Regulation of the Immune Response to Prostate Cancer

Summary

Principal Investigator: Charles G Drake
Abstract: DESCRIPTION (provided by applicant): Metastatic, hormone refractory prostate cancer is an incurable disease that kills over 40,000 men per year in the United States. No currently available therapy can extend life, underscoring the need for novel treatment regimens. This proposal is designed to test the hypothesis that immune manipulation can lead to prostatic infiltration with specific T cells and to regression of prostate tumors in a clinically relevant murine model. In addition, this proposal is intended to provide the principal investigator, Dr. Charles G. Drake, with the necessary training to transition from medical oncology fellow to independent clinician-scientist in the field of tumor immunology. Dr. Drake received an M.D. and Ph.D. under the auspices of the medical scientist training program (MSTP) at National Jewish Center for Immunology. His Ph.D. research involved the basic genetics and immunology of a murine model of systemic lupus erythematosus. After completing a residency in Internal Medicine on the Osler Medical Service at Johns Hopkins Hospital, Dr. Drake began clinical subspecialty training in Medical Oncology. Dr. Drake's career goal is to head an independent, laboratory-based research effort in tumor immunology with a focus on clinically relevant immunotherapeutic approaches. The training program described here will be mentored by Dr. Drew Pardoll, who has a proven track record in the field of tumor immunology in addition to a strong history of transitioning clinical fellows to independent research careers. Finally, the research and training program outlined in this proposal makes full use of the collaborative and educational opportunities offered by the Johns Hopkins Oncology Center, where this work will be performed.
Funding Period: 2003-09-10 - 2008-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Combined treatment effects of radiation and immunotherapy: studies in an autochthonous prostate cancer model
    Satoshi Wada
    Department of Oncology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Int J Radiat Oncol Biol Phys 87:769-76. 2013
  2. pmc Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing
    Karen Sandell Sfanos
    Department of Urology, James Buchanan Brady Urological Institute, MD, USA
    Clin Cancer Res 14:3254-61. 2008
  3. pmc A role for the transcription factor Helios in human CD4(+)CD25(+) regulatory T cells
    Derese Getnet
    Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA
    Mol Immunol 47:1595-600. 2010
  4. pmc Tc17 CD8 T cells: functional plasticity and subset diversity
    Hung Rong Yen
    Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    J Immunol 183:7161-8. 2009
  5. pmc Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+
    Karen S Sfanos
    Department of Pathology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21231, USA
    Prostate 69:1694-703. 2009
  6. pmc Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells
    Joseph F Grosso
    Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    J Immunol 182:6659-69. 2009
  7. pmc Cyclophosphamide augments antitumor immunity: studies in an autochthonous prostate cancer model
    Satoshi Wada
    Department of Oncology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    Cancer Res 69:4309-18. 2009
  8. pmc Tumor recognition and self-recognition induce distinct transcriptional profiles in antigen-specific CD4 T cells
    Derese Getnet
    Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA
    J Immunol 182:4675-85. 2009
  9. pmc Radiotherapy augments the immune response to prostate cancer in a time-dependent manner
    Timothy J Harris
    Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    Prostate 68:1319-29. 2008
  10. ncbi Current immunotherapeutic strategies in prostate cancer
    Joseph F Grosso
    Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans Street, CRB 452, Baltimore, MD 21231, USA
    Surg Oncol Clin N Am 16:861-71, x. 2007

Scientific Experts

  • Charles G Drake
  • Joseph F Grosso
  • Derese Getnet
  • Tullia C Bruno
  • Satoshi Wada
  • Hung Rong Yen
  • Drew M Pardoll
  • Timothy J Harris
  • Monica V Goldberg
  • Edward L Hipkiss
  • Kristin J Pyle
  • Charles H Maris
  • Angelo M De Marzo
  • Kiyoshi Yoshimura
  • George J Netto
  • Theodore L DeWeese
  • Karen S Sfanos
  • Angelo M DeMarzo
  • William B Isaacs
  • Alan K Meeker
  • Robert Anders
  • Karen Sandell Sfanos
  • Erik Tryggestad
  • Jing Zeng
  • John Wong
  • Fan Pan
  • Nicholas M Durham
  • Chunfa Jie
  • Edward Hipkiss
  • Kai Li Liang
  • Ching Tai Huang
  • Siaw Li Chan
  • Tim J Harris
  • Adam Adler
  • Robert A Anders
  • Robert W Georgantas
  • Cornelia L Trimble
  • Dario A A Vignali
  • Tzou Yien Lin
  • Adam J Adler
  • Lauren Xu
  • Scott Borzillary
  • Christopher J Thoburn
  • George Netto
  • Cristin C Kelleher
  • Angelo De Marzo

