35 results on '"Patrick Squiban"'
Search Results
2. Biothérapies : des médicaments comme les autres ?
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Gilles Paintaud, Dominique Tonelli, Eric Postaire, François Amalric, François Bassompierre, Laurent Becquemont, Guillaume Cartron, Dominic Cellier, Georges Dagher, Thierry Demerens, Alain Dessein, Danièle Girault, Jean-Marc Grognet, Vincent Le Gros, François Lemoine, Laurence Moachon, Marc Pallardy, Atul Pathak, Marc Peschanski, Lionel Ségard, Patrick Squiban, Daniel Vasmant, Luc Vermeesch, null HervéWatier, and Pierrette Zorzi
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Anticorps monoclonal ,business.industry ,Medicine ,Pharmacology (medical) ,business ,Molecular biology - Abstract
Resume Le terme de « biotherapies » comprend les biomedicaments, macromolecules creees grâce aux biotechnologies, et les therapies cellulaire et genique. Dans le cas des anticorps monoclonaux, le choix de la premiere dose a administrer a l’Homme est difficile car il n’existe pas toujours de modele animal pertinent. Au moment de l’autorisation de mise sur le marche, leur mecanisme d’action est insuffisamment connu, ce qui necessite des suivis de cohortes. La predisposition genetique et la pharmacocinetique sont des sources de variabilite interindividuelle. Certains effets indesirables sont previsibles, mais d’autres sont inattendus voire paradoxaux. Les therapies cellulaire et genique ex vivo consistent en la manipulation de cellules prelevees et leur reinjection en situation auto- ou allogenique. Il est difficile de leur appliquer la methodologie du developpement des medicaments. La therapie genique in vivo repose sur l’utilisation de vecteurs ou de macromolecules qui peuvent donc etre consideres comme des biomedicaments.
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- 2007
3. A propos d'un essai de Phase I de thérapie génique effectué avec un plasmide contenant l'intégralité du gène dystrophine dans la Myopathie de Duchenne/Becker
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Jean-Yves Hogrel, A. Rouche, Michel Fardeau, Patrick Squiban, Brigitte Mourot, Olivier Benveniste, Véronique Ortega, Norma B. Romero, Serge Herson, and Serge Braun
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Gynecology ,Aging ,medicine.medical_specialty ,business.industry ,Medicine ,Cell Biology ,business - Abstract
Un premier essai de therapie genique a ete realise chez des patients atteints de myopathie de Duchenne/ Becker, a l'aide d'un plasmide contenant l'integralite de la sequence codante du gene dystrophine. Cet essai de Phase I etait destine a apprecier le degre de transfection obtenue et a evaluer la tolerance au produit injecte ainsi qu'a l'expression du segment de dystrophine nouvellement synthetise. Neuf patients ont ete inclus dans l'essai, repartis en trois cohortes de trois. La premiere cohorte a recu une injection intramusculaire dans les muscles radicaux de 200 μg, la seconde une injection de 600 μg, et la troisieme deux injections a deux semaines d'intervalle de 600 μg. L'inclusion des patients s'est faite de facon sequentielle, apres examen des resultats du patient precedent par un comite de pilotage comprenant des experts independants. Le plasmide a ete retrouve dans les neuf prelevements effectues trois semaines apres la premiere (ou unique) injection. Une expression de la dystrophine exogene a ete retrouvee chez 6 patients sur 9. Cette expression a toujours ete faible, jusqu'a 6 % de fibres presentant un marquage peripherique complet, et jusqu'a 26 % de fibres presentant un marquage partiel. Les messagers de la dystrophine ont ete detectes par une RT-PCR « nichee » dans cinq des six prelevements presentant des fibres marquees. Il est remarquable de noter qu'aucune reponse immunitaire humorale ou cellulaire vis-a-vis de la dystrophine exogene n'a ete detectee. Aucune reaction secondaire locale ou generale n'a ete observee. Ces resultats, modestes mais significatifs, ouvrent la voie a de nouveaux developpements en terme de therapie genique des maladies musculaires humaines, et en particulier dans les myopathies de Duchenne et de Becker.
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- 2005
4. Phase I Study of Dystrophin Plasmid-Based Gene Therapy in Duchenne/Becker Muscular Dystrophy
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Norma B. Romero, Serge Braun, Olivier Benveniste, France Leturcq, Jean-Yves Hogrel, Glenn E. Morris, Annie Barois, Bruno Eymard, Christine Payan, Véronique Ortega, Anne-Laure Boch, Lise Lejean, Christine Thioudellet, Brigitte Mourot, Christophe Escot, Aurore Choquel, Dominique Recan, Jean-Claude Kaplan, George Dickson, David Klatzmann, Valérie Molinier-Frenckel, Jean-Gérard Guillet, Patrick Squiban, Serge Herson, and Michel Fardeau
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Adult ,musculoskeletal diseases ,congenital, hereditary, and neonatal diseases and abnormalities ,Time Factors ,Adolescent ,Biopsy ,Genetic enhancement ,Duchenne muscular dystrophy ,Genetic Vectors ,Cohort Studies ,Dystrophin ,chemistry.chemical_compound ,Plasmid ,Genetics ,medicine ,Humans ,RNA, Messenger ,Vector (molecular biology) ,Muscular dystrophy ,Muscle, Skeletal ,Promoter Regions, Genetic ,Molecular Biology ,Models, Genetic ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Histocompatibility Testing ,Muscles ,Gene Transfer Techniques ,Genetic Therapy ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Molecular biology ,Muscular Dystrophy, Duchenne ,chemistry ,biology.protein ,Molecular Medicine ,DNA ,Plasmids - Abstract
Nine patients with Duchenne or Becker muscular dystrophy were injected via the radialis muscle with a full-length human dystrophin plasmid, either once with 200 or 600 microg of DNA or twice, 2 weeks apart, with 600 microg of DNA. In the biopsies taken 3 weeks after the initial injection, the vector was detected at the injection site in all patients. Immunohistochemistry and nested reverse transcription-polymerase chain reaction indicated dystrophin expression in six of nine patients. The level of expression was low (up to 6% weak, but complete sarcolemmal dystrophin staining, and up to 26% partial sarcolemmal labeling). No side effects were observed, nor any cellular or humoral anti-dystrophin responses. These results suggest that exogenous dystrophin expression can be obtained in Duchenne/Becker patients after intramuscular transfer of plasmid, without adverse effects, hence paving the way for future developments in gene therapy of hereditary muscular diseases.
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- 2004
5. Gene-based vaccines and immunotherapeutics
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Patrick Squiban, Margaret A. Liu, Bruce Acres, Philippe Slos, Jean-Marc Balloul, Stéphane Paul, and Nadine Bizouarne
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Male ,Modified vaccinia Ankara ,Lung Neoplasms ,medicine.medical_treatment ,Uterine Cervical Neoplasms ,Breast Neoplasms ,Biology ,Cancer Vaccines ,Viral vector ,DNA vaccination ,chemistry.chemical_compound ,Cancer immunotherapy ,Antigens, Neoplasm ,Neoplasms ,Vaccines, DNA ,medicine ,Humans ,Multidisciplinary ,Papillomavirus Infections ,Prostatic Neoplasms ,Cancer ,Genetic Therapy ,Immunotherapy ,medicine.disease ,Virology ,Kidney Neoplasms ,chemistry ,Immunology ,Cytokines ,Female ,Colloquium ,Cancer vaccine ,Vaccinia - Abstract
DNA vaccines, comprised of plasmid DNA encoding proteins from pathogens, allergens, and tumors, are being evaluated as prophylactic vaccines and therapeutic treatments for infectious diseases, allergies, and cancer; plasmids encoding normal human proteins are likewise being tested as vaccines and treatments for autoimmune diseases. Examples of in vivo prophylaxis and immunotherapy, based on different types of immune responses (humoral and cellular), in a variety of disease models and under evaluation in early phase human clinical trials are presented. Viral vectors continue to show better levels of expression than those achieved by DNA plasmid vectors. We have focused our clinical efforts, at this time, on the use of recombinant viral vectors for both vaccine as well as cytokine gene transfer studies. We currently have four clinical programs in cancer immunotherapy. Two nonspecific immunotherapy programs are underway that apply adenoviral vectors for the transfer of cytokine genes into tumors in situ . An adenovirus-IFNγ construct (TG1042) is currently being tested in phase II clinical trials in cutaneous lymphoma. A similar construct, adenovirus-IL2 (TG1024), also injected directly into solid tumors, is currently being tested in patients with solid tumors (about one-half of which are melanoma). Encouraging results are seen in both programs. Two cancer vaccine immunotherapy programs focus on two cancer-associated antigens: human papilloma virus E6 and E7 proteins and the epithelial cancer-associated antigen MUC1. Both are encoded by a highly attenuated vaccinia virus vector [modified vaccinia Ankara (MVA)] and both are coexpressed with IL-2. Encouraging results seen in both of these programs are described.
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- 2004
6. A phase I trial of immunotherapy with intratumoral adenovirus-interferon-gamma (TG1041) in patients with malignant melanoma
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T. Whiteside, Alok A. Khorana, S. Phillippe, Bruce Acres, Karen Rosell, K. Kendra, M. Ross, Diana Marquis, Joseph D. Rosenblatt, Deepak M. Sahasrabudhe, Philippe Slos, Thomas J Evans, Patrick Squiban, and M. Ladrigan
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Adult ,Male ,Cancer Research ,viruses ,Genetic enhancement ,medicine.medical_treatment ,Genetic Vectors ,Injections, Intralesional ,Adenoviridae ,Interferon-gamma ,Humans ,Medicine ,In patient ,Interferon gamma ,Melanoma ,neoplasms ,Molecular Biology ,Aged ,Interleukin-6 ,business.industry ,Genetic Therapy ,Immunotherapy ,Middle Aged ,medicine.disease ,Immunology ,Cancer research ,Molecular Medicine ,Female ,beta 2-Microglobulin ,business ,medicine.drug - Abstract
Interferon-gamma (IFN-gamma) has been shown to upregulate MHC class I and II expression, and to promote generation of specific antitumor immune responses. We hypothesized that intratumoral administration of an IFN-gamma gene transfer vector facilitates its enhanced local production and may activate effector cells locally. We conducted a phase I dose-escalation study of a replication-deficient adenovirus-interferon-gamma construct (TG1041) to determine safety and tolerability of intratumoral administration, in advanced or locally recurrent melanoma.Patients were enrolled at four successive dose levels: 10(7) infectious units (iu) (n=3), 10(8) iu (n=3), 10(9) iu (n=3), and 10(10) iu (n=2) per injection per week for 3 weeks. TG1041 was injected in the same tumor nodule weekly in each patient. Safety, toxicity, local and distant tumor responses and biologic correlates were evaluated.A total of 11 patients were enrolled and received the planned three injections per cycle. One patient with stable disease received a second cycle of treatment. A maximum tolerated dose was not reached in this study. No grade 4 toxicities were observed. Two grade 3 toxicities, fever and deep venous thrombosis were observed in one patient. The most frequently reported toxicities were grade 1 pain and redness at the injected site (n=8), and grade 1 fatigue (n=5) patients. Clinical changes observed at the local injected tumor site included erythema (n=5), a minor decrease in size of the injected lesion (n=5) and significant central necrosis by histopathology (n=1). Systemic effects included stable disease in one patient. Correlative studies did not reveal evidence of immunologic activity.Weekly intratumoral administration of TG1041 appears to be safe and well tolerated in patients with advanced melanoma.
