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5. 1074P Peripheral low-density neutrophils identify a subset of NSCLC patients with high PD-L1 tumor expression that can benefit from chemo-immunotherapy

Author

Arasanz, H., Bocanegra Gondan, A.I., Teijeira, L., Garnica, M., Morilla Ruiz, I., Chocarro, L., Martínez-Aguillo, M., Ausin, K., Blanco, E., Zuazo, M., Fernandez-Hinojal, G., Echaide, M., Fernández-Rubio, L., Pineiro-Hermida, S., Ramos, P., Fernández-Irigoyen, J., Kochan, G., Vera, R., and Escors, D.

Published
2022
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11. PROCLAIM : résultats finaux de survie globale de l’essai de phase III : pemetrexed cisplatine ou étoposide cisplatine, plus radiothérapie thoracique suivie d’une chimiothérapie de consolidation dans le CBNPC non épidermoïde localement avancé

Author

Mornex, F., primary, Senan, S., additional, Hennequin, C., additional, Lartigau, E., additional, Brade, A., additional, Wang, L., additional, Vansteenkiste, J., additional, Dakhil, S., additional, Biesma, B., additional, Martinez Aguillo, M., additional, Aerts, J., additional, Govindan, R., additional, Rubio-Viqueira, B., additional, Lewanski, C., additional, Gandara, D., additional, Choy, H., additional, Mok, T., additional, Hossain, A., additional, Iscoe, N., additional, Treat, J., additional, Koustenis, A., additional, Chouaki, N., additional, and Vokes, E., additional

Published
2016
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12. IMMUNOTHERAPY/BIOLOGICAL THERAPIES

