Perez-Gracia, J.L. (Jose Luis)
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- Fibrosing cholestatic hepatitis following cytotoxic chemotherapy for small-cell lung cancer(Baishideng Publishing Group Co. Limited, 2009) Gil-Bazo, I. (Ignacio); Perez-Gracia, J.L. (Jose Luis); Lopez-Picazo, J.M. (José M.); Ceballos-Viro, J. (Jaime); Aisa, G. (Gregorio); Sola, J.J. (Jesús Javier)Fibrosing cholestatic hepatitis (FCH) is a variant of viral hepatitis reported in hepatitis B virus or hepatitis C virus infected liver, renal or bone transplantation recipients and in leukemia and lymphoma patients after conventional cytotoxic chemotherapy. FCH constitutes a well-described form of fulminant hepatitis having ex-- of a 49-year-old patient diagnosed with small-cell lung cancer who developed this condition following conventional chemotherapy-induced immunosuppression. This conventional chemotherapy for a solid tumor. In addition to a detailed report of the case, a physiopathological examination of this potentially life-threatening condition and its treatment options are discussed.
- Identification of TNF-alpha and MMP-9 as potential baseline predictive serum markers of sunitinib activity in patients with renal cell carcinoma using a human cytokine array(Nature Publishing Group, 2009) Gil-Bazo, I. (Ignacio); Prior, C. (Celia); Perez-Gracia, J.L. (Jose Luis); Gonzalez-Hernandez, A. (Alvaro); Gurpide, A. (Alfonso); Guillen-Grima, F. (Francisco); Melero, I. (Ignacio); Panizo, A. (Ángel); Grande-Pulido, E. (E.); Segura, V. (Víctor); Calvo-González, A. (Alfonso)BACKGROUND: Several drugs are available to treat metastatic renal-cell carcinoma (MRCC), and predictive markers to identify the most adequate treatment for each patient are needed. Our objective was to identify potential predictive markers of sunitinib activity in MRCC. METHODS: We collected sequential serum samples from 31 patients treated with sunitinib. Sera of six patients with extreme phenotypes of either marked responses or clear progressions were analysed with a Human Cytokine Array which evaluates 174 cytokines before and after treatment. Variations in cytokine signal intensity were compared between both groups and the most relevant cytokines were assessed by ELISA in all the patients. RESULTS: Twenty-seven of the 174 cytokines varied significantly between both groups. Five of them (TNF-alpha, MMP-9, ICAM-1, BDNF and SDF-1) were assessed by ELISA in 21 evaluable patients. TNF-alpha and MMP-9 baseline levels were significantly increased in non-responders and significantly associated with reduced overall survival and time-to-progression, respectively. The area under the ROC curves for TNF-alpha and MMP-9 as predictive markers of sunitinib activity were 0.83 and 0.77. CONCLUSION: Baseline levels of TNF-alpha and MMP-9 warrant further study as predictive markers of sunitinib activity in MRCC. Selection of patients with extreme phenotypes seems a valid method to identify potential predictive factors of response.
- Randomized crossover pharmacokinetic evaluation of subcutaneous versus intravenous granisetron in cancer patients treated with platinum-based chemotherapy(AlphaMed Press, 2007) Campanero, M.A. (Miguel Angel); Perez-Gracia, J.L. (Jose Luis); Martin-Algarra, S. (Salvador); Olier, C. (Clara); Blanco-Prieto, M.J. (María José); Fernandez-Gallego, V. (V.); Lopez-Picazo, J.M. (José M.); Gurpide, A. (Alfonso); Garcia-Foncillas, J. (Jesús); Gil-Aldea, I. (I.); Sadaba, B. (Belén); Cruz, S. (S.) de la; Ceballos-Viro, J. (Jaime); Cabello, J.P. (J.P.); Azanza, J.R. (José Ramón); Reyna, C. (Carmen)BACKGROUND: 5-HT3-receptor antagonists are one of the mainstays of antiemetic treatment, and they are administered either i.v. or orally. Nevertheless, sometimes neither administration route is feasible, such as in patients unable to admit oral intake managed in an outpatient setting. Our objective was to evaluate the bioavailability of s.c. granisetron. PATIENTS AND METHODS: Patients receiving platinum-based chemotherapy were randomized to receive 3 mg of granisetron either s.c. or i.v. in a crossover manner during two cycles. Blood and urine samples were collected after each cycle. Pharmacokinetic parameters observed with each administration route were compared by analysis of variance. RESULTS: From May to November 2005, 31 patients were included and 25 were evaluable. Subcutaneous granisetron resulted in a 27% higher area under the concentration-time curve for 0-12 hours (AUC(0-12h)) and higher levels at 12 hours, with similar values for AUC(0-24h). The maximum concentration was lower with the s.c. than with the i.v. route and was observed 30 minutes following s.c. administration. CONCLUSION: Granisetron administered s.c. achieves complete bioavailability. This is the first study that shows that s.c. granisetron might be a valid alternative to i.v. delivery. Further trials to confirm clinical equivalence are warranted. This new route of administration might be especially relevant for outpatient management of emesis in cancer patients.