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- 2003
7. Metastatic Breast Tumour Regression Following Treatment by a Gene-Modified Vaccinia Virus Expressing MUC1 and IL-2
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David Miles, Martine Baudin, S. Van Belle, B. Uzielly, Philippe Beuzeboc, Moira Shearer, Patrick Squiban, Silvia von Mensdorff-Pouilly, Joyce Taylor-Papadimitriou, Pierre Pouillart, Bruce Acres, Nadine Bizouarne, Susy Scholl, and VU University medical center
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medicine.medical_specialty ,Article Subject ,lcsh:Biotechnology ,Health, Toxicology and Mutagenesis ,medicine.medical_treatment ,lcsh:Medicine ,lcsh:Chemical technology ,lcsh:Technology ,Gastroenterology ,Virus ,Breast cancer ,Immune system ,lcsh:TP248.13-248.65 ,Internal medicine ,Genetics ,medicine ,lcsh:TP1-1185 ,Adverse effect ,Molecular Biology ,MUC1 ,biology ,lcsh:T ,business.industry ,lcsh:R ,General Medicine ,medicine.disease ,Metastatic breast cancer ,Cytokine ,Immunology ,biology.protein ,Molecular Medicine ,Antibody ,business ,Research Article ,Biotechnology - Abstract
MUC1 is expressed by glandular epithelial cells. It is overexpressed in the majority of breast tumours, making it a potential target for immune therapy. The objectives of the present study were to evaluate the anti-tumour activity and tolerance of repeated administration of TG1031 (an attenuated recombinant vaccinia virus containing sequences coding for human MUC1 and the immune stimulatory cytokine IL-2) in patients with MUC1-positive metastatic breast cancer. This was an open-label, randomised study comparing two dose levels,5×10E6and5×10E7 pfu, with 14 patients in each arm. The treatment was administered intramuscularly every 3 weeks for the first 4 doses and every 6 weeks thereafter, until progression. Two patients had a partial tumour regression (>50%), and 15 patients had stable disease as their best overall response until at least the 5th injection. Partial regression lasted for 11 months in one patient and for 12 months in the second patient who then underwent surgical resection of her hepatic metastases. The most frequent adverse events included inflammation at injection site: 7 patients, itching or pain at injection site: 5 patients, and moderate fever: 6 patients. One responding patient developed antinuclear, anti-DNA, and increased anti-TPO antibodies after the fifth injection, and which resolved at the end of treatment. The treatment regimes were well tolerated with a low toxicity profile. Although clinical efficacy remains limited, this study demonstrates the potential use of MUC1-based immune therapy in breast cancer.
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- 2003
8. Current protocol of a research phase I clinical trial of full-length dystrophin plasmid DNA in Duchenne/Becker muscular dystrophies
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Serge Herson, Olivier Benveniste, Norma B. Romero, Christine Payan, Patrick Squiban, Serge Braun, and Michel Fardeau
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musculoskeletal diseases ,Oncology ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Duchenne muscular dystrophy ,Genetic enhancement ,Phases of clinical research ,Internal medicine ,Biopsy ,medicine ,Muscular dystrophy ,Genetics (clinical) ,medicine.diagnostic_test ,biology ,business.industry ,Skeletal muscle ,medicine.disease ,Clinical trial ,medicine.anatomical_structure ,Neurology ,Pediatrics, Perinatology and Child Health ,biology.protein ,Physical therapy ,Neurology (clinical) ,Dystrophin ,business - Abstract
A phase I open clinical study on gene therapy in Duchenne and Becker muscular dystrophy, without direct individual benefit for the patient, is being performed at the Pitie-Salpetriere Hospital, Paris. The aims of this project are: (a) to determine the tolerance and the safety of the intramuscular administration of dystrophin cDNA and (b) to study the quality of the gene transfer in vivo in human patients affected by Duchenne and Becker muscular dystrophy. This clinical trial is conducted sequentially and includes three cohorts of three patients each. Patients must be at least 15 years of age. Diagnosis of Duchenne and Becker muscular dystrophy was confirmed by molecular analysis of the dystrophin gene and for each patient the abnormal expression of dystrophin was confirmed, in skeletal muscle, with antibodies directed against the deleted part of the dystrophin. This phase I study is scheduled to be completed by the end of 2002.
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- 2002
9. Current protocol of a research phase I clinical trial of full-length dystrophin plasmid DNA in Duchenne/Becker muscular dystrophies
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Christine Thioudellet, Patrick Squiban, Stéphane Blot, Michel Fardeau, and Serge Braun
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Genetics ,biology ,business.industry ,Duchenne muscular dystrophy ,Genetic enhancement ,Context (language use) ,Transfection ,Disease ,medicine.disease ,Bioinformatics ,Clinical trial ,Neurology ,Pediatrics, Perinatology and Child Health ,medicine ,biology.protein ,Neurology (clinical) ,Muscular dystrophy ,Dystrophin ,business ,Genetics (clinical) - Abstract
Since the identification of abnormalities in the dystrophin gene as primary cause of Duchenne muscular dystrophy, gene therapy has been seen as an obvious option among various approaches to treat the disease. It is also considered to be especially challenging, as in this context, one must achieve massive transfer of the gene with a sustained lifelong correction of the muscle phenotype. Our goal is to allow large scale transfection of skeletal muscle fibers of Duchenne muscular dystrophy patients with the full-length 11-kb human dystrophin cDNA. Extensive in vitro and in vivo studies, together with safety considerations and the prospects of a very efficient intra-arterial delivery procedure, led us progressively to focus our efforts on plasmid DNA administration. We are now conducting a phase I safety clinical trial which will pave the way for future therapeutic gene therapy trials for Duchenne muscular dystrophy.
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- 2002
10. Gene-based cancer immunotherapy and vaccines
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Bruce, Acres, Patrick, Squiban, and Margaret, Liu
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Extract: Cancer cells are able to escape immune detection and/or rejection by a variety of measures. Cell surface molecules, which are required for the effective policing of tissues by the immune system, are often modified, reduced or eliminated. In addition cancer cells secrete soluble molecules that inhibit the patients' ability to develop an immune response. The ability of the immune system to recognize and reject cancerous growths has been demonstrated in a series of experimental model systems. Efforts are now being made to use this knowledge for the treatment of cancer. Described below are two different gene-based approaches to stimulate the rejection of an established cancer in patients. The first involves procedures which modify the tumor itself, render it a more attractive target to the immune system, and allow immune cells to penetrate the tumor and kill the cancerous cells. The second approach requires a very powerful vaccine to stimulate a strong immune response against the tumor associated antigens in patients with an established cancer. Early efforts to harness the power of the immune system to eliminate cancer were made by Dr. William Coley very early in the 20th century. Dr. Coley injected cancerous tissue, usually sarcomas (tumors of the supportive tissues such as bone, cartilage fat or muscle), with a mix of bacteria and/or their toxins. This would result in an inflammatory response in the tumor and the influx of many immune cells.
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- 2010
11. Biotherapies: are they just like any other drugs?
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Gilles Paintaud, Dominique Tonelli, Eric Postaire, François Amalric, François Bassompierre, Laurent Becquemont, Guillaume Cartron, Dominic Cellier, Georges Dagher, Thierry Demerens, Alain Dessein, Danièle Girault, Jean-Marc Grognet, Vincent Le Gros, François Lemoine, Laurence Moachon, Marc Pallardy, Atul Pathak, Marc Peschanski, Lionel Ségard, Patrick Squiban, Daniel Vasmant, Luc Vermeesch, null HervéWatier, and Pierrette Zorzi
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Biological Products ,Biomedical Research ,business.industry ,medicine.drug_class ,Genetic enhancement ,Recombinant Fusion Proteins ,Genetic Vectors ,Follow up studies ,Antibodies, Monoclonal ,Genetic Therapy ,Monoclonal antibody ,Cell therapy ,Animal model ,In vivo ,Immunology ,Genetic predisposition ,Medicine ,Animals ,Humans ,Pharmacology (medical) ,Pharmacokinetics ,business ,Ex vivo ,Stem Cell Transplantation - Abstract
"Biotherapies" include both biopharmaceuticals and cell and gene therapies. Biopharmaceuticals are macromolecules created by biotechnologies. In the case of monoclonal antibodies, the starting dose to be given to Humans is difficult to select because there may be no relevant animal model. At the time of registration, the knowledge of the mechanism of action of monoclonal antibodies is insufficient and cohort follow up studies are needed. Genetic predisposition and pharmacokinetics are interindividual sources of variability. Some of the adverse drug reactions are predictable but others are unexpected or even paradoxical. Cell and "ex vivo" gene therapies consist in the manipulation of collected cells and their infusion in autologous or allogenic clinical settings. The methodology of the clinical development of drugs cannot be readily applied to these therapies. On the other hand, "in vivo" gene therapy uses vectors or macromolecules which can be considered as biopharmaceuticals.
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- 2007
12. [About a phase I gene therapy clinical trial with a full-length dystrophin gene-plasmid in Duchenne/Becker muscular dystrophy]
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Michel, Fardeau, Serge, Braun, Norma B, Romero, J Y, Hogrel, Andrée, Rouche, Véronique, Ortega, Brigitte, Mourot, Patrick, Squiban, Olivier, Benveniste, and Serge, Herson
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Dystrophin ,Male ,Muscular Dystrophy, Duchenne ,Reverse Transcriptase Polymerase Chain Reaction ,Biopsy ,Gene Expression ,Humans ,RNA ,DNA ,Genetic Therapy ,Muscle, Skeletal ,Injections, Intramuscular ,Plasmids - Abstract
This is the first gene transfer trial in Duchenne/Becker patients. The aim of the study was to provide evidence on transgene expression and safety of the intramuscular administration of a plasmid containing a full-length dystrophin CDNA. Nine Duchenne/Becker patients, distributed in three cohorts of three patients, were injected into their radialis muscles either once with 200 microg (first cohort) or 600 microg (second cohort) or twice, two weeks apart, with 600 microg plasmidic DNA (third cohort). The patients were enrolled sequentially upon evaluation of the data by an independant pilot committee. In the biopsies taken three weeks after the initial injection from the injected site, the plasmid was detected in all patients. An exogenous dystrophin expression was found in 6/9 patients. The level of expression was low, up to 6 % of weak complete sarcolemmal labelling, and up to 26% of partial sarcolemmal staining. Dystrophin in RNAs were detected by nested RT-PCR in five out of the six biopsies with exogenous dystrophin-positive fibers. Interestingly, neither humoral or cellular antidystrophin responses were observed. No local or general adverse effects were seen. This paves the way for future developments in gene therapy in hereditary muscle diseases, and specifically in Duchenne/Becker myopathies.
