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Dive into the research topics where Julio Cotte is active.

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Featured researches published by Julio Cotte.


Nature Medicine | 2005

Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer

Aaron P. Rapoport; Edward A. Stadtmauer; Nicole A. Aqui; Ashraf Badros; Julio Cotte; Lisa Chrisley; Elizabeth Veloso; Zhaohui Zheng; Sandra Westphal; Rebecca Mair; Nina Chi; Bashi Ratterree; Mary Francis Pochran; Sabrina Natt; Joanne Hinkle; Cheryl Sickles; Ambika Sohal; Kathleen Ruehle; Christian Lynch; Lei Zhang; David L. Porter; Selina M. Luger; Chuanfa Guo; Hong-Bin Fang; William C. Blackwelder; Kim Hankey; Dean L. Mann; Robert Edelman; Carl E. Frasch; Bruce L. Levine

Immunodeficiency is a barrier to successful vaccination in individuals with cancer and chronic infection. We performed a randomized phase 1/2 study in lymphopenic individuals after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for myeloma. Combination immunotherapy consisting of a single early post-transplant infusion of in vivo vaccine-primed and ex vivo costimulated autologous T cells followed by post-transplant booster immunizations improved the severe immunodeficiency associated with high-dose chemotherapy and led to the induction of clinically relevant immunity in adults within a month after transplantation. Immune assays showed accelerated restoration of CD4 T-cell numbers and function. Early T-cell infusions also resulted in significantly improved T-cell proliferation in response to antigens that were not contained in the vaccine, as assessed by responses to staphylococcal enterotoxin B and cytomegalovirus antigens (P < 0.05). In the setting of lymphopenia, combined vaccine therapy and adoptive T-cell transfer fosters the development of enhanced memory T-cell responses.


Nature Medicine | 2002

Adoptive transfer of costimulated CD4 + T cells induces expansion of peripheral T cells and decreased CCR5 expression in HIV infection

Bruce L. Levine; Wendy B. Bernstein; Naomi Aronson; Katia Schlienger; Julio Cotte; Steven J. Perfetto; Mary J. Humphries; Silvia Ratto-Kim; Deborah L. Birx; Carolyn M. Steffens; Alan Landay; Richard G. Carroll; Carl H. June

To study the safety and feasibility of T-cell reconstitution in HIV-infected individuals, we adoptively transferred activated autologous CD4+ T cells. Polyclonal peripheral blood CD4+ cells were costimulated ex vivo and subjects were given infusions of up to 3 × 1010 activated CD4+ cells. Dose-dependent increases in CD4+ cell counts and in the CD4:CD8 ratio were observed. Sustained increases in the fraction of cytokine-secreting T cells and decreases in the percentage of CD4+CCR5+ cells were noted in vivo, suggesting enhanced function and resistance to HIV infection. The frequency of CD4+Ki-67+ cells increased whereas CD4+ T cells containing T cell–receptor rearrangement excision circles (TRECs) decreased. These findings indicate that expansion of the peripheral T-cell pool mediated the increase in CD4 counts and suggest that approaches to reconstitute CD4 helper cell activity and decrease CCR5 expression may augment natural immunity to HIV infection.


Blood | 2011

Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma

Aaron P. Rapoport; Nicole A. Aqui; Edward A. Stadtmauer; Dan T. Vogl; Hong-Bin Fang; Ling Cai; Stephen Janofsky; Anne Chew; Jan Storek; Gorgun Akpek; Ashraf Badros; Saul Yanovich; Ming Tan; Elizabeth Veloso; Marcela F. Pasetti; Alan S. Cross; Sunita Philip; Heather Murphy; Rita Bhagat; Zhaohui Zheng; Todd Milliron; Julio Cotte; Andrea Cannon; Bruce L. Levine; Robert H. Vonderheide; Carl H. June

In a phase 1/2 two-arm trial, 54 patients with myeloma received autografts followed by ex vivo anti-CD3/anti-CD28 costimulated autologous T cells at day 2 after transplantation. Study patients positive for human leukocyte antigen A2 (arm A, n = 28) also received pneumococcal conjugate vaccine immunizations before and after transplantation and a multipeptide tumor antigen vaccine derived from the human telomerase reverse transcriptase and the antiapoptotic protein survivin. Patients negative for human leukocyte antigen A2 (arm B, n = 26) received the pneumococcal conjugate vaccine only. Patients exhibited robust T-cell recoveries by day 14 with supraphysiologic T-cell counts accompanied by a sustained reduction in regulatory T cells. The median event-free survival (EFS) for all patients is 20 months (95% confidence interval, 14.6-24.7 months); the projected 3-year overall survival is 83%. A subset of patients in arm A (36%) developed immune responses to the tumor antigen vaccine by tetramer assays, but this cohort did not exhibit better EFS. Higher posttransplantation CD4(+) T-cell counts and a lower percentage of FOXP3(+) T cells were associated with improved EFS. Patients exhibited accelerated polyclonal immunoglobulin recovery compared with patients without T-cell transfers. Adoptive transfer of tumor antigen vaccine-primed and costimulated T cells leads to augmented and accelerated cellular and humoral immune reconstitution, including antitumor immunity, after autologous stem cell transplantation for myeloma. This study was registered at www.clinicaltrials.gov as NCT00499577.


