Functional Dendritic Cells can be Derived from hES Using Scalable Production
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These findings support the use of hESC-derived DCs in therapeutic vaccine applications for cancer and other diseases. Substituting standardized, off-the-shelf hESC-derived DCs for current approaches using DCs obtained from individual patients may result in more cost effective and reliable approaches to cancer immunotherapy.
The study, authored by Geron scientists and collaborators Prof. Waldmann and Dr. Fairchild at the Sir William Dunn School of Pathology, University of Oxford, appears online in advance of print in the journal Regenerative Medicine.
Dendritic cells (DCs) are immune cells that detect pathogens (e.g. viruses or bacteria) and activate other immune cells (called T-cells) to launch an immune attack against the pathogen. DCs reside in small numbers within most tissues, particularly where there is contact with the external environment, such as the skin or gut. DCs will engulf and digest a foreign pathogen and present pieces of pathogen proteins (known as antigens) on the cell surface. The presentation of antigen by DCs activates the T-cell immune response directed against that pathogen. In a similar manner, dendritic cells can also educate the immune system to initiate an immune response against aberrant cells in the body, such as tumor cells.
The data in the Regenerative Medicine publication show that immature hESC-derived DCs are able to take up, process and present antigens, and then, following maturation in the manufacturing process, are able to migrate, produce pro-inflammatory cytokines and induce specific immune responses to both tumor and viral antigens in vitro. These data show that hESC-derived DCs display the functions of human DCs taken from the bloodstream.
The potential for DCs to stimulate potent and specific immune responses is being explored in clinical trials of DC vaccination protocols for the treatment of malignant and infectious diseases. “We are using a DC platform with our cancer vaccine directed against telomerase, GRNVAC1, currently in Phase II studies in AML,” said Thomas B. Okarma, Ph.D., M.D., Geron's president and chief executive officer. “However, GRNVAC1 and other therapies currently in development, use DCs that are generated from individual patients. Autologous cell treatments are costly to manufacture and difficult to control. Variation
between individuals and the effects of their disease and prior treatments can affect vaccine potency. We are therefore developing a second generation cancer vaccine, GRNVAC2, based on DCs derived from hESCs to generate a scalable, reliable, off-the-shelf product, free from individual patient variability.”
“The data in the current study demonstrate that DCs derived from hESCs are immunogenic and can be developed as a scalable and consistent source of DCs for immunotherapies,” said Jane S. Lebkowski, Geron’s senior vice president and chief scientific officer for regenerative medicine. “Importantly, the production protocol is defined, and does not use serum or feeder cells, an important condition for large scale production and therapeutic development.”
The defined protocol for generating hESC-derived DCs described in the current study is a stepwise process in which hESCs are first differentiated into monocytic cells, and then converted to immature DCs. Subsequent exposure to a cocktail of maturation factors generates mature hESC-derived DCs that express surface proteins and morphological characteristics typical of mature DCs derived from peripheral blood monocytes (PBM).
The data in this study show that mature hESC-derived DCs produce a number of cytokines important for T-cell stimulation, including IL-12p70, and stimulate allogeneic T-cell proliferation when co-cultured with peripheral blood mononuclear cells in a mixed leukocyte response (MLR) assay. Another key function of DCs is their ability to migrate from the site of antigen uptake to the lymph nodes in response to chemical signals. Migratory response of mature hESC-derived DCs was comparable to PBM-derived DCs in an in vitro chemotactic assay using the chemokine MIP3ß.
When a dendritic cell presents an antigen to a T-cell in vivo, it stimulates the T-cell to produce inflammatory cytokines and causes antigen-specific T-cell proliferation. In the current study using mumps, cytomegalovirus, and telomerase antigens in three separate series of experiments, the hESC-derived DCs stimulated antigen specific T-cell proliferation in each case, a prerequisite for effective in vivo immunotherapy.
“We are very enthusiastic about these data”, said Paul J. Fairchild, Ph.D., Co-Director of the Oxford Stem Cell Institute, within the James Martin 21st Century School, University of Oxford. “Allogeneic dendritic cells have great potential as a new vaccine and immunotherapy platform that could have therapeutic value across a range of infectious diseases as well as cancer.”
Geron holds a broad-ranging intellectual property portfolio relating to DC-based immunotherapies. The portfolio includes a worldwide exclusive license to patents owned by the University of Oxford covering the differentiation of DCs from hESCs, and Geron’s own patent filings for optimized and scalable productionmethods of hESC-derived DCs. It also includes co-exclusive rights to patents owned by the Rockefeller University covering methods relating to maturation of DCs in vitro as well as patents owned by Duke University covering the introduction of antigen encoding mRNA into dendritic cells for immunotherapeutic applications. These co-exclusive rights were conveyed to Geron in a 2004 license agreement with Argos Therapeutics (formerly Merix BioScience, Inc.). In addition, Geron owns intellectual property rights covering key aspects of scalable manufacturing of hESCs as well as a license to foundational hESC patents held by the Wisconsin Alumni Research Foundation.
The abstract of the publication is available at http://www.futuremedicine.com/doi/abs/10.2217/rme.09.25.