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- 2005
13. Adenovirus-mediated intralesional interferon-gamma gene transfer induces tumor regressions in cutaneous lymphomas
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Jessica C. Hassel, Friederike Fellenberg, Stefan B. Eichmüller, T Maier, Philippe Slos, Reinhard Dummer, Mirjana Urosevic, Vincent Bataille, Pascal Bleuzen, Guenter Burg, Bruce Acres, and Patrick Squiban
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Skin Neoplasms ,Lymphoma ,Genetic enhancement ,Immunology ,Gene Expression ,medicine.disease_cause ,Biochemistry ,Virus ,Adenoviridae ,Interferon-gamma ,Immune system ,medicine ,Humans ,Interferon gamma ,RNA, Messenger ,Adverse effect ,Aged ,Aged, 80 and over ,business.industry ,Genetic transfer ,Cell Biology ,Hematology ,Genetic Therapy ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Treatment Outcome ,Female ,Immunotherapy ,business ,medicine.drug - Abstract
Primary cutaneous lymphomas have been successfully treated with interferons (IFNs), counterbalancing the T-helper 2 (Th2)-skewing state. We undertook a phase 1, open-label, dose-escalating trial of repeated intratumoral administration of TG1042 in patients with advanced primary cutaneous T-cell lymphomas (CTCLs) and multilesional cutaneous B-cell lymphomas (CBCLs). TG1042 is a third-generation, nonreplicating human adenovirus vector containing a human IFN-γ cDNA insert. Nine patients (7 CTCL, 2 CBCL) were enrolled at the following TG1042 doses: 3 × 109, 3 × 1010, and 3 × 1011 total particles. Local clinical response was observed in 5 of 9 treated patients (3 patients with complete response [CR] and 2 patients with partial response [PR]). Out of these, 3 patients showed systemic CR with the clearance of other noninjected skin lesions. Clinical response lasted for a median of 3 months (range, 1-6 months). Adverse events were mostly of grades 1 and 2. Seven of 9 treated patients had a detectable TG1042-derived IFN-γ message in injected lesions after the first treatment cycle. A TG1042-IFN-γ message was also detectable after several treatment cycles. We demonstrate the induction of humoral immune response to lymphoma tumor-antigen se70-2 after treatment. Our study shows that intralesional injections of TG1042 are both safe and well tolerated. (Blood. 2004;104:1631-1638)
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- 2004
14. Phase I trial of antigen-specific gene therapy using a recombinant vaccinia virus encoding MUC-1 and IL-2 in MUC-1-positive patients with advanced prostate cancer
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Michael E Ross, Arie S. Belldegrun, Robert A. Figlin, Patrick Squiban, Barbara J. Gitlitz, Cho-Lea Tso, Arndt van Ophoven, Allan J. Pantuck, and Bruce Acres
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Male ,Cancer Research ,Time Factors ,Genetic enhancement ,T cell ,medicine.medical_treatment ,CD8 Antigens ,Immunology ,Genetic Vectors ,Vaccinia virus ,Cell Separation ,Cancer Vaccines ,Virus ,Immune system ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,Orthopoxvirus ,Aged ,Pharmacology ,Clinical Trials as Topic ,biology ,Dose-Response Relationship, Drug ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,Tumor Necrosis Factor-alpha ,Mucin-1 ,Prostatic Neoplasms ,Immunotherapy ,Genetic Therapy ,Middle Aged ,Th1 Cells ,biology.organism_classification ,Flow Cytometry ,Up-Regulation ,medicine.anatomical_structure ,Phenotype ,CD4 Antigens ,Interleukin-2 ,business ,CD8 - Abstract
MUC-1 is overexpressed on many tumor cells. In addition, aberrant glycosylation of MUC-1 on human tumors leads to exposure of cryptic peptide epitopes that play a role in tumor immunity. As such, it has been identified as a potential target for immunotherapy. The purpose of this phase 1 clinical trial was to determine the maximum tolerated dose, safety of a multiple-dose regimen, and the immunologic effect of vaccinia virus expressing MUC-1 and IL-2 genes (VV/MUC-1/IL-2) in patients with advanced prostate cancer. Five x 10(5), 5 x 10(6), and 5 x 10(7) plaque-forming units (pfu) of vaccinia viruses were used in the dose-escalating study. Viruses were given via intramuscular injection, and clinical response and immune function modulation were analyzed. No grade 3 or 4 toxicity was observed. Objective clinical response was observed after the fourth injection (0.3 ng/mL) in only one patient who received an intermediate dose of virus. Systemic immune modulation in this patient included (1) up-regulation of IL-2 (CD25) and T cell (TcR alphabeta) receptors, (2) increase in the CD4/CD8 ratio (2.5-fold) (3) augmentation of T-helper type 1 cell (TH1) (interferon-gamma and tumor necrosis factor-alpha) but not TH2 (IL-4) cytokine mRNA expression, (4) induction of natural killer cell activity and MHC independent MUC-1 specific cytotoxic T-cell activity, and (5) normalization of mRNA expression of T-cell-associated signal transduction molecules TcR-zeta and p56lck. These results suggest that VV/MUC-1/IL-2 gene therapy with a maximum tolerated dose of 5 x 10(7) pfu is safe and well tolerated.
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- 2004
15. Therapeutic cancer vaccines
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Bruce, Acres, Stephane, Paul, Helene, Haegel-Kronenberger, Bastien, Calmels, and Patrick, Squiban
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Antigen Presentation ,Antigens, Neoplasm ,Neoplasms ,T-Lymphocytes ,Vaccination ,Immune Tolerance ,Humans ,Immunotherapy, Active ,Genetic Therapy ,Lymphocyte Activation ,Cancer Vaccines - Abstract
Therapeutic vaccination against cancer-associated antigens represents an attractive option for cancer therapy in view of the comparatively low toxicity and, so far, excellent safety profile of this treatment. Nevertheless, it is now recognized that the vaccination strategies used for prophylactic vaccinations against infectious diseases cannot necessarily be used for therapeutic cancer vaccination. Cancer patients are usually immunosuppressed, and most cancer-associated antigens are self antigens. Therefore, various immunostimulation techniques are under investigation in an effort to bolster immune systems and to overcome immune tolerance to self antigens. Various strategies to stimulate antigen presentation, T-cell reactivity and innate immune activity are under investigation. Similarly, strategies to produce an immunological 'danger signal' at the site of the tumor itself are under evaluation, as it is recognized that while tumor-specific T-cells can be activated at the site of vaccination, they require appropriate signals to be attracted to a tumor. The detection, evaluation and quantification of specific immune responses generated by vaccination with cancer-associated antigens is another important area of therapeutic cancer vaccine evaluation receiving much attention and novel strategies. Multiple clinical trials have been undertaken to evaluate therapeutic vaccines in patients. Aggressive protocols such as those combining specific stimulation of T-cells and chemotherapy or strategies to block immune regulation are having some success.
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- 2004
16. Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1 as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer
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Yongxiang Zhao, Patrick Squiban, Nadine Bizouarne, Martine Baudin, Robert A. Figlin, Marc Salzberg, Eric Tartour, Miklos Pless, Bruce Acres, Christoph Rochlitz, and Richard Herrmann
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Male ,medicine.medical_treatment ,Antineoplastic Agents ,Vaccinia virus ,Virus ,chemistry.chemical_compound ,Antigen ,Neoplasms ,Drug Discovery ,Genetics ,Medicine ,Humans ,Lung cancer ,Molecular Biology ,Genetics (clinical) ,MUC1 ,business.industry ,Mucin-1 ,Cancer ,Immunotherapy ,Genetic Therapy ,medicine.disease ,chemistry ,Immunology ,Molecular Medicine ,Female ,Vaccinia ,Intramuscular injection ,business - Abstract
Background The MUC1 protein is a highly glycosylated mucin normally found at the apical surface of mucin-secreting epithelial cells in many types of tissues. MUC1 is expressed, but heavily underglycosylated, in different human tumors. TG4010 is a viral suspension of a recombinant vaccinia vector (MVA) containing DNA sequences coding for the human MUC1 antigen and interleukin-2 (IL-2). This product was developed for use as a vaccine in cancer patients whose tumors express the MUC1 antigen. The objective of the present study was to determine the safety of the product and to define the dose of TG4010 to be used in further clinical trials. Materials and methods Thirteen patients with different solid tumors were treated by repeated intramuscular injection with increasing doses of TG4010 in two separate phase I studies, one in Europe (Basel—CR) and one in the United States (UCLA—RF): a total of 6 patients were treated at a dose of 5 × 106 pfu, 3 patients at 5 × 107 pfu, and 4 patients at 108 pfu. Safety, efficacy, and different immunological tests were the endpoints of the study. Results Tolerance of TG4010 was excellent, and side effects mainly consisted of injection site pain and influenza-like symptoms. There was no apparent detrimental effect of repeated injections of the vaccinia virus. Four of thirteen evaluable patients showed stabilization of their disease for 6 to 9 months. One lung cancer patient who was initially progressing after the first injections later showed a marked decrease in the size of his metastases that lasted for 14 months. Some T cell proliferative immune responses were seen in five patients. Conclusions The administration of TG4010 was generally well tolerated in patients with metastatic tumors, and transient disease stabilization was observed in several patients, warranting further clinical studies with the product. Copyright © 2003 John Wiley & Sons, Ltd.
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- 2003
17. Current protocol of a research phase I clinical trial of full-length dystrophin plasmid DNA in Duchenne/Becker muscular dystrophies. Part II: clinical protocol
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Norma Beatriz, Romero, Olivier, Benveniste, Christine, Payan, Serge, Braun, Patrick, Squiban, Serge, Herson, and Michel, Fardeau
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Adult ,Male ,DNA, Complementary ,Reverse Transcriptase Polymerase Chain Reaction ,Biopsy ,Gene Transfer Techniques ,Genetic Therapy ,Injections, Intramuscular ,Dystrophin ,Muscular Dystrophy, Duchenne ,Clinical Protocols ,Humans ,Female ,Plasmids - Abstract
A phase I open clinical study on gene therapy in Duchenne and Becker muscular dystrophy, without direct individual benefit for the patient, is being performed at the Pitié-Salpêtrière Hospital, Paris. The aims of this project are: (a) to determine the tolerance and the safety of the intramuscular administration of dystrophin cDNA and (b) to study the quality of the gene transfer in vivo in human patients affected by Duchenne and Becker muscular dystrophy. This clinical trial is conducted sequentially and includes three cohorts of three patients each. Patients must be at least 15 years of age. Diagnosis of Duchenne and Becker muscular dystrophy was confirmed by molecular analysis of the dystrophin gene and for each patient the abnormal expression of dystrophin was confirmed, in skeletal muscle, with antibodies directed against the deleted part of the dystrophin. This phase I study is scheduled to be completed by the end of 2002.