Detail Information

Publications12

  1. ncbi Combined treatment effects of radiation and immunotherapy: studies in an autochthonous prostate cancer model
    Satoshi Wada
    Department of Oncology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Int J Radiat Oncol Biol Phys 87:769-76. 2013
    ..To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer...
  2. pmc Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing
    Karen Sandell Sfanos
    Department of Urology, James Buchanan Brady Urological Institute, MD, USA
    Clin Cancer Res 14:3254-61. 2008
    ..Little is known about the phenotype of these cells, despite accumulating evidence suggesting a potential role for chronic inflammation in the etiology of prostate cancer...
  3. pmc A role for the transcription factor Helios in human CD4(+)CD25(+) regulatory T cells
    Derese Getnet
    Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA
    Mol Immunol 47:1595-600. 2010
    ..Taken together, these data suggest that Helios may play an important role in regulatory T cell function and support the concept that Helios may be a novel target to manipulate Treg activity in a clinical setting...
  4. pmc Tc17 CD8 T cells: functional plasticity and subset diversity
    Hung Rong Yen
    Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    J Immunol 183:7161-8. 2009
    ..Tc17 also accumulated to a greater extent than did Tc1 cells, suggesting that adoptive transfer of CD8 T cells cultured in Tc17 conditions may have therapeutic potential for diseases in which IFN-gamma-producing cells are desired...
  5. pmc Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+
    Karen S Sfanos
    Department of Pathology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21231, USA
    Prostate 69:1694-703. 2009
    ....
  6. pmc Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells
    Joseph F Grosso
    Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    J Immunol 182:6659-69. 2009
    ....
  7. pmc Cyclophosphamide augments antitumor immunity: studies in an autochthonous prostate cancer model
    Satoshi Wada
    Department of Oncology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    Cancer Res 69:4309-18. 2009
    ..Taken together, these data clarify the dose, timing, and mechanism of action by which immunomodulatory cyclophosphamide can be translated to a clinical setting in a combinatorial cancer treatment strategy...
  8. pmc Tumor recognition and self-recognition induce distinct transcriptional profiles in antigen-specific CD4 T cells
    Derese Getnet
    Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA
    J Immunol 182:4675-85. 2009
    ..Interestingly, this Treg skewing was a property of even early-stage tumors, suggesting Treg induction as an important tolerance mechanism during tumor development...
  9. pmc Radiotherapy augments the immune response to prostate cancer in a time-dependent manner
    Timothy J Harris
    Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    Prostate 68:1319-29. 2008
    ..To address this, we utilized a well-established, autochthonous murine model of prostate cancer to test whether RT could augment (or diminish) the CD4 T cell response to a tumor vaccine...
  10. ncbi Current immunotherapeutic strategies in prostate cancer
    Joseph F Grosso
    Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans Street, CRB 452, Baltimore, MD 21231, USA
    Surg Oncol Clin N Am 16:861-71, x. 2007
    ..Most likely, successful immunotherapy will eventually require either the combination of multiple immunologic approaches or the combination of immunologic approaches with conventional therapy...
  11. pmc LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems
    Joseph F Grosso
    Sidney Kimmel Comprehensive Cancer Center and Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
    J Clin Invest 117:3383-92. 2007
    ..Taken together, these data demonstrate a direct role for LAG-3 on CD8+ T cells and suggest that LAG-3 blockade may be a potential cancer treatment...
  12. pmc Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen
    Charles G Drake
    Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA
    Cancer Cell 7:239-49. 2005
    ..These results suggest that immunotherapy for prostate cancer may be most efficacious when administered after androgen ablation...