eBriefing

Dendritic Cell Therapies for Cancer: Biotech's Bumpy Road to the Market

Dendritic Cell Therapies for Cancer
Reported by
Jennifer Cable

Posted February 11, 2014

Presented By

Hot Topics in Life Sciences

Overview

Dendritic cell-based cancer vaccines have shown promise in generating an immune response against tumor cells. However, we have yet to establish the best techniques for vaccine development. Research is needed to determine how to mature dendritic cells, as well as to find the most effective antigens and routes of administration. On October 28, 2013, researchers from biotech and academia convened at the New York Academy of Sciences to discuss the history and the future of dendritic cell vaccines. This Hot Topics in Life Sciences symposium, Clinical Trials of Dendritic Cell Therapies for Cancer: Biotech's Bumpy Road to the Market, highlighted the unique challenges that must be surmounted to bring these therapies to market. The speakers presented different approaches to dendritic cell vaccine development, as well as recent clinical data in various types of cancer.

Use the tabs above to find a meeting report and multimedia from this event.

Presentations available from:
Richard L. Edelson, MD (Yale School of Medicine)
Edgar G. Engleman, MD (Stanford University School of Medicine)
Thomas Felzmann, MD (Activartis Biotech GmbH, Austria)
John E. Hambor, PhD (Boehringer Ingelheim Pharmaceuticals)
Lana E. Kandalaft, PharmD, MTR, PhD (University of Pennsylvania)
Matthew Lehman (Prima BioMed, Australia)
Gregory Lizée, PhD (MD Anderson Cancer Center)
Charles A. Nicolette, PhD (Argos Therapeutics Inc.)
Sarah J. Schlesinger, MD (The Rockefeller University)
Adam Steinman
Kris Thielemans, MD, PhD (Vrije Universiteit Brussel, Belgium)
John S. Yu, MD (Cedars-Sinai Medical Center; Immunocellular Therapeutics Ltd.)


Mission Partner support for the Frontiers of Science program provided by Pfizer

Journal Articles

Approved dendritic cell-based therapy: sipuleucel-t

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Fong L, Hou Y, Rivas A, et al. Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci U S A. 2001;98(15):8809-14.

Furumoto K, Soares L, Engleman EG, Merad M. Induction of potent antitumor immunity by in situ targeting of intratumoral DCs. J Clin Invest. 2004;113(5):774-83.

Hsu FJ, Benike C, Fagnoni F, et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med. 1996;2(1):52-8.

Lyman SD, James L, Vanden Bos T, et al. Molecular cloning of a ligand for the flt3/flk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells. Cell. 1993;75(6):1157-67.

Markowicz S, Engleman EG. Granulocyte-macrophage colony-stimulating factor promotes differentiation and survival of human peripheral dendritic cells in vitro. J Clin Invest. 1990;85(3):955-61.

Mehta-Damani A, Markowicz S, Engleman EG. Generation of antigen-specific CD8+ CTLs from naive precursors. J Immunol. 1994;153(3):996-1003.

Okano F, Merad N, Furumoto K, Engleman EG. In vivo manipulation of dendritic cells overcomes tolerance to unmodified tumor-associated self antigens and induces potent antitumor immunity. J Immunol. 2005;174(5):2645-52.

Small EJ, Schellhammber PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24(19):3089-94.

Approved dendritic cell-based therapy: extracorporeal photoimmunotherapy

Barr ML, Meiser BM, Eisen HJ, et al. Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis transplantation study group. N Engl J Med. 1998;339(24):1744-51.

Dubernard JM, Lengele B, Morelon E, et al. Outcomes 18 months after the first human partial face transplantation. N Engl J Med. 2007;357(24):2451-60.

Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. N Engl J Med. 1987;316(6):297-303.

Girardi M, Berger CL, Wilson LD, et al. Transimmunization for cutaneous T cell lymphoma: a Phase I study. Leuk Lymphoma. 2006;47(8):1495-1503.

Greinix HT, Volc-Platzer B, Kalhs P, et al. Extracorporeal photochemotherapy in the treatment of severe steroid-refractory acute graft-versus-host disease: a pilot study. Blood. 2000;96(7):2426-31.

Dendritic cell-based therapies for the treatment of glioblastoma multiforme

Dohnal AM, Witt V, Holter W, et al. Phase I study of tumor Ag-loaded IL-12 secreting semi-mature DC for the treatment of pediatric cancer. Cytotherapy. 2007;9(8):755-70.