- Published
- 2002
18. Immunotherapy of metastatic melanoma by intratumoral injections of Vero cells producing human IL-2: phase II randomized study comparing two dose levels
- Author
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Lucie Heinzerling, Reinhard Dummer, Richard Herrmann, Patrick Squiban, Rudolf Morant, Bernard Escudier, Brigitte Dréno, Martine Baudin, Peter Jantscheff, Franco Cavalli, Pierre-Yves Dietrich, Bruce Acres, and Christoph Rochlitz
- Subjects
Adult ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Metastatic melanoma ,medicine.medical_treatment ,T-Lymphocytes ,Transplantation, Heterologous ,Heterologous ,Injections, Intralesional ,law.invention ,Randomized controlled trial ,law ,Immunity ,Neoplasms ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,RNA, Messenger ,Radionuclide Imaging ,Molecular Biology ,Melanoma ,Vero Cells ,Aged ,Dose-Response Relationship, Drug ,business.industry ,Immunotherapy ,Middle Aged ,Transplantation ,Dose–response relationship ,Treatment Outcome ,Vero cell ,Cancer research ,Molecular Medicine ,Interleukin-2 ,Female ,business - Abstract
Systemic IL-2 has shown some activity in metastatic melanoma, but its use is severely limited by toxicity. TG2001 is a product in which the human IL-2 cDNA was incorporated into the genome of Vero cells, a monkey fibroblast cell line. The goal of this intratumorally applied therapy was to create an antitumor immune response stimulated by xeno-antigens and local production of IL-2 in the close vicinity of tumor-specific antigens. TG2001 was reported to have a good safety profile in two previous dose-escalating phase I studies performed in 18 patients with various solid tumors, with encouraging clinical responses in three patients. The objectives of this study were to evaluate the tolerance and incidence of tumor regression in patients with metastatic melanoma, following repeated administration of Vero-IL-2 cells.This was on open-label, randomized phase II study comparing two doses of Vero-IL-2, 5x10(5) and 5x10(6) cells. Twenty-eight patients with metastatic melanoma were enrolled in the study, 14 in each treatment group. Patients received TG2001 by intratumoral injection on days 1, 3, and 5 every 4 weeks for four cycles, and every 8 weeks thereafter, until evidence of progressive disease (PD). Criteria for patient selection included histologically proven metastatic melanoma, with one tumor accessible for product administration, and at least another tumor site for response assessment. Evaluation included tumor measurements, humoral and T cell-mediated local and systemic immune response, humoral response to Vero cells, adverse events and standard laboratory parameters.None of the patients achieved a confirmed objective response. Stable disease (SD) was seen in six (43%) and eight patients (57%) at the 5x10(5) and the 5x10(6) dose level, respectively. Two patients, one in each group, died during the study (i.e., within 1 month after the last injection) due to PD. Three patients exhibited antibody responses to Vero cells. T-cell immunity, serum cytokine levels and cytokine mRNA expression in tumor biopsies did not show meaningful alterations after therapy, except for a trend toward an increase in intratumoral TH2 cytokine (IL-4 and/or IL-10) levels. The study drug was well tolerated at both dose levels and side effects mainly consisted of injection site pain and erythema, and pyrexia.The intratumoral administration of TG2001 was generally well tolerated in patients with metastatic melanoma, and transient disease stabilization was observed in 50% of patients.
- Published
- 2001
19. Enhancing Natural Killer (NK) Cell Mediated Killing of Non-Hodgkin's Lymphoma
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Shivani Srivastava, Sherif S. Farag, Patrick Squiban, Hailin Feng, Jing Liang, and Shuhong Zhang
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Antibody-dependent cell-mediated cytotoxicity ,CD20 ,Lymphokine-activated killer cell ,Janus kinase 3 ,Immunology ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Raji cell ,Interleukin 21 ,KIR3DL2 ,immune system diseases ,hemic and lymphatic diseases ,Interleukin 12 ,Cancer research ,biology.protein - Abstract
Abstract 2706 Poster Board II-682 Follicular lymphoma is incurable with the current chemo- or chemoimmunotherapy with median survival of 8–12 years. Relapse free survival after each subsequent therapy steadily decreases, resulting in an expected median survival of 4.5 years following initial relapse. Hence new treatment strategies are needed. Natural killer (NK) cells are important effector cells in mediating the anti-lymphoma effect of rituximab. Indeed, antibody-dependent cell-mediated cytotoxicity (ADCC) is a major mechanisms of action of rituximab with NK cells being important effector cells. However, in addition to ADCC, NK cells also exert natural cytotoxicity against tumor cells, which is modulated by a balance of inhibitory and activating signals through NK cell receptors. NK cell function is inhibited when their inhibitory killer immunoglobulin-like receptors (KIR) are ligated by their cognate MHC class I antigens on tumor targets. The novel agent IPH2101 (1-7F9) is a fully human monoclonal antibody directed against KIR2DL receptor that blocks the interaction of KIR with its HLA-C ligands breaking NK cell tolerance to autologous tumor cells. We investigated whether the combination of the IPH2101and Rituximab will augment the NK cell mediated cytotoxicity against CD20+ lymphoma targets as compared to rituximab alone. Raji cells are human CD20+ Burkitt lymphoma cell line cells that expresses HLA-A*03,- (ligand to inhibitory KIR3DL2); -B*71[Bw6] (no inhibitory KIR-Ligand) and -Cw*03,w*04 (group 1 and 2 of HLA-C ligands to inhibitory KIR2DL2/3 and KIR2DL1), and were chosen for study because they have HLA-C antigens that ligate the inhibitory KIR2DL2/3 and KIR2DLI receptors, making them a good target to test our hypothesis of inhibiting inhibitory KIR. NK cells were isolated from normal donor PBMC (peripheral blood mononuclear cells) with the Miltenyi NK isolation Kit. Using LDH release based cytotoxicity assay, we show (Figure 1) that the treatment of target Raji cells with Rituximab significantly enhanced natural cytotoxicity of the purified NK cells against Raji cells. IPH2101alone treatment of NK cells also significantly enhanced the cytotoxicity of Raji cells, however, the combination of IPH2101treated NK cells against Rituximab treated Raji cells significantly enhanced cytotoxicity beyond that observed with each agent alone. Effector: Target (E:T) ratios of 14:1 or less, from more than 5 random donors showed similar results indicating a synergistic, or at least and additive effect ( representative experiment shown Figure 1) . In these experiments purified NK cells were treated with 30ug/ml of IPH2101for 30 min and Raji targets were treated with 0.1-30ug/ml of Rituximab for 30 min. NK cells in the presence or absence of IPH2101were co-cultured with Raji cells in the presence or absence of Rituximab for 4 hour in a 96 well plate. NK cytotoxicity was assessed with an LDH release based assay. Our results suggest that there is a positive cooperation between natural cytotoxicity mediated through KIR-MHC blockade and that mediated by ADCC. Indeed, wee have shown that the blockade of KIR-MHC class I interaction by anti-KIR blocking antibody (IPH2101) augments the cytotoxicity of freshly isolated normal donor NK cells against CD20+ lymphoma cell lines as compared to rituximab alone, providing a rationale for the clinical investigation of the combination of IPH2101 (1-7F9) and rituximab in non-Hodgkin's lymphoma Disclosures: Squiban: Innate pharma: Employment.
- Published
- 2009
20. Novel Monoclonal Antibody Enhances Natural Killer (NK) Cell Cytotoxicity against Multiple Myeloma (MM): Interim Phase 1 Trial Results
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Marc Marzetto, Rafat Abonour, Patrick Squiban, Sherif S. Farag, Alain C. Mita, Swaminathan Padmanabhan, Don M. Benson, Courtney E. Bakan, Jerome Tollier, Craig C. Hofmeister, Attaya Suvannasankha, Pascale Andre, Megan K. Smith, and Michael A. Caligiuri
- Subjects
business.industry ,KIR Ligand ,Immunology ,Cmax ,Cell Biology ,Hematology ,Pharmacology ,medicine.disease ,Biochemistry ,Transplantation ,Cell killing ,Pharmacokinetics ,Antigen ,Pharmacodynamics ,Medicine ,business ,Multiple myeloma - Abstract
Abstract 2880 Poster Board II-856 Background: MM is increasing in incidence and remains incurable. .NK cells have modest killing activity against MM tumor cells in part because of inhibitory KIR receptors which recognize HLA class 1 antigens on MM tumor cell targets. However, experimental and clinical data in the allogeneic transplant setting suggest that NK cell stimulation by a mismatch between donor KIR and patient KIR ligand may improve outcomes for MM after a reduction of tumor burden by previously administered treatments. To mimic this effect with a pharmaceutical agent, 1-7F9/IPH2101, a fully human IgG4 anti-KIR mAb specific for KIR2DL1/2/3 (HLA-C specific KIRs) was generated (Romagne et al., Blood June, 2009). 1-7F9/IPH 2101 enhances patient NK cell cytotoxicity against autologous MM tumor cells in vitro. We present the interim results of the human phase I trial of this agent in patients with relapsed/refractory MM. Methods: An open-label, single-agent, dose-escalation, multiple dose safety and tolerability study of IPH2101 is being conducted in heavily pre-treated patients with relapsed/refractory MM. Dose escalation with IPH2101 (0.0003, 0.003, 0.015, 0.075, 0.3, 1, 3 mg/kg as IV infusion) is being studied using a 3+3 scheme. Re-dosing criteria (1/month x 4 months) are based on safety data from previous dosing. KIR occupancy, pharmacokinetics (PK), pharmacodynamics, effects on NK cell maturation, and biological effects of IPH 2101 are being monitored in all patients. Results: Currently, dose escalation is entering the final (3 mg/kg) cohort. Data from the first 22 treated patients are available. No Dose Limiting Toxicity (DLT) has been observed. 1 pt (at DL1) has been replaced and 3 additional pts have been enrolled (at DL4) due to an SAE an acute renal failure possibly related to drug. Related Adverse Events were seen in 4/22 patients (18%). 12/22 pts received at least 2 doses (6pts had 2, 1 pt had 3 and 5 pts had 4 cycles-median 2). KIR full occupancy (> 90%) for at least 3 weeks is reached at 1mg /kg. In accordance with the pre-clinical PK/PD model there is a clear relationship between exposure (Cmax) and KIR occupancy. No deleterious effect on NK cell maturation has been seen. IPH 2101 has been well tolerated to date. In the cohorts accrued to date, two heavily pre-treated patients, both with high-risk cytogenetics, showed evidence to suggest disease stabilization while receiving IPH-2101. Conclusions: IPH 2101 improves autologous NK cell killing of MM tumor cells by blocking inhibitory KIR. In the on-going clinical trial, the antibody appears safe and well tolerated at the doses tested. Updated study results will be presented at the time of the meeting This immunotherapeutic approach may hold promise as treatment for MM and further study is warranted. Disclosures: Squiban: Innate pharma: Employment. Marzetto:Innate Pharma: Employment. Andre:Innate Pharma: Employment. Tollier:Innate Pharma: Employment.
