Glenn Dranoff, MD
Associate Professor of Medicine, Harvard Medical School
Centers/Programs
Department
Medical Oncology/Hematologic Neoplasia
Area of Research
Granulocyte-Macrophage Based Cancer Vaccines
Contact Information
Glenn Dranoff, MDDana-Farber Cancer Institute
44 Binney Street
Dana 520C
Boston, MA 02115
Office phone: (617) 632-5051
Fax: (617) 632-5167
E-mail: glenn_dranoff@dfci.harvard.edu
Preferred contact method: e-mail
Research
Granulocyte-Macrophage Based Cancer Vaccines
We have demonstrated that vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor (GM-CSF) generates potent, specific, and long-lasting antitumor immunity in multiple murine tumor models. Vaccination requires the participation of both CD4 and CD8 positive lymphocytes and likely involves augmenting the function of professional antigen-presenting cells, such as macrophages and dendritic cells. To test whether this approach will also augment antitumor immunity in cancer patients, we conducted a phase I clinical trial of vaccination with lethally irradiated, autologous melanoma cells engineered to secrete human GM-CSF. This study revealed the diffuse infiltration of pre-existing tumor masses with large numbers of CD4 and CD8 positive T lymphocytes and plasma cells following vaccination, but not before. We also observed the targeted destruction of tumor blood vessels by lymphocytes, eosinophils, and neutrophils.
Based on these promising results, we have expanded our trials to include patients with lung, ovarian, and breast carcinoma, myeloid leukemias, and pediatric solid tumors. To intensify the potency of immunity, we have also administered a blocking antibody to CTLA-4 (a negative immune regulator) to previously vaccinated subjects. Preliminary clinical results indicate that CTLA-4 blockade can accomplish significant additional tumor destruction, albeit with a risk of autoimmunity.
Using clinical samples obtained from these studies, we are cloning the antigens that are the targets of T and B cell immune responses in vaccinated patients. These studies have yielded many interesting targets identified including MICA, ML-IAP, progranulin, and angiopoietins.
Using gene-targeting techniques in embryonic stem cells, we have also generated mice lacking GM-CSF, interleukin-3, and interferon-gamma. Remarkably, these mice spontaneously develop diverse hematologic and solid tumors in association with infection and inflammatory disease. The unexpected high frequency and broad spectrum of tumors implies that cytokine-mediated regulation of cell growth and immune homeostasis is a critical determinant of cancer susceptibility.
Recent Awards
- Stohlman Scholar, Leukemia and Lymphoma Society, 2005
- American Society of Clinical Investigation, 2004
- Academy of Cancer Immunology, 2001
- Biochemistry Award in Gene Therapy, Eli Lilly, 1996
Biography
Dr. Dranoff received his MD from Duke University in 1985. He completed an internship and residency in internal medicine at the Massachusetts General Hospital and a clinical fellowship in medical oncology at DFCI. He did his postdoctoral training with Dr. Richard Mulligan at the Whitehead Institute for Biomedical Research. His research focuses on understanding the molecular and cellular mechanisms underlying the stimulation of tumor immunity and on the development of cancer vaccines.
Select Publications
- Soiffer RJ, Hodi FS, Haluska F, Jung K, Gillessen S, Singer S, Tanabe K, Duda R, Mentzer S, Jaklitsch M, Bueno R, Clift S, Hardy S, Neuberg D, Mulligan RC, Webb I, Mihm M, Dranoff G. Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma. J Clin Oncol 2003;21:3343-50.
- Salgia R, Lynch T, Skarin A, Lucca J, Lynch C, Jung K, Hodi FS, Jaklitsch M, Mentzer S, Swanson S, Lukanich J, Bueno R, Wain J, Mathisen D, Wright C, Fidias P, Donahue D, Clift S, Hardy S, Neuberg D, Mulligan R, Webb I, Sugarbaker D, Mihm M, Dranoff G. Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma. J Clin Oncol 2003;21:624-30.
- Ho VT, Vanneman M, Kim H, Sasada T, Kang YJ, Pasek M, Cutler C, Koreth J, Alyea E, Sarantopoulos S, Antin JH, Ritz J, Canning C, Kutok J, Mihm MC, Dranoff G, Soiffer R. Biologic activity of irradiated, autologous, granulocyte-macrophage colony stimulating factor secreting leukemia cell vaccines early after allogeneic stem cell transplantation. Proc. Natl. Acad. Sci. U.S.A. 2009;106:15825-15830.
- Dougan M and Dranoff G. Immune therapy for cancer. Ann. Rev. Immunol. 2009;27:83-117
- Ali OA, Emerich D, Dranoff G, Mooney DJ. In situ regulation of DC subsets and T cells mediates tumor regression in mice. Sci. Transl. Med. 2009;1:8ra19
- Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, MacRae S, Nelson M, Canning C, Lowy I, Korman A, Lautz D, Russell S, Jaklitsch, Ramaiya N, Chen TC, Neuberg D, Allison JP, Mihm MC, and Dranoff G. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc. Natl. Acad. Sci. U.S.A. 2008;105:3005-3010
- Jinushi M, Nakazaki Y, Dougan M, Carrasco DR, Mihm M, Dranoff G. MFG-E8 mediated uptake of apoptotic cells by APCs links the pro- and anti-inflammatory activities of GM-CSF. J. Clin. Invest. 2007;117:1902-1913.