Author

Campian, J., primary, Gladstone, D., additional, Ambady, P., additional, Ye, X., additional, King, K., additional, Borrello, I., additional, Petrik, S., additional, Golightly, M., additional, Holdhoff, M., additional, Grossman, S., additional, Bhardwaj, R., additional, Chakravadhanula, M., additional, Ozols, V., additional, Georges, J., additional, Carlson, E., additional, Hampton, C., additional, Decker, W., additional, Chiba, Y., additional, Hashimoto, N., additional, Kagawa, N., additional, Hirayama, R., additional, Tsuboi, A., additional, Oji, Y., additional, Oka, Y., additional, Sugiyama, H., additional, Yoshimine, T., additional, Choi, B., additional, Gedeon, P., additional, Herndon, J., additional, Sanchez-Perez, L., additional, Mitchell, D., additional, Bigner, D., additional, Sampson, J., additional, Choi, Y. A., additional, Pandya, H., additional, Gibo, D. M., additional, Debinski, W., additional, Cloughesy, T. F., additional, Liau, L. M., additional, Chiocca, E. A., additional, Jolly, D. J., additional, Robbins, J. M., additional, Ostertag, D., additional, Ibanez, C. E., additional, Gruber, H. E., additional, Kasahara, N., additional, Vogelbaum, M. A., additional, Kesari, S., additional, Mikkelsen, T., additional, Kalkanis, S., additional, Landolfi, J., additional, Bloomfield, S., additional, Foltz, G., additional, Pertschuk, D., additional, Everson, R., additional, Jin, R., additional, Safaee, M., additional, Lisiero, D., additional, Odesa, S., additional, Liau, L., additional, Prins, R., additional, Gholamin, S., additional, Mitra, S. S., additional, Richard, C. E., additional, Achrol, A., additional, Kahn, S. A., additional, Volkmer, A. K., additional, Volkmer, J. P., additional, Willingham, S., additional, Kong, D., additional, Shin, J. J., additional, Monje-Deisseroth, M., additional, Cho, Y.-J., additional, Weissman, I., additional, Cheshier, S. H., additional, Kanemura, Y., additional, Sumida, M., additional, Yoshioka, E., additional, Yamamoto, A., additional, Kanematsu, D., additional, Takada, A., additional, Nonaka, M., additional, Nakajima, S., additional, Goto, S., additional, Kamigaki, T., additional, Takahara, M., additional, Maekawa, R., additional, Shofuda, T., additional, Moriuchi, S., additional, Yamasaki, M., additional, Kebudi, R., additional, Cakir, F. B., additional, Gorgun, O., additional, Agaoglu, F. Y., additional, Darendeliler, E., additional, Lin, Y., additional, Wang, Y., additional, Qiu, X., additional, Jiang, T., additional, Zhang, G., additional, Wang, J., additional, Okada, H., additional, Butterfield, L., additional, Hamilton, R., additional, Drappatz, J., additional, Engh, J., additional, Amankulor, N., additional, Lively, M., additional, Chan, M., additional, Salazar, A., additional, Potter, D., additional, Shaw, E., additional, Lieberman, F., additional, Choi, Y., additional, Park, J., additional, Phuphanich, S., additional, Wheeler, C., additional, Rudnick, J., additional, Hu, J., additional, Mazer, M., additional, Wang, H., additional, Nuno, M., additional, Guevarra, A., additional, Sanchez, C., additional, Fan, X., additional, Ji, J., additional, Chu, R., additional, Bender, J., additional, Hawkins, E., additional, Black, K., additional, Yu, J., additional, Reap, E., additional, Archer, G., additional, Norberg, P., additional, Schmittling, R., additional, Nair, S., additional, Cui, X., additional, Snyder, D., additional, Chandramohan, V., additional, Kuan, C.-T., additional, Yan, H., additional, Reardon, D., additional, Li, G., additional, Recht, L., additional, Fink, K., additional, Nabors, L., additional, Tran, D., additional, Desjardins, A., additional, Chandramouli, N., additional, Duic, J. P., additional, Groves, M., additional, Clarke, A., additional, Hawthorne, T., additional, Green, J., additional, Yellin, M., additional, Rigakos, G., additional, Spyri, O., additional, Nomikos, P., additional, Stavridi, F., additional, Grossi, I., additional, Theodorakopoulou, I., additional, Assi, A., additional, Kouvatseas, G., additional, Papadopoulou, E., additional, Nasioulas, G., additional, Labropoulos, S., additional, Razis, E., additional, Ravi, A., additional, Tang, D. N., additional, Sharma, P., additional, Sengupta, S., additional, Sampath, P., additional, Soto, H., additional, Erickson, K., additional, Malone, C., additional, Hickey, M., additional, Ha, E., additional, Young, E., additional, Ellingson, B., additional, Kruse, C., additional, Sul, J., additional, Hilf, N., additional, Kutscher, S., additional, Schoor, O., additional, Lindner, J., additional, Reinhardt, C., additional, Kreisl, T., additional, Iwamoto, F., additional, Fine, H., additional, Singh-Jasuja, H., additional, Teijeira, L., additional, Gil-Arnaiz, I., additional, Hernandez-Marin, B., additional, Martinez-Aguillo, M., additional, Sanchez, S. d. l. C., additional, Viudez, A., additional, Hernandez-Garcia, I., additional, Lecumberri, M. J., additional, Grandez, R., additional, de Lascoiti, A. F., additional, Garcia, R. V., additional, Thomas, A., additional, Fisher, J., additional, Baron, U., additional, Olek, S., additional, Rhodes, H., additional, Gui, J., additional, Hampton, T., additional, Tafe, L., additional, Tsongalis, G., additional, Lefferts, J., additional, Wishart, H., additional, Kleen, J., additional, Miller, M., additional, Ernstoff, M., additional, Fadul, C., additional, Vlahovic, G., additional, Peters, K., additional, Ranjan, T., additional, Friedman, A., additional, Friedman, H., additional, Lally-Goss, D., additional, Wainwright, D., additional, Dey, M., additional, Chang, A., additional, Cheng, Y., additional, Han, Y., additional, Lesniak, M., additional, Weller, M., additional, Kaulich, K., additional, Hentschel, B., additional, Felsberg, J., additional, Gramatzki, D., additional, Pietsch, T., additional, Simon, M., additional, Westphal, M., additional, Schackert, G., additional, Tonn, J. C., additional, Loeffler, M., additional, Reifenberger, G., additional, Xu, M., additional, and Patil, C., additional