- Published
- 2009
21. IPH2101, a Novel Anti-Inhibitory KIR Monoclonal Antibody, and Lenalidomide Combine to Enhance the Natural Killer (NK) Cell Versus Multiple Myeloma (MM) Effect
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Patrick Squiban, Sherif S. Farag, Carli N Greenfield, Lana Alghothani, Don M. Benson, Courtney E. Bakan, Shuhong Zhang, François Romagné, Jing Liang, Shivani Srivastava, Craig C. Hofmeister, Pascale Andre, Megan K. Smith, and Michael A. Caligiuri
- Subjects
Granzyme B production ,Lymphokine-activated killer cell ,Immunology ,Cell Biology ,Hematology ,Pharmacology ,Biology ,NKG2D ,Immune complex formation ,Biochemistry ,Interleukin 21 ,Cell killing ,Cancer cell ,Cancer research ,medicine ,Lenalidomide ,medicine.drug - Abstract
Abstract 3870 Poster Board III-806 Background NK cell activity against tumor cells is regulated by a balance of inhibitory and activating signals mediated by receptors on NK cells that recognize inhibitory and activating ligands expressed by cancer cells. IPH2101 (1-7F9) is a novel monoclonal anti-inhibitor KIR blocking antibody that has been shown to augment NK cell function against MM targets. Moreover, lenalidomide has been shown to expand and activate NK cells in vivo and in vitro. We have previously reported that the combination of IPH2101 and lenalidomide enhances NK cell mediated cytotoxicity against MM cells compared to each agent alone (Zhang et al., AACR 2009). We expand our studies to investigate potential mechanisms for the enhancement of NK cell activity by the combination of IPH2101 and lenalidomide. Methods The effects of IPH2101 and lenalidomide alone and in combination were studied using primary human NK cells from healthy donors as well as from MM patients. The MM cell lines U266 and RPMI 8226 as well as primary tumor cells from marrow aspirates of MM patients served as target cells. The effect of lenalidomide on MM activating and inhibitory ligand expression was studied by flow cytometry. NK cell trafficking was investigated with standard transwell plate migration assay. Immune complex formation between NK cell effectors and MM tumor targets was characterized by flow cytometry in control conditions and with NK cells pre-treated with IPH2101 and lenalidomide. The effects of IPH2101 and lenalidomide were studied regarding interferon-gamma and granzyme B production by ELISPOT and target-specific cytotoxicity studies were conducted to complement effector-based assays. Results IPH2101 (30 ug/ml) significantly enhanced cytotoxicity against U266 cells and primary MM tumor cells by both purified NK cells at effector:target (E:T) ratios of 10:1 or less, and also of freshly isolated peripheral blood mononuclear cells (PBMC) at E:T ratios of 60:1 or less, from more than 10 random donors. In addition, treatment of PBMC with 5-10 μmol/L lenalidomide for 72h without interleukin (IL)-2 increased NK cell lysis of U266. Treatment of PBMC from normal donors did not enhance the expression of the NK receptors KIR, NKG2D, NCR, TRAIL, and DNAM-1. Incubation of U266 cells with lenalidomide (5 uM) for 3-5 days resulted in significant enhancement of cytotoxicity by normal donor NK cells. This was associated with upregulation of the activating ligands, MICA, ULBP-2, DR4, and CD112. Using blocking antibodies to NKG2D, TRAIL, and DNAM-1, lenalidomide enhancement of MM cell killing was abrogated indicating the importance of the modulation of the ligands to the latter receptors by lenalidomide. Although IPH2101 and lenalidomide did not significantly increase NK cell migration into normal media, migration was enhanced 2.98-fold (+/− 0.36, p < 0.05) towards U266 cell targets (n= 3, p < 0.05) and MM patient serum 3.2-fold (+/− 0.4, n=3, p < 0.05). IPH2101 and lenalidomide also led to a 2.3-fold (+/− 0.43, p < 0.05) increase in immune complex formation between NK cells and MM tumor cells. IPH2101 and lenalidomide also augmented NK cell interferon gamma production against MM (control mean 303 spots/well +/− 13 versus 525 +/− 83, n=3, p < 0.05) and granzyme B production (control mean 115 +/− 98 versus 449 +/−72, n=3, p < 0.05). Importantly, in all experiments described herein, the effects of IPH2101 and lenalidomide together were greater than either agent alone. Conclusions Taken together, our data suggest that IPH2101 and lenalidomide may exert complementary mechanisms on both effector and target cells to enhance NK cell mediated killing of MM cells. Moreover, these agents have no predicted clinical cross-toxicities. A single-agent phase 1 clinical trial of IPH2101 has shown the mAb to be safe and well tolerated in MM patients. These findings support a phase 1/2 clinical trial of IPH2101 with lenalidomide as a first dual-innate immunotherapy for patients with MM. Disclosures: Andre: Innate Pharma: Employment. Squiban:Innate pharma: Employment. Romagne:Innate Pharma: Employment.
- Published
- 2009
22. Phase I/II Study of IPH1101, γσ T Cell Agonist, Combined with Rituximab, in Low Grade Follicular Lymphoma Patients
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Hélène Sicard, Pierre Soubeyran, Catherine Thieblemont, Philippe Solal-Celigny, Lucile Beautier, Hervé Ghesquières, Guy Laurent, Fabien Audibert, Eric Jourdan, Sylvie Lafaye de Micheaux, Jean-François Rossi, Vincent Delwail, and Patrick Squiban
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,T cell ,Immunology ,Follicular lymphoma ,Context (language use) ,Cell Biology ,Hematology ,Pharmacology ,medicine.disease ,Biochemistry ,Clinical trial ,medicine.anatomical_structure ,Internal medicine ,Pharmacodynamics ,medicine ,Cytotoxic T cell ,Rituximab ,business ,Adverse effect ,medicine.drug - Abstract
Abstract 1649 Poster Board I-675 Non-conventional γσ T lymphocytes are innate immunity effectors bearing potent anti-tumoral activity, particularly against malignant B cells. IPH1101 is an agonist of γσ T cells, which in the presence of low doses of IL-2 potentiates their direct cytotoxic activity. ADCC is a major molecular mechanism underlying rituximab's efficacy. Increasing the number and the activation state of killer lymphocytes mediating ADCC is therefore believed to be beneficial for therapeutic potency. Since γσ T cells have been found to be capable of mediating ADCC, modulating γσ T cells in the context of rituximab is worth being tested in a clinical trial. The main purpose is to assess the clinical efficacy of IPH1101 with low doses of IL-2, combined with a standard rituximab treatment, in patients (pts) with follicular lymphoma. This is an open label, multinational study consisting of a dose escalation Phase (ph) I-like part followed by a ph II part. The ph I part has shown a good safety and immuno-biological efficacy profile for the highest dose of IL-2. Consequently, the pts of the phase II part were treated with the combination of rituximab (375 mg/m2) administered 4 times weekly, IPH1101 (750 mg/m2) administered i.v. 3 times (every 3 weeks) and IL-2 (8 MIU) administered daily s.c. for 5 days starting on the day of each IPH1101 administration. All pts presented low grade FL which had relapsed after 1 to 4 lines of previous therapy including at least one rituximab-containing line. Inclusion criteria set forth that pts should have no lesion > 7 cm. Results We report here the end of recruitment and updated data on 45 patients and more than 100 cycles of IPH1101. Overall safety was good, and most of the drug-related adverse events were, as expected, flu like symptoms of grade 1 or 2. The SAEs reported were 2 hypotensions, 1 bronchospasm, 1 allergic reaction (back pain), 1 glomerular filtration decrease, 1 ALAT elevation, 1 hypertension and 1 asthenia. The immuno-biological follow up demonstrated the very good pharmacodynamic profile of IPH1101 in these patients and these data are presented in details in another abstract from Lucas et al. To date, in the first set of evaluable patients (12 pts) and after at least 3 months post treatment, investigators reported about 75% of response and 50% of CR. Most of the responses are already confirmed by an independent panel. Conclusion These observations confirm the good safety and the biological rationale of this approach. Furthermore, the response rate in this first set of pts is encouraging in the context of previously treated patients. Updated results will be presented at the meeting. Disclosures Laurent: Innate pharma: Honoraria. Lafaye de Micheaux:Innate Pharma: Employment. Solal-Celigny:Innate Pharma: Research Funding. Soubeyran:Innate Pharma: Research Funding. Delwail:Innate Pharma: Honoraria. Ghesquières:innate pharma: Honoraria. Thieblemont:Innate Pharma: Honoraria. Jourdan:Innate Pharma: Honoraria. Beautier:Innate Pharma: Employment. Squiban:Innate pharma: Employment. Rossi:Innate Pharma: Honoraria.