Human Gene Therapy | 2013

Efficient clinical scale gene modification via zinc finger nuclease-targeted disruption of the HIV co-receptor CCR5

Dawn A. Maier; Andrea L. Brennan; Shuguang Jiang; Gwendolyn Binder-Scholl; Gary Lee; Gabriela Plesa; Zhaohui Zheng; Julio Cotte; Carmine Carpenito; Travis Wood; S. Kaye Spratt; Dale Ando; Philip D. Gregory; Michael C. Holmes; Elena E. Perez; James L. Riley; Richard G. Carroll; Carl H. June; Bruce L. Levine

Since HIV requires CD4 and a co-receptor, most commonly C-C chemokine receptor 5 (CCR5), for cellular entry, targeting CCR5 expression is an attractive approach for therapy of HIV infection. Treatment of CD4(+) T cells with zinc-finger protein nucleases (ZFNs) specifically disrupting chemokine receptor CCR5 coding sequences induces resistance to HIV infection in vitro and in vivo. A chimeric Ad5/F35 adenoviral vector encoding CCR5-ZFNs permitted efficient delivery and transient expression following anti-CD3/anti-CD28 costimulation of T lymphocytes. We present data showing CD3/CD28 costimulation substantially improved transduction efficiency over reported methods for Ad5/F35 transduction of T lymphocytes. Modifications to the laboratory scale process, incorporating clinically compatible reagents and methods, resulted in a robust ex vivo manufacturing process capable of generating >10(10) CCR5 gene-edited CD4+ T cells from healthy and HIV+ donors. CD4+ T-cell phenotype, cytokine production, and repertoire were comparable between ZFN-modified and control cells. Following consultation with regulatory authorities, we conducted in vivo toxicity studies that showed no detectable ZFN-specific toxicity or T-cell transformation. Based on these findings, we initiated a clinical trial testing the safety and feasibility of CCR5 gene-edited CD4+ T-cell transfer in study subjects with HIV-1 infection.


Clinical Cancer Research | 2009

Rapid Immune Recovery and Graft-versus-Host Disease ^ like Engraftment Syndrome following Adoptive Transfer of Costimulated Autologous T Cells

Aaron P. Rapoport; Edward A. Stadtmauer; Nicole A. Aqui; Dan T. Vogl; Anne Chew; Hong-Bin Fang; Stephen Janofsky; Kelly Yager; Elizabeth Veloso; Zhaohui Zheng; Todd Milliron; Sandra Westphal; Julio Cotte; Hong Huynh; Andrea Cannon; Saul Yanovich; Gorgun Akpek; Ming Tan; Kristen Virts; Kathleen Ruehle; Carolynn Harris; Sunita Philip; Robert H. Vonderheide; Bruce L. Levine; Carl H. June

Purpose: Previously, we showed that adoptive transfer of in vivo vaccine-primed and ex vivo (anti-CD3/anti-CD28) costimulated autologous T cells (ex-T) at day +12 after transplant increased CD4 and CD8 T-cell counts at day +42 and augmented vaccine-specific immune responses in patients with myeloma. Here, we investigated the safety and kinetics of T-cell recovery after infusing ex-T at day +2 after transplant. Experimental Design: In this phase I/II two-arm clinical trial, 50 patients with myeloma received autografts after high-dose melphalan followed by infusions of ex-T at day +2 after transplant. Patients also received pretransplant and posttransplant immunizations using a pneumococcal conjugate vaccine only (arm B; n = 24) or the pneumococcal conjugate vaccine plus an HLA-A2–restricted multipeptide vaccine for HLA-A2+ patients (arm A; n = 26). Results: The mean number of T cells infused was 4.26 × 1010 (range, 1.59-5.0). At day 14 after transplant, the median CD3, CD4, and CD8 counts were 4,198, 1,545, and 2,858 cells/μL, respectively. Interleukin (IL)-6 and IL-15 levels increased early after transplant and IL-15 levels correlated significantly to day 14 T-cell counts. Robust vaccine-specific B- and T-cell responses were generated. T-cell infusions were well tolerated with no effect on hematopoietic recovery. Eight patients (16%) developed a T-cell “engraftment syndrome” characterized by diarrhea and fever that was clinically and histopathologically indistinguishable from grade 1 to 3 acute graft-versus-host disease (GVHD) of the gastrointestinal tract (seven patients) and/or grade 1 to 2 cutaneous GVHD (four patients). Conclusions: Adoptive T-cell transfers achieve robust T-cell recovery early after transplant and induce moderate-to-severe autologous GVHD in a subset of patients.


Blood | 2013

Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV.

