A phase I, open label, dose escalation and cohort expansion study to evaluate the safety and immune response to autologous dendritic cells (DC) transduced with AdGMCA9 (DC-AdGMCAIX) in patients with mRCC.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 490-490 ◽  
Author(s):  
Fairooz F. Kabbinavar ◽  
Nazy Zomorodian ◽  
Arie S. Belldegrun ◽  
Steven G. Wong ◽  
Adrian Bot ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Dose Escalation ◽  
Clear Cell ◽  
Fusion Gene ◽  
Recombinant Adenovirus ◽  
Ex Vivo ◽  
Open Label ◽  
Antitumor Effects ◽  
Expansion Cohort

490 Background: Carbonic anhydrase IX (CAIX) is an attractive target for the development of a RCC specific vaccine. We developed a fusion gene construct, GM-CSF + CAIX, transduced by a replication deficient adenovirus into autologous dendritic cells (DC) that are injected in patients with mRCC. This is a ph1 study of cancer vaccine against CAIX gene expressed on RCC tumors. Methods: A recombinant adenovirus encoding the GMCSF-CAIX fusion gene (AdGMCAIX) was produced per GMP in collaboration with the NCI RAID program. The final product is produced in an in-house GMP cell processing facility using DCs cultured ex vivo from patients’ PBMC's and engineered with AdGMCAIX prior to intradermal injection. The transduced DCs are expected to stimulate an antigen specific immune response against CAIX expressing RCC, leading to a potential anti-tumor effect. Dose escalation in 3 dose cohorts (5 X 106, 15 X 106, and 50 X 106 cells/administration) follows the std 3+3 ph1 design with an expansion cohort. DC-AdGMCAIX is given intradermally Q 2 weeks X 3 doses. The primary aim is safety of DC-AdGMCAIX injections. Secondary aims are to evaluate immune responses & the antitumor effects per RECIST 1.1. Pts with clear cell mRCC with ECOG 0-1 & measurable disease & adequate organ function were enrolled. Results: Six pts with clear cell mRCC are enrolled. Four pts received all 3 planned vaccine doses and the fifth pt only the 1st dose. No SAE’s were seen to date. One pt had chills that lasted several minutes and transient Gr1 leucopenia. One pt has worsening of pre-existing proteinuria, though unclear if related to the vaccine. One pt has PD & the other two have SD on D85 scans. Tumor bx shows intra-tumoral infiltration by T cells. Conclusions: These early data show that autologous DC transduced by Ad-GMCAIX vector can be safely given to mRCC patients without any acute SAE’s noted at the doses tested so far. The study will complete its 3rd cohort & expansion cohort enrollment. This data support the further development of Ad-GMCAIX vaccine strategies either alone or in combination with approved therapies. Funding: Supported by NCI RAID Initiative NSC 740833 and Kite Pharma.

A phase I, open-label, dose-escalation and cohort expansion study evaluating the safety and immune response to autologous dendritic cells transduced with AdGMCA9 in patients with metastatic renal cell carcinoma.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 653-653
Author(s):  
Izak Faiena ◽  
Nazy Zomorodian ◽  
Begonya Comin-Anduix ◽  
Ankush Sachadeva ◽  
Adrian Bot ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Clear Cell ◽  
Fusion Gene ◽  
Recombinant Adenovirus ◽  
Antitumor Effects ◽  
Gm Csf

653 Background: We developed a fusion gene construct, GM-CSF + CAIX, transduced by a replication deficient adenovirus into autologous dendritic cells (DC) that are injected in patients with metastatic RCC (mRCC) in this phase 1 study targeting CAIX overexpressed on RCC tumors. Methods: A recombinant adenovirus encoding the GMCSF-CAIX fusion gene (AdGMCAIX) manufactured per GMP in collaboration with the NCI Rapid Access to Intervention Development (RAID) program. The final product was produced using DCs produced ex-vivo from patients’ peripheral blood mononuclear cells (PBMC), by culturing with GM-CSF & IL-4, then engineered with AdGMCAIX prior to intradermal injection. The injected transduced DCs were expected to stimulate an antigen specific immune response against CAIX expressing RCC. Three dose escalation cohorts (5, 15, and 50 X 106 cells/administration) were injected based on 3+3 design. DC-AdGMCAIX was given intradermally q2wkX3 doses. The primary aim is safety. Secondary aims are to evaluate immune responses & antitumor effects per RECIST 1.1. Eligibility criteria included patients with clear cell mRCC with ECOG 0-1, measurable disease, and adequate organ function. Results: Fifteen patients with clear cell mRCC were enrolled. Nine patients received all 3 planned vaccine doses, comprising DC expressing CAIX, CD11c and other relevant markers. No serious adverse events (SAEs) were seen. Grade 1/2 AEs include fatigue (3/1), leukopenia (1/1) and flu-like symptoms (0/1). Of the 9 patients who received treatment, 1 expired of progressive disease (PD), 2 patients were lost to follow-up and 6 patients are alive. Of the 6 patients, 5 have PD and are currently receiving standard-of-care therapies, and 1 has completed treatment with stable disease at 6 mon follow up and is being evaluated for retreatment. Conclusions: These early data show that autologous DC transduced by Ad-GMCAIX vector can be safely given to mRCC patients without any SAEs noted at the doses tested. These data support further development of Ad-GMCAIX vaccine strategies, either alone, or in combination with approved therapies. Clinical trial information: NCT01826877.