- Clinical development of combination strategies in immunotherapy: are we ready for more than one investigational product in an early clinical trial?(Future Medicine, 2009) Berraondo, P. (Pedro); Martinez-Forero, I. (Iván); Alfaro, C. (Carlos); Perez-Gracia, J.L. (Jose Luis); Sangro, B. (Bruno); Gurpide, A. (Alfonso); Hervas-Stubbs, S. (Sandra); Ochoa, M.C. (María Carmen); Melero, J.A. (José A.); Melero, I. (Ignacio); Suarez, N. (Natalia)Stimulating the innate and adaptive immunity against cancer necessitates the tricking of a system evolved to fight microbial pathogens and directing its activity towards transformed self-tissue. Efficacious interventions to start and sustain the response will probably require a number of agents to tamper simultaneously or sequentially with several immune mechanisms. Although master switches controlling various functions may exist, the goal of a curative immune response will probably demand the combined actions of several therapeutic components. Synergy occurs when drugs interact in ways that enhance or magnify one or more effects or side effects. In cancer immunotherapy, two agents that have minor or no therapeutic effects as single agents can be powerful when combined. Mouse experimentation provides multiple examples of synergistic combinations. Elements to be combined include chiefly: tumor vaccines, adoptive T-cell therapies, cytokines, costimulatory molecules, molecular deactivation of immunosuppressive or tolerogenic pathways and immunostimulatory monoclonal antibodies. These novel therapies, even as single agents, are extremely complex products to be developed owing to the associated biomolecules, cell therapies or gene therapies. At present, drug-development programs are run individually for each immunotherapeutic agent and combinations are considered only at a later stage in clinical development, even in the absence of formal compulsory regulations to prevent clinical trials with combinations. As a result, instead of the search for maximal efficacy, ease of combination with standard treatments, intellectual property management, regulations and business-based decisions often guide the way. Even though the maximal effort must be made in order to prevent adverse effects in patients, it seems reasonable that combination pilot trials should be performed at an early stage, following safe completion of Phase I trials. These trials should be performed based on evidence for synergy in animal models and be simplified in terms of regulatory requirements. Such 'short-cut' combination immunotherapy trials can bring much needed efficacy earlier to the bedside.
- Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma(Nature Publishing Group, 2019) Berraondo, P. (Pedro); Perez-Gracia, J.L. (Jose Luis); Rodriguez-Ruiz, M.E. (María Esperanza); Lopez-Diaz-de-Cerio, A. (Ascensión); Tejada-Solis, S. (Sonia); Diez-Valle, R. (Ricardo); Goicoechea, I. (Iosune); Inoges, S. (Susana); Gurpide, A. (Alfonso); Melero, I. (Ignacio); Choi, J. (Jungmin); Porciuncula, A. (Angelo); Idoate, M.A. (Miguel Ángel); Andrea, C.E. (Carlos Eduardo) de; López-Janeiro, Á. (Álvaro); Gallego-Perez-Larraya, J. (Jaime); Villarroel-Espindola, F. (Franz); Schalper, K.A. (Kurt A.); Giraldez, M. (Miriam); Fernandez-Sanmamed, M. (Miguel)Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, produces only modest benefits to survival1,2. Here, to explore the feasibility, safety and immunobiological effects of PD-1 blockade in patients undergoing surgery for glioblastoma, we conducted a single-arm phase II clinical trial (NCT02550249) in which we tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients (27 salvage surgeries for recurrent cases and 3 cases of primary surgery for newly diagnosed patients). Availability of tumor tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumor immune microenvironment using multiple molecular and cellular analyses. Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later.
