Open AccessJournal Article
Bioactivity of Autologous Irradiated Renal Cell Carcinoma Vaccines Generated by ex Vivo Granulocyte-Macrophage Colony-stimulating Factor Gene Transfer
Jonathan W. Simons,Elizabeth M. Jaffee,Christine E. Weber,Hyam I. Levitsky,William G. Nelson,Michael A. Carducci,Audrey J. Lazenby,Lawrence K. Cohen,Christy C. Finn,Shirley M. Clift,Karen M. Hauda,Lisa A. Beck,Kristin M. Leiferman,Albert H. Owens,Steven Piantadosi,Glenn Dranoff,Richard C. Mulligan,Drew M. Pardoll,Fray F. Marshall +18 more
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TLDR
This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.Abstract:
Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose-escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication-defective retroviral vector MFG was used for GM-CSF gene transfer. No dose-limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.read more
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References
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A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma
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TL;DR: In this paper, a gene was identified that directed the expression of antigen MZ2-E on a human melanoma cell line, which belongs to a family of at least three genes.
Journal ArticleDOI
Vaccination with Irradiated Tumor Cells Engineered to Secrete Murine Granulocyte-Macrophage Colony-Stimulating Factor Stimulates Potent, Specific, and Long-Lasting Anti-Tumor Immunity
Glenn Dranoff,Elizabeth M. Jaffee,Audrey J. Lazenby,Paul Golumbek,Hyam I. Levitsky,Katja Brose,Valerie Jackson,Hirofumi Hamada,Drew M. Pardoll,Richard C. Mulligan +9 more
TL;DR: The results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines and the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone.
Journal ArticleDOI
The Basic Science of Gene Therapy
TL;DR: A large number of key technical issues need to be resolved before gene therapy can be safely and effectively applied in the clinic, and future technological developments will be critical for the successful practice of gene therapy.
Journal ArticleDOI
Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens
Alex Yee-Chen Huang,Paul Golumbek,Mojgan Ahmadzadeh,Elizabeth M. Jaffee,Drew M. Pardoll,Hyam I. Levitsky +5 more
TL;DR: MHC class I-restricted antigens are efficiently transferred in vivo to bone marrow-derived antigen-presenting cells, which suggests that human leukocyte antigen matching may be less critical in the application of tumor vaccines than previously thought.