scholarly journals Distinct Roles of Adenovirus Vector-Transduced Dendritic Cells, Myoblasts, and Endothelial Cells in Mediating an Immune Response against a Transgene Product

2002 ◽  
Vol 76 (6) ◽  
pp. 2899-2911 ◽  
Author(s):  
Stéphanie Mercier ◽  
Hanne Gahéry-Segard ◽  
Martine Monteil ◽  
Renée Lengagne ◽  
Jean-Gérard Guillet ◽  
...  
Keyword(s):  
Immune Response ◽  
Endothelial Cells ◽  
Dendritic Cells ◽  
Recombinant Adenovirus ◽  
Ex Vivo ◽  
Adenovirus Vector ◽  
Cell Types ◽  
T Cell Response ◽  
Specific Response ◽  
Melanoma Tumor

ABSTRACT Adenovirus-mediated gene delivery via the intramuscular route efficiently promotes an immune response against the transgene product. In this study, a recombinant adenovirus vector encoding β-galactosidase (AdβGal) was used to transduce dendritic cells (DC), which are antigen-presenting cells, as well as myoblasts and endothelial cells (EC), neither of which present antigens. C57BL/6 mice received a single intramuscular injection of AdβGal-transduced DC, EC, or myoblasts and were then monitored for anti-β-galactosidase (anti-β-Gal) antibody production, induction of gamma interferon-secreting CD8+ T cells, and protection against melanoma tumor cells expressing β-Gal. While all transduced cell types were able to elicit an antibody response against the transgene product, the specific isotypes were distinct, with exclusive production of immunoglobulin G2a (IgG2a) antibodies following injection of transduced DC and EC versus equivalent IgG1 and IgG2a responses in mice inoculated with transduced myoblasts. Transduced DC induced a strong ex vivo CD8+ T-cell response at a level of 50% of the specific response obtained with the AdβGal control. In contrast, this response was 6- to 10-fold-lower in animals injected with transduced myoblasts and EC. Accordingly, only animals injected with transduced DC were protected against a β-Gal tumor challenge. Thus, in order to induce a strong and protective immune response to an adenovirus-encoded transgene product, it is necessary to transduce cells of dendritic lineage. Importantly, it will be advantageous to block the transduction of DC for adenovirus-based gene therapy strategies.

Dendritic Cells Derived In Vitro From Acute Myelogenous Leukemia Cells Stimulate Autologous, Antileukemic T-Cell Responses

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 780-786 ◽  
Author(s):  
A. Choudhury ◽  
J.C. Liang ◽  
E.K. Thomas ◽  
L. Flores-Romo ◽  
Q.S. Xie ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Acute Myelogenous Leukemia ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Ex Vivo ◽  
Myelogenous Leukemia ◽  
Interleukin 4 ◽  
Acute Myelogenous

Abstract We have previously reported that leukemic dendritic cells (DC) can be generated ex vivo from myelomonocytic precursors in chronic myelogenous leukemia. In this study we report the generation of DC from acute myelogenous leukemia (AML) cells and their potent ability to stimulate leukemia-specific cytolytic activity in autologous lymphocytes. DC were generated in vitro using granulocyte-macrophage colony-stimulating factor +interleukin-4 in combination with either tumor necrosis factor- or CD40 ligand (CD40L). Cells from 19 AML patients with a variety of chromosomal abnormalities were studied for their ability to generate DC. In all but 1 case, cells with the morphology, phenotypic characteristics, and T-cell stimulatory properties of DC could be generated. These cells expressed high levels of major histocompatibility complex class I and class II antigens as well as the costimulatory molecules B7-2 and ICAM-1. In three cases these cells were determined to be of leukemic origin by fluorescence in situ hybridization for chromosomal abnormalities or Western blotting for the inv(16) fusion gene product. Autologous lymphocytes cocultured with AML-derived DC (DC-AL) were able to lyse autologous leukemia targets, whereas little cytotoxicity was noted against autologous, normal cells obtained from the patients during remission. We conclude that leukemia derived DC may be useful for immunotherapy of many AML patients.