- Carcinoma microcítico de pulmón(Ediciones Universidad de Navarra, 2007) Perez-Gracia, J.L. (Jose Luis); Martin-Algarra, S. (Salvador); Lopez-Picazo, J.M. (José M.); Gurpide, A. (Alfonso); Garcia-Foncillas, J. (Jesús); Viteri, S. (S.)El cáncer microcítico de pulmón es uno de los tumores sólidos más agresivos, por su rápido crecimiento y por su tendencia a metastatizar desde fases tempranas. Sin embargo, también es uno de los tumores más sensibles a los tratamientos de quimioterapia y radioterapia, con los cuales algunos pacientes con enfermedad limitada pueden sobre- vivir a largo plazo. Estas características han hecho de este tumor un modelo clínico sobre el cual se han probado múltiples estrategias de tratamiento, incluyendo tratamientos concomitantes con quimioterapia y radioterapia, esquemas de quimioterapia alternante o de altas dosis con soporte hematológico o la utilización de radioterapia holocraneal profi láctica. Además en los últimos años el cáncer microcítico de pulmón también se ha empleado como plataforma de desarrollo de tratamientos dirigidos contra dianas específi cas o de inmunoterapia. INGLÉS: Small cell lung cancer is one of the most aggressive solid tumors because of its rapid growth and early tendency to spread to distant organs. Nonetheless, it is also one of the most sensitive tumors to chemotherapy and radiotherapy, which can give patients with limited disease a chance to become long-term survivors. These characteristics have made this tumor a clinical model to explore various treatment strategies, including concomitant chemotherapy and radiotherapy, alternant chemotherapy, high-dose chemotherapy with hematologic support, or use of whole-brain prophylactic radiotherapy. In addition, in recent years, small cell lung cancer has been used as a platform to develop some new targeted therapy agents or immunotherapeutic approaches.
- Patient-reported outcomes in a phase III, randomized study of sunitinib versus interferon-{alpha} as first-line systemic therapy for patients with metastatic renal cell carcinoma in a European population(Oxford University Press, 2009-11) Gonzalez-Larriba, J.L. (José Luis); Perez-Gracia, J.L. (Jose Luis); Pardo, A. (A.); Garcia-del-Muro, X. (X.); Diaz-Cerezo, S. (S.); Ruiz, M.A. (M. A.); Abrio, M.V. (M. V.); Castellano, D. (Daniel); Guzman, C. (C.); Grande-Pulido, E. (E.)BACKGROUND: The purpose of this study is to evaluate the impact on the health-related quality of life (HRQoL) of sunitinib versus interferon-alpha (IFN-alpha) treatment in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: In all, 304 mRCC patients (European cohort) were randomized 1 : 1 to receive sunitinib (50 mg/day for 4 weeks, followed by 2 weeks off) or IFN-alpha (9 million units s.c. injection three times/week). The following questionnaires were completed (days 1 and 28 per cycle): Functional Assessment of Cancer Therapy-General (FACT-G), the FACT-Kidney Symptom Index and the EuroQol Group's EQ-5D self-report questionnaire (EQ-5D). Results correspond to an ongoing trial with progression-free survival time as primary end point, and patients were still being followed up. Data were analyzed using repeated measures mixed effects models (MEMs) that allow the inclusion of initial differences and uncompleted repeated measures, with the assumption of data missing at random. Six-cycle results were included. RESULTS: Results consistently showed that patients in sunitinib group experienced statistically significantly milder kidney-related symptoms, better cancer-specific HRQoL and general health status (in social utility scores) during the study period as measured by these patient-reported outcome end points. No statistical differences between groups were found on the FACT-G physical well-being subscale or the EQ-5D VAS values. CONCLUSIONS: Results from MEM showed the sunitinib's benefit on HRQoL compared with IFN-alpha.
- SEOM clinical guideline for treatment of kidney cancer (2017)(Springer, 2018) Grande, E. (Enrique); Gallardo, E. (Enrique); Chirivella-González, I. (I.); Perez-Gracia, J.L. (Jose Luis); Sepúlveda-Sánchez, J.M. (J. M.); Garcia-del-Muro, X. (X.); Gonzalez-del-Alba, A. (Aránzazu); Suárez, C. (Cristina); Méndez-Vidal, M.J. (M. J.); Campayo, M. (M.)The goal of this article is to provide recommendations about the management of kidney cancer. Based on pathologic and molecular features, several kidney cancer variants were described. Nephron-sparing techniques are the gold standard of localized disease. After a randomized trial, sunitinib could be considered in adjuvant treatment in high-risk patients. Patients with advanced disease constitute a heterogeneous population. Prognostic classification should be considered. Both sunitinib and pazopanib are the standard options for first-line systemic therapy in advanced renal cell carcinoma. Based on the results of two randomized trials, both nivolumab and cabozantinib should be considered the standard for second and further lines of therapy. Response evaluation for present therapies is a challenge.