- Published
- 2009
23. Characterization of Early Natural Killer Cell Reconstitution Following Autologous Transplantation in Multiple Myeloma
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Patrick Squiban, Megan K. Smith, Steven M. Devine, Michael A. Caligiuri, Pascale Andre, Courtney E. Bakan, Carli N Greenfield, Craig C. Hofmeister, Yvonne A. Efebera, Don M. Benson, Lana Alghothani, and François Romagné
- Subjects
Granzyme B production ,Interferon-gamma production ,Lymphocyte ,Immunology ,Cell Biology ,Hematology ,Biology ,NKG2D ,Biochemistry ,Natural killer cell ,Interleukin 21 ,Immunophenotyping ,medicine.anatomical_structure ,medicine ,Autologous transplantation - Abstract
Abstract 4641 Background Despite the advent of novel therapies, multiple myeloma (MM) remains incurable and high-dose chemotherapy (HDC) with autologous stem cell transplantation (SCT) remains an important therapy for this incurable malignancy. Prior research has suggested that early lymphocyte immune reconstitution following HDC/SCT may be associated with improved outcomes; however, little is known regarding the biologic mechanisms underlying this phenomenon. A potent natural killer (NK) cell versus MM effect has also been demonstrated by our group and others previously, and NK cells are the first lymphocyte subset to recover following HDC/SCT. Herein, we characterize the nature of this recovery to suggest that the early post-transplant period may be an especially favorable environment in which to augment the NK cell versus MM effect to improve outcomes for patients with MM undergoing HDC/SCT. Methods With informed consent and under institutional review board approval, peripheral blood samples from patients with multiple myeloma undergoing HDC/SCT were collected on the day of first peripheral white cell count > 1500/uL post- HDC/SCT. All patients received intravenous melphalan (200mg/m2) as the preparative regimen. Mononuclear cells were isolated and, by flow cytometry, CD56(+),CD3(-) NK cells were comprehensively immunophenotyped for expression of inhibitory and activating ligands. NK cell activation and cytotoxicity were assessed by ELISPOT and chromium release assays. Clinical outcome was assessed as a function of early NK cell recovery. Results 11 patients (median age 57, 8 male, 3 female) with a median of 1 prior regimen to transplant (range 1-9) have been assessed to date. 1 patient was mobilized with AMD-3100, 3 had cyclophosphamide mobilizations and 7 were mobilized with neupogen alone. The average CD34(+) cell dose received was 5.22 (+/- SD 2.39). The median day of peripheral white cell recovery was day +12 (range 11-18). The median absolute lymphocyte count on sample procurement day was 410 (range 340 – 820), of which an average of 37% (range 13 – 70) were NK cells. Although total white count on procurement day correlated with CD34(+) cell dose (p = 0.02), neither absolute lymphocyte count or NK cell count correlated significantly with CD34(+) cell dose and mobilization strategy did not affect NK cell count. NK cell reconstitution correlated with best response to HDC/SCT (p=0.02), the average NK cell count for patients ultimately achieving CR was 389 (+/- 131) as compared to those achieving PR or less (171 +/- 101). Interestingly, nearly half of reconstituting NK cells (46% +/- SD 20) expressed CD117 (c-kit receptor), a marker shown previously to be associated with earlier stages of NK cell development. Inhibitory KIR (CD158a on 36% +/-17 and CD158b on 36% +/- 24) and NKG2A (76% +/- 10) expression also seemed restricted to the CD117(+) NK cells. This population of NK cells also displayed NKG2D (25% +/- 22) and CD16 (73% +/-8). Reconstituting NK cells were capable of interferon gamma production against MM tumor targets similar to NK cells isolated from healthy donors (E:T = 20:1, 956 +/- 98 spots/well versus 896 +/-85, p = n/s). Granzyme B production against MM tumor targets also compared to normal controls (E:T = 20:1, 547 +/- 66 versus 573 +/- 50, p= n/s). Moreover, reconstituting NK cells showed enhanced cytotoxicity against MM tumor targets when pre-treated with an inhibitory KIR blocking antibody (IPH2101/1-7F9) similar to healthy donor NK cells. Discussion Taken together, we provide quantitative and qualitative data to suggest that early NK cell recovery post-SCT may contribute to outcome in patients with MM. This may be an optimal period to implement immunomodulatory strategies to augment NK cell function to improve outcomes for patients with MM undergoing HDC/SCT. Reconstituting NK cells, although exhibiting a relatively unique immunophenotype compared to mature NK cells in healthy, normal donors, appear to retain properties of activation and cytotoxicity. Given the favorable effector:target ratio in vivo following SCT, these results support further research into immunotherapeutic manipulation of the reconstituting NK cell clone to improve efficacy of HDC/SCT in patients with MM. Disclosures: Andre: Innate Pharma: Employment. Squiban:Innate Pharma: Employment. Romagne:Innate Pharma: Employment.
- Published
- 2009
24. Novel monoclonal antibody that enhances natural killer (NK) cell cytotoxicity against multiple myeloma (MM): Preclinical data and interim phase I clinical trial results
- Author
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M. Smith, F. Romagne, N. Wagtmann, C. E. Bakan, Patrick Squiban, Sherif S. Farag, Michael A. Caligiuri, Alain C. Mita, Don M. Benson, and Craig C. Hofmeister
- Subjects
Cancer Research ,Lymphokine-activated killer cell ,medicine.drug_class ,business.industry ,Phases of clinical research ,Human leukocyte antigen ,medicine.disease ,Monoclonal antibody ,Preclinical data ,Interleukin 21 ,Oncology ,Antigen ,Immunology ,medicine ,business ,Multiple myeloma - Abstract
3032 Background: MM is increasing in incidence and remains incurable. NK cells have modest killing activity against MM cells in part because of inhibitory signals from HLA class 1 antigens which act via the KIR receptors on NK cells. A novel anti-KIR blocking antibody (1–7F9 named IPH 2101) enhances patient NK cell cytotoxicity against autologous MM tumor cells in vitro and appears safe in an ongoing phase 1 clinical trial. Methods: NK cells from healthy controls or patients were pre-treated with IPH 2101 or IgG4 isotype control and co-cultured with MM cell lines or autologous MM tumor targets. NK cell production of interferon-gamma (IFN-γ) or granzyme B (GrB) were measured by ELISPOT. An open-label, single-agent, phase 1 dose escalation study of IPH 2101 is being conducted in patients with relapsed/refractory MM. KIR binding, pharmacokinetics, pharmacodynamics, effects on NK cell maturation, and biological effects of IPH 2101 are being monitored in all patients. Results: At an effector to target (E:T) ratio of 1:1, IPH 2101 significantly enhances NK cell IFN-γ release against MM targets (mean 33 spots/well ± 12, SEM vs. 11 ± 0.3, p = 0.005). At an E:T ratio of 10:1, IPH 2101 enhances NK cell cytotoxicity, by GrB release, of patient NK cells against autologous MM tumor cells (mean 111 spots/well ± 14, SEM vs 56 ± 10, p = 0.002). By Western blot, IPH 2101 may reduce levels of src, a kinase known to be involved in inhibitory KIR signaling. Dose escalation in the phase 1 study has been completed from 0.0003 mg/kg to 0.075 mg/kg in 14 evaluable patients. At the highest dose tested, KIR occupancy has been detected at a mean 95% ± 1.4 at 2 hours post dose, lasting up to 56% ± 18 during 2 weeks post dose. At this dose level, PK data show good correspondence with previous modeling activity. No deleterious effect on NK cell maturation has been seen. IPH 2101 has been well tolerated to date. Conclusions: IPH 2101 improves autologous NK cell killing of MM tumor cells by blocking inhibitory KIR. In the ongoing clinical trial, the antibody appears safe and well tolerated at the doses tested. This immunotherapeutic approach may hold promise as treatment for MM and further study is warranted. [Table: see text]
- Published
- 2009
25. In Follicular Lymphoma (FL), γδt-Lymphocytes (γδT) Are Present and Expandable from Peripheral Blood and Rare in Tumour Lymph Nodes, Mostly in Peri-Follicular Areas
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Hélène Sicard, Valérie Costes, Patrick Squiban, Majda Saifi, Sylvie Lafaye de Micheaux, Guillaume Cartron, Jean-François Rossi, Thérèse Rousset, and Mounia Sabrina Braza
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Pathology ,medicine.medical_specialty ,Chemokine ,Immunology ,CCL19 ,Follicular lymphoma ,C-C chemokine receptor type 7 ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Aldesleukin ,medicine ,biology.protein ,Stromal cell-derived factor 1 ,Lymph ,Lymph node - Abstract
Background: The tumour microenvironment plays an important role in the biology of FL. Different cell populations have been explored, including T-regulatory lymphocytes, macrophages, and T-cell subpopulation. The involvement of γδT in lymph nodes from FL patients or from inflammatory diseases has been rarely documented. So far, their histological pattern and prognosis significance are unknown and must be defined in order to develop new therapeutic programs including in vivo or ex vivo expansion of γδT, as developed particularly in B-cell malignancies by us and different groups. In this study, we analyzed from FL patients 1/the number of circulating γδT and their ex vivo expansion, 2/ the presence and distribution of γδT in tumour lymph nodes, and different chemokines, in comparison to inflammatory lymph nodes (ILN), by immunochemistry. Patients and Methods: Circulating γδT cells were counted in peripheral blood from patients having FL by FACS analysis. Blood samples from 34 patients were collected and expanded in vitro by using γδT ligands, referred to as “phosphoantigens”, including IPH1101 (used in clinical trials) and interleukin 2. Tumour samples from 51 patients (35 at diagnosis and 16 at relapse) having FL were collected from a single institution. Immunochemistry was used to study numbers and distribution of CD8, γδT cells, and the expression of CCL19, 21 and SDF1 chemokines. CCR7/γδT cells were analyzed by double immunofluorescence. Results were compared to 28 samples from patients having ILN. Results: The mean of circulating γδT was 0.36% (0.03–2.5) representing a mean of 2.2% of the CD3 cells. The mean percentage of γδT cells obtained after in vitro culture was 85% (2.1–95) with a mean 220-fold expansion (2-1050). The median number of γδT cells (cells/mm2) in FL lymph node was 18 versus 47.5 in the ILN (mean: 30 versus 82,5), P Conclusions: These observations suggest that γδT cells are present and expandable in PB from patients having FL including patients with advanced disease. In addition, γδT are not abundant in lymph nodes of patients with FL compared to ILN, but γδT conserve their CCR7+ phenotype. This deficiency could be explained by migratory problems provoked by a lack of CCL19 chemokine expression. As γδT have been demonstrated to kill tumour cells, including B-malignant cells, they could be considered as essential targets for immune therapy in different cancers including B-cell malignancies, but their activation and trafficking has to be considered.