Published
2013
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14. 1153 POSTER Percentage decrease in Haemoglobin values after chemotherapy and radiation therapy as a predictive response factor to Epoetin beta

Author

Martinez Lopez, E., primary, Asín Felipe, G., additional, Romero Rojano, P., additional, Rico Osés, M., additional, Manterola Burgaleta, A., additional, Martinez Aguillo, M., additional, Villafranca Iturre, E., additional, Arias de la Vega, F., additional, and Domínguez Domínguez, M.A., additional

Published
2007
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15. Paclitaxel, cisplatin, and gemcitabine combination chemotherapy within a multidisciplinary therapeutic approach in metastatic nonsmall cell lung carcinoma.

Author

Rodriguez, Javier, Cortes, Javier, Calvo, Emiliano, Azinovic, Ignacio, Fernandez-Hildago, Oscar, Martinez-Monge, Rafael, Garzon, Carlos, de Irala, Jokin, Martinez-Aguillo, Maite, Ramon y Cajal, Teresa, Brugarolas, Antonio, Rodriguez, J, Cortes, J, Calvo, E, Azinovic, I, Fernandez-Hildago, O, Martinez-Monge, R, Garzon, C, de Irala, J, and Martinez-Aguillo, M

Published
2000
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17. Plasma fractalkine contributes to systemic myeloid diversity and PD-L1/PD-1 blockade in lung cancer.

Author

Bocanegra A, Fernández-Hinojal G, Ajona D, Blanco E, Zuazo M, Garnica M, Chocarro L, Alfaro-Arnedo E, Piñeiro-Hermida S, Morente P, Fernández L, Remirez A, Echaide M, Martinez-Aguillo M, Morilla I, Tavira B, Roncero A, Gotera C, Ventura A, Recalde N, Pichel JG, Lasarte JJ, Montuenga L, Vera R, Pio R, Escors D, and Kochan G

Subjects
Animals, Humans, Mice, B7-H1 Antigen genetics, Biomarkers, Chemokine CX3CL1 genetics, Chemokine CX3CL1 therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms genetics
Abstract

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., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Published
2023
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18. 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.

Author

Bocanegra A, Fernandez-Hinojal G, Zuazo-Ibarra M, Arasanz H, Garcia-Granda MJ, Hernandez C, Ibañez M, Hernandez-Marin B, Martinez-Aguillo M, Lecumberri MJ, Fernandez de Lascoiti A, Teijeira L, Morilla I, Vera R, Escors D, and Kochan G

Subjects
Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, B7-H1 Antigen metabolism, CD4-Positive T-Lymphocytes metabolism, Female, Humans, Lung Neoplasms diagnostic imaging, Lung Neoplasms drug therapy, Male, Middle Aged, Programmed Cell Death 1 Receptor metabolism, B7-H1 Antigen antagonists & inhibitors, Biomarkers, Tumor metabolism, Immunotherapy, Lung Neoplasms immunology, Lung Neoplasms therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors
Abstract

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.

Published
2019
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19. PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer.

Author

Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, and Vokes E

Subjects
Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung pathology, Chemoradiotherapy, Cisplatin administration & dosage, Consolidation Chemotherapy, Etoposide administration & dosage, Female, Humans, Lung Neoplasms pathology, Male, Middle Aged, Neoplasm Staging, Pemetrexed administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung radiotherapy, Lung Neoplasms drug therapy, Lung Neoplasms radiotherapy
Abstract