- Cytokines in clinical cancer immunotherapy(Springer Science and Business Media LLC, 2019) Berraondo, P. (Pedro); Etxeberria, I. (Iñaki); Perez-Gracia, J.L. (Jose Luis); Rodriguez-Ruiz, M.E. (María Esperanza); Aznar, M.A. (María Ángela); Castañon, E. (Eduardo); Ponz-Sarvise, M. (Mariano); Ochoa, M.C. (María Carmen); Melero, I. (Ignacio); Fernandez-Sanmamed, M. (Miguel)Cytokines are soluble proteins that mediate cell-to-cell communication. Based on the discovery of the potent anti-tumour activities of several pro-inflammatory cytokines in animal models, clinical research led to the approval of recombinant interferon-alpha and interleukin-2 for the treatment of several malignancies, even if efficacy was only modest. These early milestones in immunotherapy have been followed by the recent addition to clinical practice of antibodies that inhibit immune checkpoints, as well as chimeric antigen receptor T cells. A renewed interest in the anti-tumour properties of cytokines has led to an exponential increase in the number of clinical trials that explore the safety and efficacy of cytokine-based drugs, not only as single agents, but also in combination with other immunomodulatory drugs. These second-generation drugs under clinical development include known molecules with novel mechanisms of action, new targets, and fusion proteins that increase half-life and target cytokine activity to the tumour microenvironment or to the desired effector immune cells. In addition, the detrimental activity of immunosuppressive cytokines can be blocked by antagonistic antibodies, small molecules, cytokine traps or siRNAs. In this review, we provide an overview of the novel trends in the cytokine immunotherapy field that are yielding therapeutic agents for clinical trials.
- Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ(Springer Verlag, 2010) Dubrot, J. (Juan); Martinez-Forero, I. (Iván); Jure-Kunkel, M. (María); Alfaro, C. (Carlos); Perez-Gracia, J.L. (Jose Luis); Morales-Kastresana, A. (Aizea); Hervas-Stubbs, S. (Sandra); Ochoa, M.C. (María Carmen); Melero, I. (Ignacio); Palazon, A. (Asís); Prieto, J. (Jesús); Milheiro, F. (Francisca); Romero-Trevejo, J.L. (José Lorenzo); Chen, L. (Lieping)BACKGROUND/AIMS: Cancer therapy with agonist anti-CD137 mAbs has been shown to induce immune-mediated tumor rejections in mice, and equivalent agents of this kind are currently being tested in cancer patients. Previous reports indicated that CD137 stimulation induced polyclonal infiltrates of T lymphocytes in the liver. This study characterizes the liver infiltrates and the target dependency of the phenomena and addresses the question of whether tumors nested in the liver are a more favorable target for CD137-based immunotherapy. METHODS: Liver infiltrates were studied with conventional histology and multiple color flow cytometry of total liver leukocytes. CD137(-/-) mice, mice with a single rearrangement of the TCR (OT-1 mice) and Rag(-/-) mice were used to clarify molecular requirements. Mice implanted with MC38 colon carcinomas either subcutaneously or inside the liver were used for comparative studies under treatment with agonist anti-CD137 mAbs. RESULTS: CD137 treatment caused mononuclear inflammation in the portal spaces of the liver, which gave rise to moderate increases in transaminases without signs of cholestasis. Marked increases in the numbers of CD8+ T cells were observed, including CD8+ T lymphocytes co-expressing CD11c. Infiltrates were absent in CD137(-/-) mice and mitigated in mice harboring a single transgenic TCR on their CD8 T cells. Despite the tumor-independent accumulation of T cells in the liver, immunotherapeutic effects were not more prominent against tumors located in this organ. CONCLUSIONS: Target-dependent effects of CD137 stimulation lead to liver infiltration with T cells, but lymphocyte enrichment in this organ does not privilege this site for immunotherapeutic effects against transplanted tumors.