- Published
- 2008
26. Vγ9Vδ2 T (γδ) lymphocytes: a promising approach for immunotherapy of solid tumors
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Jaafar Bennouna, Fabien Calvo, E. Viey, Jerome Tiollier, Patrick Squiban, Hélène Sicard, S. Lafaye de Micheaux, Samuel Salot, E. Bompas, and Vincent Levy
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Cancer Research ,Oncology ,business.industry ,medicine.medical_treatment ,Immunology ,Medicine ,Cytotoxic T cell ,Immunotherapy ,business ,Blood lymphocyte - Abstract
3064 Background: The Vγ9Vd2 T (γd) blood lymphocyte subset has a strong cytotoxic potential and can be selectively activated with chemically-synthesized, structural analogues of non-conventional antigens like BrHPP (IPH1101). Their proliferation requires low dose of Interleukin-2 (IL-2). Methods: We developed several in vitro and in vivo models to assess the immunotherapeutic potential of IPH1101-activated γd cells: - Direct cytotoxicity assays on patient-derived primary tumor cell lines - Extensive pharmacodynamics in the non human primate (NHP) - Small scale in vitro amplification assays for IPH1101-sensitive patient pre-selection Then, two Phase I clinical trials were performed in solid tumor patients: - Autologous cell therapy with ex vivo IPH1101- expanded γd cells (1, 4 or 8.109 cells) - Direct administration of IPH1101 (200 to 1800 mg/m2 i.v.) and low dose IL-2 (106 U/m2 s.c.). Results: In NHP, IPH1101 and low dose IL-2 induce early pro-inflammatory cytokine release and dose-dependent γd cell amplification in peripheral blood. In vitro, mRCC tumor cells are efficiently and selectively killed by autologous γd cells. In Phase I clinical trials, both ex vivo expanded γd cells and IPH1101 were well tolerated. - Cell therapy-related AEs included mainly gastrointestinal disorders, flu-like symptoms and hypotension. Six patients showed stabilized disease. Median duration of stabilization was 25.7 weeks. 2 pts treated with 4.109 or 8.109 cells showed substantial tumor shrinkage at the 14-week evaluation (-22% and -48%, respectively). - When IPH1101 was administered with low dose of IL-2, a significant increase of blood γd T cells was observed (up to 240 times the basal values) and in terms of clinical activity assessment, among the evaluable mRCC population (n=15), 8 patients presented disease stabilization for more than 35 weeks, including 6 for more than 51 weeks. Conclusions: For the first time, a specific γd immunotherapy was fully developed and led to Phase I clinical trials. It has been found well tolerated. Encouraging signs of disease stabilisation in mRCC patients suggest that γd may have a role in the treatment of cancers resistant to conventional therapies. A phase 2 is ongoing in mRCC patients. No significant financial relationships to disclose.
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- 2007
27. Enhancing Lysis of B Cell Lymphoma by Innovative γδ T Cell Immunotherapies Using Agonist IPH1101 (Phosphostim, BrHPP)
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Hélène Sicard, Jean-François Rossi, Guy Laurent, Patrick Squiban, Sylvie Lafaye de Micheaux, Jerome Tiollier, Volker Kunzmann, Julie Gertner, and Jean-Jacques Fournié
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business.industry ,Lymphocyte ,T cell ,Immunology ,Follicular lymphoma ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Antigen ,Aldesleukin ,Medicine ,Cytotoxic T cell ,Rituximab ,business ,B-cell lymphoma ,medicine.drug - Abstract
Since the early 90’s, it was observed that blood γδ T cells could kill a broad variety of tumor cells, including malignant B-cells, in vitro as well as in human PBMC-reconstituted NOD-SCID mice. Today, with specific antigens activating γδ T cells like IPH1101 (Phosphostim, BrHPP), these effector cells can be strongly amplified in vivo and their cytotoxic activity toward B-Non Hodgkin’s Lymphoma (B-NHL) enhanced. Furthermore, γδ T cells are potential effectors of ADCC which is one of the major mechanisms underlying rituximab efficacy for the depletion of B-NHL: we demonstrated in short-term standard cytotoxicity assays that there is a strong synergy between IPH1101-activated γδ cells and rituximab for the killing of B-NHL lines of various histologies (mantle cell, follicular and Burkitt’s lymphomas). Impressive results were obtained with follicular lymphoma (FL) cells (RL and Karpas-422) for which the addition of rituximab in the co-culture containing stimulated γδ T cells and FL cells resulted in target cell lysis as high as 70% at E:T ratio of 30:1 whereas stimulated γδ T cells alone induced less than 30% lysis in the same conditions. We are currently running a cognitive biological study using blood samples from FL and multiple myeloma patients: PBMC purified from these patients are cultured in a standardized assay in the presence of IPH1101 and IL-2 in order to evaluate the proportion of patients whose γδ cells can efficiently respond to IPH1101-treatment. A Phase I, dose-escalation study is currently being conducted in France and Germany in sequential cohorts of patients with B-NHL relapsing after polychemotherapy with rituximab. In this first clinical trial, included patients are selected, among other criteria, upon their ability to respond to IPH1101 in vitro in this standardized culture. The objective is to determine the MTD, pharmacokinetic and pharmacodynamic parameters of IPH1101 administered i.v. on Day 1, in combination with low dose of aldesleukin (1 MIU/m2/day) on Days 1 to 5. Low doses IL-2 (1/10th of the therapeutic dose) are required to sustain γδ proliferation in response to IPH1101. The following escalating dose levels of IPH1101 have been established for this study: 100, 300, 600, 900 and 1200 mg/m2. To date 7 patients have been treated at dose levels 100, 300 and 600 mg/m2 without any signs of toxicity and with significant target γδ lymphocyte population amplification. Updated results will be presented at the time of the conference. A phase II study of IPH1101 associated with low dose of IL-2 in combination with rituximab in FL patients progressing after one or more rituximab-containing lines of treatment is proposed. Its objective will be to assess the clinical efficacy of the combination and investigate the relationship between biological activity and clinical efficacy of the combination. This strategy is strongly sustained by convincing scientific data and stands for a very innovative combination of immunotherapies.
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- 2006
28. Vaccine immunotherapy with MVA-Muc1-IL2 (TG4010) in prostate cancer patients with biochemical failure
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Walter M. Stadler, R. Ahman, Patrick Squiban, Jean-Marc Limacher, A. Derbij, Robert Dreicer, Allan J. Pantuck, Bruce Acres, and Nadine Bizouarne
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Biochemical failure ,Immunotherapy ,medicine.disease ,digestive system ,biological factors ,digestive system diseases ,Prostate cancer ,Internal medicine ,medicine ,Mucin glycoprotein ,skin and connective tissue diseases ,business ,neoplasms ,MVA-MUC1-IL2 ,MUC1 ,Target antigen - Abstract
4518 Background: Over-expression, non-polarity and under-glycosylation of the mucin glycoprotein molecule, MUC1, are associated with many cancers, making MUC1 an attractive target antigen for vacci...
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- 2005
29. Phase II study of the cancer vaccine TG4010 in metastatic renal cell carcinoma
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Olivier Rixe, F. Ringeisen, Claude Linassier, Bruce Acres, J. P. Machiels, Thierry Velu, Eugeniu Banu, J. F. Rossi, Patrick Squiban, and Stéphane Oudard
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Interleukin 2 ,Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,Phases of clinical research ,medicine.disease ,Vaccination ,Oncology ,Antigen ,Renal cell carcinoma ,Interferon ,Cancer research ,Medicine ,Cancer vaccine ,business ,neoplasms ,MUC1 ,medicine.drug - Abstract
4653 Background: MUC1 is a glycoprotein located at the apical surface of glandular epithelial cells. In some tumors, MUC1 is often aberrantly over-expressed and hypoglycosylated, unmasking new antigenic epitopes. This makes it a potential target for tumor-specific vaccination. In renal cell carcinoma (RCC), MUC1 expression is associated with a poor prognosis. TG4010 is a cancer vaccine based on a modified vaccinia virus (MVA) expressing both MUC1 and Interleukin 2. The phase II study objective was to determine the overall response rate of TG4010 alone and in combination with cytokines in a two-step design. Methods: Patients (pts) with progressive metastatic RCC, expressing MUC1 in at least 50% of the tumour cells, received subcutaneous injections of TG4010 weekly for 6 weeks then every 3 weeks until progression, then the TG4010 was combined with Interferon alpha-2a (INF) and Interleukin 2 (IL2). Response to treatment was evaluated every 12 weeks according to the RECIST criteria. Median time to progression...
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- 2005
30. Adenovirus Mediated Interferon-gamma Expression in Cutaneous Lymphoma: Monitoring of Local and Systemic Events
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Patrick Squiban, Bruce Acres, Stefan Eichmueller, Reinhard Dummer, Pascal Bleuzen, and Mirjana Urosevic
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Pharmacology ,Cancer Research ,business.industry ,Immunology ,medicine ,Immunology and Allergy ,Interferon gamma ,medicine.disease ,business ,Cutaneous lymphoma ,medicine.drug - Published
- 2004
31. Phase I/II study of adenovirus-interferon-γ (TG1042) in primary cutaneous lymphomas (CL)
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Mirjana Urosevic, B. Acres, Guenter Burg, Reinhard Dummer, Vincent Bataille, Patrick Squiban, Philippe Slos, and P. Bleuzen
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Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,T cell ,law.invention ,medicine.anatomical_structure ,Phase i ii ,Oncology ,Interferon γ ,law ,medicine ,Cancer research ,Recombinant DNA ,Immunohistochemistry ,In patient ,business ,Severe toxicity ,B cell - Abstract
3039 Background: CL has been successfully treated with interferons (IFNs), which can offset the Th2 dominance associated with CL. Intratumoral (IT) injection of TG1042 (a non-replicating recombinant adenovirus with a human IFN-g cDNA insert) allows high local levels of IFN-g without severe toxicity induced by systemic delivery. Methods: We undertook a phase I/II, open-label, trial of repeated, IT injection of TG1042 in patients with advanced primary T cell (CTCL) and multilesional B cell (CBCL) cutaneous lymphomas. The designated lesions were injected on days 1, 8, and 15 with no injection in the fourth week (1 cycle) and thereafter up to 4 cycles. Immunohistochemistry and qPCR were performed on injected lesions biopsied at baseline and after each cycles. In the phase I, 9 patients were enrolled in 3 successive cohorts at the doses of 3x10E9 total particles (tp), 3x10E10 and 3x10E11 tp. In the phase II, 7 out of 27 additional planned patients have been treated at 3x10E11 tp. Results: To date 12 CTCL and 4...
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- 2004
32. 577. MVA-MUC1-IL2 Vaccine Immunotherapy for Patients Post-Prostatectomy with Rising PSA and No Evident Metastases
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Nadine Bizouarne, Caroline Beunkens, Frederick Ahman, Teresa Maciejewska, Allan J. Pantuck, Bruce Acres, Robert Dreicer, and Patrick Squiban
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Modified vaccinia Ankara ,MVA-MUC1-IL2 Vaccine ,viruses ,medicine.medical_treatment ,digestive system ,Virus ,chemistry.chemical_compound ,Drug Discovery ,Genetics ,Medicine ,skin and connective tissue diseases ,neoplasms ,Molecular Biology ,MUC1 ,Pharmacology ,business.industry ,Cancer ,Immunotherapy ,medicine.disease ,Acquired immune system ,digestive system diseases ,chemistry ,Immunology ,Molecular Medicine ,Vaccinia ,business - Abstract
Background: Over-expression, non-polarity and under-glycosylation of the mucin glycoprotein molecule, MUC1, are associated with many cancers, making MUC1 an attractive target antigen for vaccine immunotherapy of cancer. MVA (Modified Vaccinia Ankara), a highly attenuated Vaccinia virus, is non-propagative in most mammalian cells and has an excellent safety profile. We have produced a recombinant MVA expressing MUC1 and IL2 (TG4010). Murine studies have shown that TG4010 can induce a MUC1 specific immune response associated with the elimination of MUC1 expressing tumors.