Felzmann T, Huttner KG, Breuer SK, et al. Semi-mature IL-12 secreting dendritic cells present exogenous antigen to trigger cytolytic immune responses. Cancer Immunol Immunother. 2005;54(8):769-80.

Huttner KG, Breuer SK, Paul P, et al. Generation of potent anti-tumor immunity in mice by interleukin-12-secreting dendritic cells. Cancer Immunol Immunother. 2005;54(1):67-77.

Okada H, Kalinski P, Ueda R, et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J Clin Oncol. 2011;29(3):330-6.

Phuphanich S, Wheeler CJ, Rudnick JD, et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother. 2013;62(1):125-35.

Rebetz J, Tian D, Persson A, et al. Glial progenitor-like phenotype in low-grade glioma and enhanced CD133-expression and neuronal lineage differentiation potential in high-grade glioma. PLoS One. 2008;3(4):e1936.

Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105-11.

Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459-66.

Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-96.

Wheeler CJ, Black KL, Liu G, et al. Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. Cancer Res. 2008;68(14):5955-64.

Xu Q, Liu G, Yuan X, et al. Antigen-specific T-cell response from dendritic cell vaccination using cancer stem-like cell-associated antigens. Stem Cells. 2009;27(8):1734-40.

Yuan X, Curtin J, Xiong Y, et al. Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene. 2004;23(58):9392-400.

Dendritic cell vaccines in ovarian cancer

Adams SF, Levine DA, Cadungog MG, et al. Intraepithelial T cells and tumor proliferation: impact on the benefit from surgical cytoreduction in advanced serous ovarian cancer. Cancer. 2009;115(13):2891-902.

Chiang CL, Hagemann AR, Leskowitz R, et al. Day-4 myeloid dendritic cells pulsed with whole tumor lysate are highly immunogenic and elicit potent anti-tumor responses. PLoS One. 2011;6(12):e28732.

Chiang CL, Kandalaft LE, Tanyi J, et al. A dendritic cell vaccine pulsed with autologous hypochlorous acid-oxidized ovarian cancer lysate primes effective broad antitumor immunity: from bench to beside. Clin Cancer Res. 2013;19(17):4801-15.

Chiang CL, Maier DA, Kandalaft LE, et al. Optimizing parameters for clinical-scale production of high IL-12 secreting dendritic cells pulsed with oxidized whole tumor cell lysate. J Transl Med. 2011;9:198.

Clarke B, Tinker AV, Lee CH, et al. Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss. Mod Pathol. 2009;22(3):393-402.

Edwards RP, Gooding W, Lembersky BC, et al. Comparison of toxicity and survival following intraperitoneal recombinant interleukin-2 for persistent ovarian cancer after platinum: twenty-four-hour versus 7-day infusion. J Clin Oncol. 1997;15(11):3399-3407.

Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A. 2007;104(9):3360-5.

Han LY, Fletcher MS, Urbauer DL, et al. HLA class I antigen processing machinery component expression and intratumoral T-cell infiltrate as independent prognostic markers in ovarian carcinoma. Clin Cancer Res. 2008;14(11):3372-9.

Kandalaft LE, Chiang CL, Tanyi J, et al. A Phase I vaccine trial using dendritic cells pulsed with autologous oxidized lysate for recurrent ovarian cancer. J Transl Med. 2013;11:149.

Kandalaft LE, Powell DJ Jr., Chiang CL, et al. Autologous lysate-pulsed dendritic cell vaccination followed by adoptive transfer of vaccine-primed ex vivo co-stimulated T cells in recurrent ovarian cancer. Oncoimmunology. 2013;2(1):e22664.

Loveland BE, Zhao A, White S, et al. Mannan-MUC1-pulsed dendritic cell immunotherapy: a phase I trial in patients with adenocarcinoma. Clin Cancer Res. 2006;12(3 Pt 1):869-77.

Neller MA, Lopez JA, Schmidt CW. Antigens for cancer immunotherapy. Semin Immunol. 2008;20(5):286-95.

Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A. 2005;102(51):18538-43.

Vaughan S, Coward JI, Bast RC Jr., et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer. 2011;11(10):719-25.

Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348(3):203-13.

