Fernández-Hinojal, G. (Gonzalo)
- Publications
- item.page.relationships.isContributorAdvisorOfPublication
- item.page.relationships.isContributorOfPublication
4 results
Search Results
Now showing 1 - 4 of 4
- Early Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics(2020) Kochan, G. (Grazyna); Chocarro, L. (Luisa); Gato-Cañas, M. (María); Bocanegra, A. (Ana); López, P. (Paúl); Hernández, C. (Carlos); Zuazo, M. (Miren); Morilla, I. (Idoia); Fernández-Hinojal, G. (Gonzalo); Arasanz, H. (Hugo); Hernández, B. (Berta); Alberdi, N. (Nerea); Teijeira, L. (Lucía); Escors, D. (David); Martinez-Aguillo, M. (M.); Vera, R. (Ruth)Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on radiological evaluation present important technical limitations. No biomarkers have been identified yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy after progression to platinum-based therapy were prospectively studied. Samples from peripheral blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified by flow cytometry and correlated with HPD as identified with radiological criteria. A strong expansion of highly differentiated CD28− CD4 T lymphocytes (CD4 THD) between the first and second cycle of therapy was observed in HPD patients. After normalizing, the proportion of posttreatment/pretreatment CD4 THD was significantly higher in HPD when compared with the rest of patients (median 1.525 vs. 0.990; p = 0.0007), and also when stratifying by HPD, non-HPD progressors, and responders (1.525, 1.000 and 0.9700 respectively; p = 0.0025). A cut-off value of 1.3 identified HPD with 82% specificity and 70% sensitivity. An increase of CD28− CD4 T lymphocytes ≥ 1.3 (CD4 THD burst) was significantly associated with HPD (p = 0.008). The tumor growth ratio (TGR) was significantly higher in patients with expansion of CD4 THD burst compared to the rest of patients (median 2.67 vs. 0.86, p = 0.0049), and also when considering only progressors (median 2.67 vs. 1.03, p = 0.0126). A strong expansion of CD28− CD4 lymphocytes in peripheral blood within the first cycle of therapy is an early differential feature of HPD in NSCLC treated with immune-checkpoint inhibitors. The monitoring of T cell dynamics allows the early detection of this adverse outcome in clinical practice and complements radiological evaluation.
- Prognostic capacity of peripheral blood-derived biomarkers in NSCLC patients treated with PD-1/PD-L1 blockade immunotherapy(Universidad de Navarra, 2022-01-20) Fernández-Hinojal, G. (Gonzalo); Kochan, G. (Grazyna); Pio, R. (Rubén)El cáncer de pulmón genera una importante carga de morbimortalidad a nivel mundial. Durante la última década ha existido un importante desarrollo terapéutico por la aprobación de fármacos de inmunoterapia, especialmente en el bloqueo de PD-1 y PD-L1 en pacientes sin dianas terapéuticas. Pese a la propuesta de numerosos biomarcadores, resulta difícil identificar aquellos pacientes que se benefician del tratamiento y obtienen respuestas prolongadas. En este estudio observacional retrospectivo, se recogieron variables clínicas junto con la composición corporal medida por TC, así como extracción muestras de sangre periférica tras el inicio de tratamiento en una cohorte de pacientes con carcinoma no microcítico pulmonar avanzado en tratamiento con inmunoterapia. Se realizó una citometría de flujo multidimensional para la detección e inmunofenotipado de diferentes poblaciones mieloides. Además se analizó la concentración de 45 proteínas circulantes solubles en plasma, agrupados como puntos de control inmunes y quimiocinas mediante Luminex®. En contraste con bibliografía previa, no encontramos diferencias respecto a tasas de respuesta según la composición corporal. Respecto a variables clínicas, observamos un incremento de neutrófilos en sangre periférica en los pacientes no respondedores, así como una aceleración de este fenómeno previamente al deterioro clínico y fallecimiento del paciente, y un descenso paralelo de las cifras absolutas de linfocitos. No observamos diferencias respecto a las cifras de monocitos y plaquetas. Un inmunofenotipado preciso de estas poblaciones mediante citometría de flujo permitió detectar una predominancia de monocitos en respondedores y su correlación con la respuesta al tratamiento. Los niveles de expresión de PD-L1 en estas poblaciones mieloides se puede asociar con las respuestas al tratamiento de inmunoterapia. Las concentraciones de varias proteínas circulantes entre las que se encuentran TIM-3, HVEM, IFN-gamma y VEGF se asociaron con la actividad del tratamiento y el pronóstico de la enfermedad, con impacto en supervivencia global. Además, la histopatología del tumor primario fue un factor diferencial importante en el perfil de acti-vidad de estos tratamientos. Finalmente, se realizó un análisis multivariante de la cohorte. El número previo de líneas de tratamiento, un estatus funcional medido por ECOG > 2, el número de localizaciones metastásicas incluyendo las lesiones hepáticas, el incremento de neutrófilos circulantes medidos por citometría de flujo, y las concentraciones plasmáticas de MCP1 e IL-17alfa se establecieron como predictores independientes de supervivencia.