Purpose: The phase III PROCLAIM study evaluated overall survival (OS) of concurrent pemetrexed-cisplatin and thoracic radiation therapy (TRT) followed by consolidation pemetrexed, versus etoposide-cisplatin and TRT followed by nonpemetrexed doublet consolidation therapy., Patients and Methods: Patients with stage IIIA/B unresectable nonsquamous non-small-cell lung cancer randomly received (1:1) pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) intravenously every 3 weeks for three cycles plus concurrent TRT (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for four cycles (arm A), or standard therapy with etoposide 50 mg/m(2) and cisplatin 50 mg/m(2) intravenously, every 4 weeks for two cycles plus concurrent TRT (60 to 66 Gy) followed by two cycles of consolidation platinum-based doublet chemotherapy (arm B). The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS hazard ratio of 0.74 with a type 1 error of .05., Results: Enrollment was stopped early because of futility. Five hundred ninety-eight patients were randomly assigned (301 to arm A, 297 to arm B) and 555 patients (283 in arm A, 272 in arm B) were treated. Arm A was not superior to arm B in terms of OS (hazard ratio, 0.98; 95% CI, 0.79 to 1.20; median, 26.8 v 25.0 months; P = .831). Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events (64.0% v 76.8%; P = .001), including neutropenia (24.4% v 44.5%; P < .001), during the overall treatment period., Conclusion: Pemetrexed-cisplatin combined with TRT followed by consolidation pemetrexed was not superior to standard chemoradiotherapy for stage III unresectable nonsquamous non-small-cell lung cancer., (© 2016 by American Society of Clinical Oncology.)

Published
2016
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20. EPB41L3, TSP-1 and RASSF2 as new clinically relevant prognostic biomarkers in diffuse gliomas.

Author

Perez-Janices N, Blanco-Luquin I, Tuñón MT, Barba-Ramos E, Ibáñez B, Zazpe-Cenoz I, Martinez-Aguillo M, Hernandez B, Martínez-Lopez E, Fernández AF, Mercado MR, Cabada T, Escors D, Megias D, and Guerrero-Setas D

Subjects
Aged, Biomarkers, Tumor analysis, Brain Neoplasms mortality, DNA Methylation genetics, Disease-Free Survival, Female, Fluorescent Antibody Technique, Glioma mortality, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Male, Middle Aged, Prognosis, Reverse Transcriptase Polymerase Chain Reaction, Brain Neoplasms genetics, Glioma genetics, Microfilament Proteins genetics, Thrombospondin 1 genetics, Tumor Suppressor Proteins genetics
Abstract

Hypermethylation of tumor suppressor genes is one of the hallmarks in the progression of brain tumors. Our objectives were to analyze the presence of the hypermethylation of EPB41L3, RASSF2 and TSP-1 genes in 132 diffuse gliomas (astrocytic and oligodendroglial tumors) and in 10 cases of normal brain, and to establish their association with the patients' clinicopathological characteristics. Gene hypermethylation was analyzed by methylation-specific-PCR and confirmed by pyrosequencing (for EPB41L3 and TSP-1) and bisulfite-sequencing (for RASSF2). EPB41L3, RASSF2 and TSP-1 genes were hypermethylated only in tumors (29%, 10.6%, and 50%, respectively), confirming their cancer-specific role. Treatment of cells with the DNA-demethylating-agent 5-aza-2'-deoxycytidine restores their transcription, as confirmed by quantitative-reverse-transcription-PCR and immunofluorescence. Immunohistochemistry for EPB41L3, RASSF2 and TSP-1 was performed to analyze protein expression; p53, ki-67, and CD31 expression and 1p/19q co-deletion were considered to better characterize the tumors. EPB41L3 and TSP-1 hypermethylation was associated with worse (p = 0.047) and better (p = 0.037) prognosis, respectively. This observation was confirmed after adjusting the results for age and tumor grade, the role of TSP-1 being most pronounced in oligodendrogliomas (p = 0.001). We conclude that EPB41L3, RASSF2 and TSP-1 genes are involved in the pathogenesis of diffuse gliomas, and that EPB41L3 and TSP-1 hypermethylation are of prognostic significance.

Published
2015
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