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- 2004
33. Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1 as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer.
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Christoph Rochlitz, Robert Figlin, Patrick Squiban, Marc Salzberg, Miklos Pless, Richard Herrmann, Eric Tartour, Yongxiang Zhao, Nadine Bizouarne, Martine Baudin, and Bruce Acres
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LUNG cancer ,IMMUNOTHERAPY ,EPITHELIAL cells ,TUMORS ,CANCER cells ,NUCLEOTIDE sequence ,ANTIGENS ,VACCINIA - Abstract
The MUC1 protein is a highly glycosylated mucin normally found at the apical surface of mucin-secreting epithelial cells in many types of tissues. MUC1 is expressed, but heavily underglycosylated, in different human tumors. TG4010 is a viral suspension of a recombinant vaccinia vector (MVA) containing DNA sequences coding for the human MUC1 antigen and interleukin-2 (IL-2). This product was developed for use as a vaccine in cancer patients whose tumors express the MUC1 antigen. The objective of the present study was to determine the safety of the product and to define the dose of TG4010 to be used in further clinical trials. Thirteen patients with different solid tumors were treated by repeated intramuscular injection with increasing doses of TG4010 in two separate phase I studies, one in Europe (BaselCR) and one in the United States (UCLARF): a total of 6 patients were treated at a dose of 5 × 10
6 pfu, 3 patients at 5 × 107 pfu, and 4 patients at 108 pfu. Safety, efficacy, and different immunological tests were the endpoints of the study. Tolerance of TG4010 was excellent, and side effects mainly consisted of injection site pain and influenza-like symptoms. There was no apparent detrimental effect of repeated injections of the vaccinia virus. Four of thirteen evaluable patients showed stabilization of their disease for 6 to 9 months. One lung cancer patient who was initially progressing after the first injections later showed a marked decrease in the size of his metastases that lasted for 14 months. Some T cell proliferative immune responses were seen in five patients. The administration of TG4010 was generally well tolerated in patients with metastatic tumors, and transient disease stabilization was observed in several patients, warranting further clinical studies with the product. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]- Published
- 2003
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34. A phase I study of the anti-natural killer inhibitory receptor (KIR) monoclonal antibody (1-7F9, IPH2101) in elderly patients with acute myeloid leukemia (AML)
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B. Damholt, Didier Blaise, Norbert Vey, J. H. Bourhis, Thomas Prebet, Dominique Bordessoule, Patrick Squiban, Aude Charbonnier, Hervé Dombret, and Daniel Olive
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Cancer Research ,medicine.drug_class ,business.industry ,Myeloid leukemia ,Consolidation Chemotherapy ,Inhibitory postsynaptic potential ,Monoclonal antibody ,In vitro ,Oncology ,Lytic cycle ,KIR2DL1 ,Immunology ,medicine ,business ,Receptor - Abstract
3015 Background: The outcome of the majority of patients with AML remains poor, especially in the oldest patients. Allogeneic SCT is a curative approach for AML. In some models, it has been shown that KIR mismatch is important for the anti-leukemic effect of the graft, most probably through unleashed NK cells towards AML blasts, as suggested by enhanced in vitro NK lytic activity of KIR-HLA mismatched donor NK against recipient blasts. To mimic this effect with a pharmaceutical agent, a fully human IgG4 anti-KIR mAb specific for KIR2DL1/2/3 (HLA-C specific KIRs) was generated. We present the results of the first-in-human phase I trial of this agent in patients with AML in complete remission (CR). Methods: Patients aged 60–80 years with non promyelocytic AML in first CR following induction and 1–6 cycles of consolidation chemotherapy, normal renal, and hepatic functions, KIR-expression on patient NK-cells and who signed informed consent were eligible.Dose escalation (0.0003, 0.003, 0.015, 0.075, 0.3, 1, 3 mg/kg) was studied using a 3+3 scheme. Pharmacokinetic (PK) and circulating cytokines (MIP1β, TNF) were measured by ELISA. KIR occupancy and activation markers (CD69) were monitored by flow cytometry. Results: To date, inclusion has been completed until 1mg/kg cohort. Data of the first 15 patients (end of 0.3 mg/kg cohort) are available. No dose limiting toxicity has been observed. Side effects that could be related to drug administration were mild and transient. The first dose level resulted in a transient KIR occupancy ranging from 20 to 50%. PK values were then in line with modelling data, resulting at 0.3 mg/kg in a Cmax= 6350 ± 504 ng/mL, >80% KIR saturation for one week, and desaturation in the following week. As expected for an IgG4, NK cell numbers were unaffected by the treatment. Upregulation of CD69 on NK cells and concomitant increases in TNF and MIP1b circulating cytokines were observed in some patients at the highest doses (0.075, 0.1, 0.3 mg/kg) but a dose dependency has not been reached yet. Conclusions: Anti-KIR treatment is safe and well tolerated to date. At the 0.3mg/kg dose, MTD has not been reached, but a one week receptor blockade and signs of NK activation were observed. [Table: see text]
35. A Phase I Study of the Anti-Natural Killer Inhibitory Receptor (KIR) Monoclonal Antibody (1-7F9, IPH2101) in Elderly Patients with Acute Myeloid Leukemia (AML): Clinical and Immunological Effects of a Single Dose Followed by Repeated Dosing
- Author
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Patrick Squiban, Aude Charbonnier, Pascale Andre, Jerome Tiollier, Daniel Olive, Dominique Bordessoule, Norbert Vey, Jean-Henri Bourhis, François Romagné, Stéphane de Botton, Christine d’Arnoux, Didier Blaise, Thomas Prebet, Nicolas Boissel, and Hervé Dombret
- Subjects
biology ,business.industry ,medicine.medical_treatment ,Immunology ,Cmax ,Cell Biology ,Hematology ,Immunotherapy ,Pharmacology ,NKG2D ,Biochemistry ,Transplantation ,Pharmacokinetics ,biology.protein ,Medicine ,Antibody ,Adverse effect ,business ,Ex vivo - Abstract
Abstract 632 Background: Non cytotoxic treatments such as immunotherapy represent promising approaches for the post-remission therapy of elderly patients with AML for which relapse free survival is short. The therapeutic potential of natural Killer (NK) cells has been revealed by the KIR mismatch allogeneic transplant model where the anti-leukemic effect of the graft is due to unleashed NK cells towards AML blasts, as suggested by enhanced in vitro NK lytic activity of KIR-HLA mismatched donor NK against recipient blasts (Miller et al. 2005; Ruggeri et al. 2002). To mimic this effect with a pharmaceutical agent, a fully human IgG4 anti-KIR mAb specific for KIR2DL1/2/3 (HLA-C specific KIRs), the 1-7F9/IPH2101, was generated (Romagne et al., Blood 2009). We present the results of the First in Human phase I trial of this agent in patients with AML in complete remission (CR). Methods: Patients aged 60-80 years with non promyelocytic AML in first CR following induction and 1-6 cycles of consolidation chemotherapy, normal renal and hepatic functions, KIR-expression on NK-cells and who signed informed consent were eligible for Protocol IPH2101-101. Dose escalation (IPH2101: 0.0003, 0.003, 0.015, 0.075, 0.3, 1, 3 mg/kg as iv infusion) was studied using a 3+3 scheme. Patients still in CR who had tolerated the single dose administration were eligible for an extension trial (Protocol IPH2101-102) investigating repeated doses of IPH2101 (1/ month x 6 months) using the dose the patient was allocated to in protocol IPH2101-101. Pharmacokinetic (PK) and circulating cytokines (IL-1b, IL-6, IFN-g, MIP-1β and TNF-a) were measured by ELISA. KIR occupancy and activation markers (CD69) were monitored by flow cytometry. Results: 23 patients, median age 71 years (range 61-79) in first CR of AML for a median of 20 weeks have been included in IPH2101-101. 3 patients (13%) had achieved CR after 2 induction courses, 5 patients (22%) had unfavorable cytogenetics, and 5 patients (22%) had high WBC at diagnosis. Planned dose escalation has been completed and no Dose Limiting Toxicity (DLT) has been recorded. 2 patients (in DL 4 and 5) have been replaced (one relapsed before 4 weeks of follow-up; the other had no detectable antibody after injection). Related Adverse Events seen in 14/23 patients (61%) were mild (grade ≤2) and transient. For doses above 0.075 mg/kg, ½ life ranged between 11-28 days. For doses above 0.3mg/kg, full saturation (>90% KIR occupancy) has been observed for 28 days to up to 6 weeks (at the 3 mg/kg DL). IPH2101 had no effect on the number and distribution of the peripheral lymphocyte subsets or the expression of NK receptors (KIRs, CD94/NKG2A, CD85j, NKp46, NKp30 or NKG2D). NK cell function tested by ex vivo cytotoxicity assay was not impaired after treatment. From dose 1 mg/kg (5/6 patients), IL-1b and IL-6 increased 6h post-dosing (2 to 8 fold increase and 2 to 15 fold increase compare to pre-dose, respectively) and decreased to pre-dose concentrations within 24h. Furthermore increase in TNF-a during the first hour was often correlated with CD69 up-regulation on NK cells. 8 patients received repeated doses of IPH2101 (0.0003 mg/kg: 2 patients, 0.003 mg/kg: 2 patients, 0.015 mg/kg: 1 patient, 1 mg/kg: 3 patients, 3 mg/kg pending) as part of the extension trial. No grade 3-4 related toxicities were observed. 2 patients completed the 6 courses, 5 patients were withdrawn for relapse and 1 patient is still ongoing at 1mg/kg. In accordance with the pre-clinical PK/PD model there is a clear relationship between exposure (Cmax) and KIR occupancy. Moreover the inter-patient variability is low (PK data) to moderate (KIR occupancy data). Median follow-up is 47 weeks. Among the 21 evaluable patients 11 patients are alive, 15 relapsed with 10 death, 6 are still in remission (1 patient in DL1, 2 patients in DL6 and 3 patients in DL7). Conclusions: Anti KIR treatment is safe and well tolerated and MTD has not been reached for doses producing full KIR saturation for 4 weeks, confirming the specificity of the immunological effects. Retreatment for prolonged period of time is feasible and safe. Signs of NK cell activation can be observed for doses above 0.3 mg/kg. IPH2101 deserves further investigation in patients with AML. Disclosures: Vey: INNATE PHARMA: Consultancy. d'Arnoux:INNATE PHARMA: Employment. Romagne:INNATE PHARMA: Employment. Andre:INNATE PHARMA: Employment. Tiollier:INNATE PHARMA: Employment. Squiban:INNATE PHARMA: Employment. Blaise:INNATE PHARMA: Consultancy. Olive:INNATE PHARMA: Research Funding.
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