Baraibar-Argota, I. (Iosune)
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- Novel therapeutic strategy to prevent immune escape in metastatic NSCLC through combined PD-1 and Id1 blockade(Universidad de Navarra, 2021-06-08) Baraibar-Argota, I. (Iosune); Gil-Bazo, I. (Ignacio)According to the Global Cancer Observatory (http://gco.iarc.fr), primary lung cancer ranks as the most common tumor worldwide and the leading cause of cancer-related mortality. In 2020, 2.2 million new lung cancer cases were diagnosed, which comprises 12.2% of total cancers.
- KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target(BMC, 2018) Gil-Bazo, I. (Ignacio); Román, M. (Marta); Vicent, S. (Silvestre); Nadal, E. (Ernest); Rolfo, C. (Christian); Baraibar-Argota, I. (Iosune); Lopez, I. (Inés)Lung neoplasms are the leading cause of death by cancer worldwide. Non-small cell lung cancer (NSCLC) constitutes more than 80% of all lung malignancies and the majority of patients present advanced disease at onset. However, in the last decade, multiple oncogenic driver alterations have been discovered and each of them represents a potential therapeutic target. Although KRAS mutations are the most frequently oncogene aberrations in lung adenocarcinoma patients, effective therapies targeting KRAS have yet to be developed. Moreover, the role of KRAS oncogene in NSCLC remains unclear and its predictive and prognostic impact remains controversial. The study of the underlying biology of KRAS in NSCLC patients could help to determine potential candidates to evaluate novel targeted agents and combinations that may allow a tailored treatment for these patients. The aim of this review is to update the current knowledge about KRAS-mutated lung adenocarcinoma, including a historical overview, the biology of the molecular pathways involved, the clinical relevance of KRAS mutations as a prognostic and predictive marker and the potential therapeutic approaches for a personalized treatment of KRAS-mutated NSCLC patients.
- Id1 and PD-1 Combined Blockade Impairs Tumor Growth and Survival of KRAS-mutant Lung Cancer by Stimulating PD-L1 Expression and Tumor Infiltrating CD8+ T Cells(2020) Gil-Bazo, I. (Ignacio); Pio, R. (Rubén); Román, M. (Marta); Puyalto, A. (Ander); Collantes, M. (María); Lozano-Moreda, T. (Teresa); Vicent, S. (Silvestre); Garcia-Ros, D. (David); Villalba-Esparza, M. (María); Caglevic, C. (Christian); Ecay, M. (Margarita); Rodríguez-Remírez, M. (M.); Alignani, D. (Diego); Rolfo, C. (Christian); Guruceaga, E. (Elizabeth); Moreno, H. (Haritz); Andrea, C.E. (Carlos Eduardo) de; Ortiz-Espinosa, S. (Sergio); Vilalta, A. (Anna); Torregrosa, M.S. (María Soledad); Baraibar-Argota, I. (Iosune); Lopez, I. (Inés); Calvo-González, A. (Alfonso); Ajona, D. (Daniel); Oliver, A. (Ana); Lasarte, J.J. (Juan José)The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because of immunosuppression. New immunotherapy-based combinations are under investigation in an attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth impairment and overall survival improvement. Mechanistically, multiplex quantification of CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration. Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1 expression and harnessing tumor infiltration of CD8+ T lymphocytes.
- Chemotherapy after immunotherapy failure in patients with advanced gastrointestinal tumors(Elsevier, 2018) Martin-Romano, P. (Patricia); Ortega-Montes, A. (Ana); Rodriguez-Ruiz, M.E. (María Esperanza); Ponz-Sarvise, M. (Mariano); Castañon-Alvarez, E. (Eduardo); Melero, I. (Ignacio); Resano, L. (Leyre); Baraibar-Argota, I. (Iosune); Fernandez-Sanmamed, M. (Miguel)First line therapies usually induce the longest progression free survival (PFS) in metastatic gastrointestinal cancers (GIC) as compared to subsequent lines of treatment. However, immunotherapy (IT) due to its mechanisms of action could influence sensitivity to conventional cancer therapy (CCT) after progression to IT and thereby, influence both tumor growth rate (TGR) and PFS. We have studied TGR and PFS before and after participation in phase I IT trials.
- Combination of pegylated liposomal doxorubicin plus gemcitabine in heavily pretreated metastatic breast cancer patients: Long-term results from a single institution experience(Wiley, 2017) Espinos, J. (Jaime); Martin-Romano, P. (Patricia); Lopez-Picazo, J.M. (José M.); Santisteban, M. (Marta); Legaspi, J. (Jairo); Aramendia, J.M. (J.M.); Baraibar-Argota, I. (Iosune); Fernández, Ó.A. (Óscar A.)The combination of Pegylated Liposomal Doxorubicin (PLD) plus Gemcitabine (GEM) has been previously investigated in the treatment of metastatic breast cancer (MBC). PLD is a doxorubicin formulation with prolonged circulation time and better tissue distribution. GEM is a nucleoside analog with nonoverlapping toxicity compared to PLD. The aim of our study was to assess efficacy, toxicity, and long-term outcome of this combination. Patients with heavily treated MBC were retrospectively analyzed. Chemotherapy consisted of PLD 25 mg/m2 and GEM 800 mg/m2 day 1, on a three-week schedule. Cardiac function was evaluated baseline and during treatment. Radiological response was graded according to RECIST criteria v1.1. Toxicity was scored according to CTCAE v4.0. Progression-free survival (PFS) and overall survival (OS) were evaluated. From 2001 to 2014, 122 pts were included. Median age was 55 (range: 28-84). Median previous treatment schedules in the metastatic scenario were 3 (range: 1-15). Most patients received prior anthracyclines (85%). Median number of metastatic sites was 2 (range: 1-7). Median number of cycles delivered was 5 (range: 1-36). Overall response rate was 31% (5% complete responses; 26% partial responses). Stable and progressive diseases were observed in 32% and 26% of patients. Grade ≥3 neutropenia was observed in 29 patients (24%). Grade ≥3 hand-foot syndrome was detected in 17 patients (14%), mostly since cycle 3 (88%). Median cumulative PLD dose was 125 mg/m2. At a median follow-up of 101 months, median PFS and OS were 7 and 22 months, respectively. PLD-GEM combination achieves remarkable long-term outcomes with an acceptable toxicity profile in patients with MBC.