Dendritic cell vaccines using mRNA antigens

DeBenedette MA, Calderhead DM, Ketteringham H, et al. Priming of a novel subset of CD28+ rapidly expanding high-avidity effector memory CTL by post maturation electroporation-CD40L dendritic cells is IL-12 dependent. J Immunol. 2008;181(8):5296-305.

DeBenedette MA, Calderhead DM, Tcherepanova IY, et al. Potency of mature CD40L RNA electroporated dendritic cells correlates with IL-12 secretion by tracking multifunctional CD8(+)/CD28(+) cytotoxic T-cell response in vitro. J Immunother. 2011;34(1):45-57.

Motzer RJ, Escudier B, Bukowski R, et al. Prognostic factors for survival in 1059 patients treated with sunitinib for metastatic renal cell carcinoma. Br J Cancer. 2013;108(12):2470-7.

Nicolette CA, Healey D, Tcherepanova I, et al. Dendritic cells for active immunotherapy: optimizing design and manufacture in order to develop commercially and clinically viable products. Vaccine. 2007;25(Suppl 2):B47-B60.

Pal SK, Hu A, Figlin RA. A new age for vaccine therapy in renal cell carcinoma. Cancer J. 2013;19(4):365-70.

Routy JP, Nicolette C. Arcelis AGS-004 dendritic cell-based immunotherapy for HIV infection. Immunotherapy. 2010;2(4):467-76.


Websites

Activartis: An Overview of Studies
Information on the Activartis dendritic cell vaccine, AV0113.

Activartis: GBM-Vax Study – Early Results
Results from the phase II study of AV0113 in glioblastoma.

cureglioma.info
Educational website on brain tumors with full text journal links, created by Michael A. Meyer, MD, University of Buffalo professor of clinical neurology and nuclear medicine.

Immunocellular Therapeutics
Information on ICT-107, ICT-121, and ICT-140 dendritic cell-based vaccines.

Prima BioMed: CVac
Information on Prima BioMed's dendritic cell vaccine, CVac.

Organizers

John E. Hambor, PhD

Boehringer Ingelheim Pharmaceuticals
publications

John E. Hambor is a distinguished research fellow at Boehringer Ingelheim, where he coordinates a strategic postdoctoral research program focused on developing new drug concepts in collaboration with academic investigators. He was previously a consultant with the Cell Therapy Group, specializing in stem cell-based drug discovery; CEO of CellDesign; and a developer of stem cell technologies at Pfizer, where he identified and validated new drug targets in the areas of inflammation and immunology and developed stem cell-based assays for drug efficacy and safety studies. Hambor received an MS in microbiology from Miami University of Ohio and earned a PhD in pathology from Case Western Reserve University. As a postdoctoral fellow at Yale University in the Department of Immunobiology, he researched the molecular basis of CD8 expression during T-cell development. He has been an adjunct assistant professor at Connecticut College since 2000, where he teaches immunology. He also serves as a member of the board of directors for the VA Connecticut Research and Education Foundation.

Jennifer Henry, PhD

The New York Academy of Sciences
 

Jennifer Henry is the director of Life Sciences at the New York Academy of Sciences. Henry joined the Academy in 2009, before which she was a publishing manager in the Academic Journals division at Nature Publishing Group. She also has eight years of direct editorial experience as editor of Functional Plant Biology for CSIRO Publishing in Australia. She received her PhD in plant molecular biology from the University of Melbourne, specializing in the genetic engineering of transgenic crops. As director of Life Sciences, she is responsible for developing scientific symposia across a range of life sciences, including biochemical pharmacology, neuroscience, systems biology, genome integrity, infectious diseases and microbiology. She also generates alliances with organizations interested in developing programmatic content.


Speakers

Richard L. Edelson, MD

Yale School of Medicine
website | publications

Richard L. Edelson is a graduate of the Yale University School of Medicine. He trained in internal medicine at the University of Chicago and in dermatology at Harvard University and completed a dual fellowship in the Immunology Laboratory of the National Institute of Allergy and Infectious Diseases, NIH, and the Medical Oncology Branch of the National Cancer Institute, NIH. He was the originator of extracorporeal photochemo-therapy (ECP), the first FDA-approved cellular immunotherapy for cancer, which to date has been administered as a primary treatment for T-cell lymphoma and as a therapy for graft-versus-host disease and organ transplant rejection. After a decade on the faculty of Columbia University College of Physicians and Surgeons, he relocated to Yale University as professor and chairman of its Department of Dermatology in 1986. He also served as the director of the Yale University Comprehensive Cancer Center from 2003 to 2009. He has organized two past New York Academy of Sciences symposia: Antigen and Clone-Specific Immuno-regulation and Clinically Relevant Basic Biology of Cutaneous T Cell Lymphoma.