Pablo Tebas; David Stein; Gwendolyn Binder-Scholl; Rithun Mukherjee; Troy Brady; Tessio Rebello; Laurent Humeau; Michael Kalos; Emmanouil Papasavvas; Luis J. Montaner; Daniel Schullery; Farida Shaheen; Andrea L. Brennan; Zhaohui Zheng; Julio Cotte; Vladimir Slepushkin; Elizabeth Veloso; Adonna Mackley; Wei-Ting Hwang; Faten Aberra; Jenny Zhan; Jean D. Boyer; Ronald G. Collman; Frederic D. Bushman; Bruce L. Levine; Carl H. June

We report the safety and tolerability of 87 infusions of lentiviral vector–modified autologous CD4 T cells (VRX496-T; trade name, Lexgenleucel-T) in 17 HIV patients with well-controlled viremia. Antiviral effects were studied during analytic treatment interruption in a subset of 13 patients. VRX496-T was associated with a decrease in viral load set points in 6 of 8 subjects (P = .08). In addition, A → G transitions were enriched in HIV sequences after infusion, which is consistent with a model in which transduced CD4 T cells exert antisense-mediated genetic pressure on HIV during infection. Engraftment of vector-modified CD4 T cells was measured in gut-associated lymphoid tissue and was correlated with engraftment in blood. The engraftment half-life in the blood was approximately 5 weeks, with stable persistence in some patients for up to 5 years. Conditional replication of VRX496 was detected periodically through 1 year after infusion. No evidence of clonal selection of lentiviral vector–transduced T cells or integration enrichment near oncogenes was detected. This is the first demonstration that gene-modified cells can exert genetic pressure on HIV. We conclude that gene-modified T cells have the potential to decrease the fitness of HIV-1 and conditionally replicative lentiviral vectors have a promising safety profile in T cells.


Cytotherapy | 2009

Efficient clinical-scale enrichment of lymphocytes for use in adoptive immunotherapy using a modified counterflow centrifugal elutriation program

Daniel J. Powell; Andrea L. Brennan; Zhaohui Zheng; Hong Huynh; Julio Cotte; Bruce L. Levine

BACKGROUND AIMS Clinical-scale lymphocyte enrichment from a leukapheresis product has been performed most routinely using costly magnetic bead separation systems that deplete monocytes, but this procedure may leave behind residual beads or antibodies in the enriched cell product. Counterflow centrifugal elutriation has been demonstrated previously to enrich monocytes efficiently for generation of dendritic cells. This study describes a modified elutriation procedure for efficient bead-free economical enrichment of lymphocytes from leukapheresis products from healthy donors and study subjects with human immunodeficiency virus (HIV) infection or malignancy. METHODS Modified program settings and conditions for the CaridianBCT Elutra device were investigated to optimize lymphocyte enrichment and recovery. Lymphocyte enrichment was measured using a novel approach utilizing cell sizing analysis on a Beckman Coulter Multisizer and confirmed by flow cytometry phenotypic analysis. RESULTS Efficient enrichment and recovery of lymphocytes from leukapheresis cell products was achieved using modified elutriation settings for flow rate and fraction volume. Elutriation allowed for enrichment of larger numbers of lymphocytes compared with depletion of monocytes by bead adherence, with a trend toward increased lymphocyte purity and yield via elutriation, resulting in a substantial reduction in the cost of enrichment per cell. Importantly, significant lymphocyte enrichment could be accomplished using leukapheresis samples from healthy donors (n=12) or from study subjects with HIV infection (n=15) or malignancy (n=12). CONCLUSIONS Clinical-scale closed-system elutriation can be performed efficiently for the selective enrichment of lymphocytes for immunotherapy protocols. This represents an improvement in cost, yield and purity over current methods that require the addition of monocyte-depleting beads.


Blood | 2003

Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected hematopoietic cell transplantation.

Ginna G. Laport; Bruce L. Levine; Edward A. Stadtmauer; Stephen J. Schuster; Selina M. Luger; Stephan A. Grupp; Nancy Bunin; Frank J. Strobl; Julio Cotte; Zhaohui Zheng; Brian P. Gregson; Patricia M. Rivers; Robert H. Vonderheide; David Liebowitz; David L. Porter; Carl H. June


Journal of hematotherapy | 1998

Large-Scale Production of CD4+ T Cells from HIV-1-Infected Donors After CD3/CD28 Costimulation*

Bruce L. Levine; Julio Cotte; Carolynn C. Small; Richard G. Carroll; James L. Riley; Wendy B. Bernstein; Dennis E. Van Epps; R. Alan Hardwick; Carl H. June


Clinical Immunology | 2004

Immune reconstitution following autologous transfers of CD3/CD28 stimulated CD4+ T cells to HIV-infected persons ☆

Wendy B. Bernstein; Josephine H. Cox; Naomi Aronson; LaRee Tracy; Katia Schlienger; Silvia Ratto-Kim; Robin P. Garner; Julio Cotte; Zhaohui Zheng; Lena E. Winestone; Caroline Liebig; Lynee M. Galley; Mark Connors; Deborah L. Birx; Richard G. Carroll; Bruce L. Levine

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Bruce L. Levine

University of Pennsylvania

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Carl H. June

University of Pennsylvania

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Zhaohui Zheng

University of Pennsylvania

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Elizabeth Veloso

University of Pennsylvania

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Andrea L. Brennan

University of Pennsylvania

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Gorgun Akpek

Rush University Medical Center

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Nicole A. Aqui

University of Pennsylvania

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