DF/HCC Program Affiliation

Leader, Cancer Immunology Program
Member, Prostate Cancer Program
Member, Leukemia Program
Member, Lymphoma and Myeloma Program
Member, Lung Cancer Program
Member, Cutaneous Oncology and Melanoma Program

DF/HCC Associations

Member, Center Scientific Council

Research Abstract

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 anti-tumor immunity in multiple murine tumor model systems. 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 anti-tumor immunity in patients with cancer, we have conducted several Phase I clinical trials of vaccination with lethally irradiated, autologous tumor cells engineered to secrete human GM-CSF in patients with advanced melanoma, non-small cell lung carcinoma, or myeloid leukemia. These studies have shown the diffuse infiltration of pre-existing tumor masses following vaccination with large numbers of CD4 and CD8 positive T lymphocytes and plasma cells. The targeted destruction of tumor blood vessels by lymphocytes, eosinophils, and neutrophils has also been observed. We are currently cloning the antigens which are the targets of T and B cell immune responses in vaccinated patients. We have also generated mice lacking GM-CSF, interleukin-3, and interferon-gamma by gene targeting techniques in embryonic stem cells. Remarkably, these mice spontaneously develop at high frequency diverse hematologic and solid neoplasms within a background of chronic inflammation and infection. The mechanisms underlying tumor formation are under active study.

Publications

• Jinushi M, Vanneman M, Munshi NC, Tai YT, Prabhala RH, Ritz J, Neuberg D, Anderson KC, Carrasco DR, Dranoff G. MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proc Natl Acad Sci U S A 2008 Jan 29; 105(4):1285-90
  PMID: 18202175
• 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 antiinflammatory activities of GM-CSF. J Clin Invest 2007 Jul; 117(7):1902-13
  PMID: 17557120
• Enzler T, Gillessen S, Dougan M, Allison JP, Neuberg D, Oble DA, Mihm M, Dranoff G. Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of beta cells. Blood 2007 Aug 1; 110(3):954-61
  PMID: 17483299
• Jinushi M, Hodi FS, Dranoff G. Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity. Proc Natl Acad Sci U S A 2006 Jun 5;
  PMID: 16754847
• Hodi FS, Dranoff G. Combinatorial cancer immunotherapy. Adv Immunol 2006; 90:341-68
  PMID: 16730268
• Enzler T, Gillessen S, Manis JP, Ferguson D, Fleming J, Alt FW, Mihm M, Dranoff G. Deficiencies of GM-CSF and interferon gamma link inflammation and cancer. J Exp Med 2003 May 5; 197(9):1213-9
  PMID: 12732663
• Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, Davis T, Henry-Spires R, MacRae S, Willman A, Padera R, Jaklitsch MT, Shankar S, Chen TC, Korman A, Allison JP, Dranoff G. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A 2003 Apr 15; 100(8):4712-7
  PMID: 12682289
• Schmollinger JC, Vonderheide RH, Hoar KM, Maecker B, Schultze JL, Hodi FS, Soiffer RJ, Jung K, Kuroda MJ, Letvin NL, Greenfield EA, Mihm M, Kutok JL, Dranoff G. Melanoma inhibitor of apoptosis protein (ML-IAP) is a target for immune-mediated tumor destruction. Proc Natl Acad Sci U S A 2003 Mar 18; 100(6):3398-403
  PMID: 12626761