We present two clinical cases of patients with non-small cell lung cancer (NSCLC) and PD-L1-negative tumors treated with atezolizumab that showed either objective responses or progression. These patients showed major differences in the distribution of PD-L1 expression within systemic immune cells. Based on these results, an exploratory study was carried out with 32 cases of NSCLC patients undergoing PD-L1/PD-1 blockade therapies, to compare PD-L1 expression profiles and their relationships with clinical outcomes. Significant differences in the percentage of PD-L1+ CD11b+ myeloid cell populations were found between objective responders and non-responders. Patients with percentages of PD-L1+ CD11b+ cells above 30% before the start of immunotherapy showed response rates of 50%, and 70% when combined with memory CD4 T cell profiling. These findings indicate that quantification of systemic PD-L1+ myeloid cell subsets could provide a simple biomarker for patient stratification, even if biopsies are scored as PD-L1 null
Open Access
PD1 signal transduction pathways in T cells
(Impact Journals, 2017) Arasanz Esteban, Hugo; Gato Cañas, María; Zuazo Ibarra, Miren; Ibañez Vea, María; Breckpot, Karine; Kochan, Grazyna; Escors Murugarren, David; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
The use of immune checkpoint inhibitors for the treatment of cancer is revolutionizing oncology. Amongst these therapeutic agents, antibodies that block PD-L1/PD1 interactions between cancer cells and T cells are demonstrating high efficacies and low toxicities. Despite all the recent advances, very little is yet known on the molecular intracellular signaling pathways regulated by either PD-L1 or PD1. Here we review the current knowledge on PD1-dependent intracellular signaling pathways, and the consequences of disrupting PD1 signal transduction.