Dendritic Cells Derived In Vitro From Acute Myelogenous Leukemia Cells Stimulate Autologous, Antileukemic T-Cell Responses

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 780-786 ◽  
Author(s):  
A. Choudhury ◽  
J.C. Liang ◽  
E.K. Thomas ◽  
L. Flores-Romo ◽  
Q.S. Xie ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Acute Myelogenous Leukemia ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Ex Vivo ◽  
Myelogenous Leukemia ◽  
Interleukin 4 ◽  
Acute Myelogenous

We have previously reported that leukemic dendritic cells (DC) can be generated ex vivo from myelomonocytic precursors in chronic myelogenous leukemia. In this study we report the generation of DC from acute myelogenous leukemia (AML) cells and their potent ability to stimulate leukemia-specific cytolytic activity in autologous lymphocytes. DC were generated in vitro using granulocyte-macrophage colony-stimulating factor +interleukin-4 in combination with either tumor necrosis factor- or CD40 ligand (CD40L). Cells from 19 AML patients with a variety of chromosomal abnormalities were studied for their ability to generate DC. In all but 1 case, cells with the morphology, phenotypic characteristics, and T-cell stimulatory properties of DC could be generated. These cells expressed high levels of major histocompatibility complex class I and class II antigens as well as the costimulatory molecules B7-2 and ICAM-1. In three cases these cells were determined to be of leukemic origin by fluorescence in situ hybridization for chromosomal abnormalities or Western blotting for the inv(16) fusion gene product. Autologous lymphocytes cocultured with AML-derived DC (DC-AL) were able to lyse autologous leukemia targets, whereas little cytotoxicity was noted against autologous, normal cells obtained from the patients during remission. We conclude that leukemia derived DC may be useful for immunotherapy of many AML patients.

scholarly journals Safety and activity of IT-139, a ruthenium-based compound, in patients with advanced solid tumours: a first-in-human, open-label, dose-escalation phase I study with expansion cohort

ESMO Open ◽  
2017 ◽  
Vol 1 (6) ◽  
pp. e000154 ◽  
Author(s):  
Howard A Burris ◽  
Suzanne Bakewell ◽  
Johanna C Bendell ◽  
Jeffrey Infante ◽  
Suzanne F Jones ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Solid Tumours ◽  
Open Label ◽  
Label Dose ◽  
Expansion Cohort

scholarly journals Preferential Infection of Mature Dendritic Cells by Mouse Hepatitis Virus Strain JHM

2006 ◽  
Vol 80 (5) ◽  
pp. 2506-2514 ◽  
Author(s):  
Haixia Zhou ◽  
Stanley Perlman
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Virus Strain ◽  
Hepatitis Virus ◽  
Ex Vivo ◽  
Mouse Hepatitis Virus ◽  
Demyelinating Diseases ◽  
Immature Cells

ABSTRACT Mouse hepatitis virus strain JHM (MHV-JHM) causes acute encephalitis and acute and chronic demyelinating diseases in mice. Dendritic cells (DCs) are key cells in the initiation of innate and adaptive immune responses, and infection of these cells could potentially contribute to a dysregulated immune response; consistent with this, recent results suggest that DCs are readily infected by another strain of mouse hepatitis virus, the A59 strain (MHV-A59). Herein, we show that the JHM strain also productively infected DCs. Moreover, mature DCs were at least 10 times more susceptible than immature DCs to infection with MHV-JHM. DC function was impaired after MHV-JHM infection, resulting in decreased stimulation of CD8 T cells in vitro. Preferential infection of mature DCs was not due to differential expression of the MHV-JHM receptor CEACAM-1a on mature or immature cells or to differences in apoptosis. Although we could not detect infected DCs in vivo, both CD8+ and CD11b+ splenic DCs were susceptible to infection with MHV-JHM directly ex vivo. This preferential infection of mature DCs may inhibit the development of an efficient immune response to the virus.

scholarly journals Nanovaccine impact on dendritic cells: transcriptome analysis enables new insights into antigen and adjuvant effects

Nanomedicine ◽  
2020 ◽  
Vol 15 (21) ◽  
pp. 2053-2069
Author(s):  
David Paßlick ◽  
Jonas Reinholz ◽  
Johanna Simon ◽  
Keti Piradashvili ◽  
Shuai Jiang ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Transcriptome Analysis ◽  
Soluble Form ◽  
Antitumor Effects ◽  
Form Versus ◽  
Interferon Stimulated Genes ◽  
Effective Immune Response ◽  
Adjuvant Effects ◽  
Proteome Expression

Aim: For vaccines the combination between an antigen and adjuvants are both crucially important to trigger an effective immune response in dendritic cells. Innovative adjuvants like resiquimod or muramyldipeptide have their target protein inside the cell. Materials & methods: Up/downregulation and proteome expression was investigated for the adjuvant combination resiquimod and muramyldipeptide in a soluble form versus encapsulated into a nanocarrier. Results: We found that 1225 genes were upregulated after nanocarrier treatment while 478 genes were downregulated. Most prominent were interferon-stimulated genes with more than 25-times higher expression after nanocarrier treatment, for example RSAD2 and ISG15, which were recently found to have antiviral or antitumor effects. Conclusion: Encapsulation gives a more effective upregulation of vaccine-related genes.

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