- Plasma fractalkine contributes to systemic myeloid diversity and PD-L1/PD-1 blockade in lung cancer(2023) Tavira, B. (Beatriz); Fernández, L. (Leticia); Kochan, G. (Grazyna); Pio, R. (Rubén); Chocarro, L. (Luisa); Ventura, A. (Alfonso); Alfaro-Arnedo, E. (Elvira); Remirez, A. (Ana); Gotera-Rivera, C. (Carolina); Bocanegra, A. (Ana); Ajona-Martínez-Polo, D. (Daniel); Recalde, N. (Nerea); Piñeiro-Hermida, S. (Sergio); Pichel, J.G. (José G.); Zuazo, M. (Miren); Morilla, I. (Idoia); Fernández-Hinojal, G. (Gonzalo); Blanco, E. (Ester); Echaide, M. (Miriam); Montuenga-Badia, L.M. (Luis M.); Morente, P. (Pilar); Escors, D. (David); Garnica, M. (Maider); Martinez-Aguillo, M. (M.); Roncero, A. (Alejandra); Vera, R. (Ruth); Lasarte, J.J. (Juan José)Recent studies highlight the importance of baseline functional immunity for immune checkpoint blockade therapies. High-dimensional systemic immune profiling is performed in a cohort of non-small-cell lung cancer patients undergoing PD-L1/PD-1 blockade immunotherapy. Responders show high baseline myeloid phenotypic diversity in peripheral blood. To quantify it, we define a diversity index as a potential biomarker of response. This parameter correlates with elevated activated monocytic cells and decreased granulocytic phenotypes. High-throughput profiling of soluble factors in plasma identifies fractalkine (FKN), a chemokine involved in immune chemotaxis and adhesion, as a biomarker of response to immunotherapy that also correlates with myeloid cell diversity in human patients and murine models. Secreted FKN inhibits lung adenocarcinoma growth in vivo through a prominent contribution of systemic effector NK cells and increased tumor immune infiltration. FKN sensitizes murine lung cancer models refractory to anti-PD-1 treatment to immune checkpoint blockade immunotherapy. Importantly, recombinant FKN and tumor-expressed FKN are efficacious in delaying tumor growth in vivo locally and systemically, indicating a potential therapeutic use of FKN in combination with immunotherapy.
- Prognostic value of human leukocyte antigen G expression in solid tumors: a systematic review and meta-analysis(2023) Perez-Segura, P. (Pedro); Ocaña, A. (Alberto); Benítez-Fuentes, J.D. (Javier David); Mittal, A. (Abhenil); Amir, E. (Eitan); Fernández-Hinojal, G. (Gonzalo); Molto, C. (Consolación); Bartolome, J. (Javier); Manzano, A. (Aranzazu); Tamimi, F. (Faris)Introduction Identification of modulators of the immune response with inhibitory properties that could be susceptible for therapeutic intervention is a key goal in cancer research. An example is the human leukocyte antigen G (HLA-G), a nonclassical major histocompatibility complex (MHC) class I molecule, involved in cancer progression.Methods In this article we performed a systematic review and meta-analysis on the association between HLA-G expression and outcome in solid tumors. This study was performed in accordance with PRISMA guidelines and registered in PROSPERO.Results A total of 25 studies met the inclusion criteria. These studies comprised data from 4871 patients reporting overall survival (OS), and 961 patients, reporting disease free survival (DFS). HLA-G expression was associated with worse OS (HR 2.09, 95% CI = 1.67 to 2.63; P < .001), that was higher in gastric (HR = 3.40; 95% CI = 1.64 to 7.03), pancreatic (HR = 1.72; 95% CI = 0.79 to 3.74) and colorectal (HR = 1.55; 95% CI = 1.16 to 2.07) cancer. No significant differences were observed between the most commonly utilized antibody (4H84) and other methods of detection. HLA-G expression was associated with DFS which approached but did not meet statistical significance.Discussion In summary, we describe the first meta-analysis associating HLA-G expression and worse survival in a variety of solid tumors.