Edgar G. Engleman, MD

Stanford University School of Medicine
website | publications

Edgar G. Engleman is a professor of pathology and medicine at Stanford University School of Medicine, where he directs the Stanford Blood Center. The center supplies blood products to Stanford and nearby community hospitals, and performs histocompatibility and genetic testing in support of the organ transplant programs at Stanford. Although his early research was directed at identifying and characterizing subsets of human T cells, for the past 25 years his group has been studying dendritic cell biology. After developing methods for isolating and arming human dendritic cells, he conceived of the idea of using these cells to vaccinate patients against their own tumors. Twenty years ago, Engleman and his collaborators at Stanford began performing dendritic cell trials in cancer patients. Based on encouraging results, he co-founded Dendreon Corporation, a biotech company dedicated to developing dendritic cell-based cancer vaccines. The company's first vaccine, Sipuleucel-T or Provenge, was approved by the FDA in 2010 for the treatment of patients with advanced prostate cancer. Engleman has co-founded several other biotech companies, including Vivo Ventures, an investment firm that invests in biomedical companies in the U.S. and China.

Thomas Felzmann, MD

Activartis Biotech GmbH, Austria
website | publications

Thomas Felzmann holds an MD from the Medical University Wien, Austria, where he also worked as a postdoctoral fellow in the Institute of Immunology. His clinical training in oncology began in 1990, and in 1992 he returned to full-time research as a postdoctoral associate at the NIH. He began training in pediatric oncology in 1995 and was charged with the establishment of the Laboratory of Tumour Immunology at the St. Anna Children's Cancer Research Institute in Austria. Over the next 5 years his team developed a proprietary dendritic cell-based cancer vaccine technology for which patents have since been granted. In 2000 he began conducted a series of trials and in 2010 initiated a randomized efficacy study. Since 2003, the clinical development of the vaccine has been conducted by Activartis.

Lana E. Kandalaft, PharmD, MTR, PhD

University of Pennsylvania
website | publications

Lana E. Kandalaft joined the Ovarian Cancer Research Center at the University of Pennsylvania in 2008 as director of clinical development and operations and as an assistant professor of obstetrics and gynecology with a special focus on whole tumor lysate vaccine development. Kandalaft holds a PharmD from the University of Jordan School of Pharmacy, Jordan, and a PhD in cell biology and drug delivery from the Welsh School of Pharmacy, UK. She also holds a Master's degree in translational research from the University of Pennsylvania. She completed her postdoctoral fellowship training at the National Cancer Institute (NCI), NIH, focusing on preclinical animal models and cancer therapeutics. She continued working at the NCI as a senior research fellow before joining the University of Pennsylvannia. She recently became the director of the Developmental Therapeutics Center at the Department of Oncology and the Ludwig Branch in Switzerland. She continues to be an adjunct assistant professor at the University of Pennsylvania, working on whole tumor lysate vaccine approaches.

Matthew Lehman

Prima BioMed, Australia
website

Matthew Lehman is the CEO of Prima BioMed. He has experience in clinical research, development programs, and obtaining drug approval, with specific expertise in clinical development strategies, operations, and outsourcing. Lehman was previously chief operating officer for Prima BioMed and for SPRI Clinical Trials, where he managed clinical operations. He leads Prima BioMed's research and development plans and clinical trials for the CVac ovarian cancer therapy vaccine. Lehman holds an MS from Columbia University.

Gregory Lizée, PhD

MD Anderson Cancer Center
website | publications

Gregory Lizée earned his PhD at the University of British Columbia, Canada, where he worked on characterizing the role of the MHC class I (MHC-I) cytoplasmic tail in murine antiviral immune responses. He since completed a postdoctoral fellowship at the Surgery Branch of the National Cancer Institute, NIH, led by Dr. Steven Rosenberg and best known for their pioneering immunotherapy trials for the treatment of human cancer. In 2005, Lizée established his own research at the MD Anderson Cancer Center, where he has continued his mechanistic studies on human DC antigen presentation. His work on the motifs within the cytoplasmic domain of MHC-I molecules could have important implications for human cancer vaccines. More recently, Lizée has been focused on identifying MHC-I ligands directly from the surface of patient tumor cell lines and biopsies using a combined approach encompassing MS-based proteomics, genomics, and bioinformatics. The goal of this project is to develop personalized cancer vaccines that are not restricted by tumor type or patient HLA haplotype, or limited by a lack of known target antigens.

Charles A. Nicolette, PhD

Argos Therapeutics Inc.
website | publications

Charles A. Nicolette received his PhD in biochemistry and cellular and developmental biology from the State University of New York at Stony Brook and completed his doctoral dissertation and postdoctoral fellowship at Cold Spring Harbor Laboratory. Nicolette was previously the director of antigen discovery for cancer vaccine development at Genzyme Corporation, where he directed pre-clinical, translational and clinical stage programs for six years. He joined Argos Therapeutics in 2003 and has overseen the development of pipeline products. He is the inventor on dozens of patent applications, primarily relating to vaccine development for malignant and infectious diseases.

Sarah J. Schlesinger, MD

The Rockefeller University
website | publications

Sarah J. Schlesinger is a research associate professor in the laboratory of cellular immunology and physiology at The Rockefeller University and a research scientist at the Aaron Diamond AIDS Research Center, a world-renowned biomedical research institute. Schlesinger has been actively engaged in HIV/AIDS and HIV vaccine research for 10 years. She led the Dendritic Cell Program at the Division of Retrovirology at the Walter Reed Army Institute of Research for 12 years and is now an active member of the research team at Aaron Diamond, working to develop a vaccine to halt the spread of the AIDS epidemic.

Kris Thielemans, MD, PhD

Vrije Universiteit Brussel, Belgium
publications

Kris Thielemans has been one of the first to use dendritic cells for the immunotherapy of cancer in Belgium. For more than 10 years, his lab has worked on modifying dendritic cells to make them more immunogenic against tumor antigens. Those methods of modification include mRNA electroporation and lentiviral transduction. Both the transfection conditions of mouse and human dendritic cells and the stability of the mRNA for highest possible expression have been optimized. The lab has an EU-approved GMP facility in Brussels to produce clinical-grade mRNA for use either as an API or an IMP in various clinical trials (cancer and infectious diseases).

James B. Trager, PhD

Dendreon Corporation
website | publications

James B. Trager is vice president of research at Dendreon Corporation. Trager earned his doctorate at the University of California, Berkeley, studying the role of auto-phosphorylation on signaling by the v-src tyrosine kinase in the lab of Dr. G. Steven Martin. At Geron, Trager was part of a team that cloned hTERT, the protein component of human telomerase; identified key interactions between the protein and RNA components of the enzyme; and brought the first telomerase inhibitor to the clinic. Trager has maintained his focus on novel cancer therapeutics at Dendreon, where he is responsible for new product development, biomarker identification, and clinical immunology. He has worked to bring Provenge, the first FDA-approved cellular immunotherapy for cancer, through clinical study and to the market. Current challenges include in-depth characterization of the Provenge mechanism of action, identification of biomarkers predictive of patient response to Provenge, and development of next-generation cellular immunotherapies for cancer. Trager is a graduate of St. John's College in Santa Fe and a former Peace Corps volunteer in the Central African Republic.

John S. Yu, MD

Cedars-Sinai Medical Center; Immunocellular Therapeutics Ltd.
website | publications

John S. Yu is the medical director of the Brain Tumor Center at Cedars-Sinai Medical Center and a professor and vice chair in the Department of Neurosurgery. He is conducting extensive research in immune and stem cell therapy for brain tumors. Yu received his MD from Harvard Medical School and Master's degree from the Harvard University Department of Genetics. He received neurosurgical residency training at Massachusetts General Hospital, where he also completed a neuroscience fellowship at the National Institute of Mental Health Neuroimmunology Unit and was a Culpeper Scholar in the Molecular Neurogenetics Unit. In 2006, he founded Immunocellular Therapeutics, a clinical-stage biotechnology public company focused on dendritic cell therapy for cancer.


Jennifer Cable

Jennifer Cable lives in New York City, where she experiments with different outlets to communicate science. She enjoys bringing science to scientists and nonscientists alike. She writes for Nature Structural and Molecular Biology, Bitesize Bio, Under the Microscope, and the Nature New York blog. She received a PhD from the University of North Carolina at Chapel Hill for her research in investigating the structure/function relationship of proteins.

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