Hematopoietic Chemoprotection in Glioblastoma Patients

Summary

Principal Investigator: Hans Peter Kiem
Affiliation: Fred Hutchinson Cancer Research Center
Country: USA
Abstract: Glioblastoma is the most common subtype of primary brain tumors in adults. These tumors are highly invasive. Median survival after diagnosis is approximately 12 months. Chemotherapy with nitrosourea, methylating agents such as procarbazine or temozolomide, or other agents is effective and can prolong survival. However, a significant obstacle to the treatment has been the hematopoietic toxicity of chemo- therapeutic agents like 1,3-bis(2-chloroethyl)-1 -nitrosourea (BCNU) and temozolomide, which has limited the ability to dose-escalate the drugs. This hematopoietic toxicity is even more pronounced when BCNU or temozolomide are combined with O6-benzylguanine (O6-BG), an agent which inhibits O6-alkylguanine DNA alkyltransferase, a major resistance mechanism in gliomas. We have recently demonstrated in a clinically relevant large animal model that genetic modification of hematopoietic stem cells with the P140K mutant of methylguanine methyltransferase (MGMT) results in chemoprotection and the ability to administer higher doses of temozolomide and BCNU when given in combination with O6-BG. Based on these findings we hypothesize that chemoprotection with MGMT (P140K) will allow the administration of higher doses of temozolomide and thus potentially improve the efficacy of this drug in the treatment of patients with high-grade gliomas. Since efficient engraftment of gene-modified cells is important for the success of this strategy, we propose a 2-part approach. In the first part, we propose a dose-escalation of temozolomide with a fixed dose of BCNU to enhance engraftment of gene-modified chemoprotected peripheral blood stem cells, followed by fixed doses of temozolomide with O6-BG. The initial dose of BCNU and temozolomide will be based on the maximum tolerated dose (MTD) published by the North American Brain Tumor Consortium. This approach will allow us to maximize engraftment of chemoprotected cells and thus also maximize the ability to dose-escalate temozolomide. The initial dose of temozolomide will be based on the published MTD for this combination. In the second part of the study, we will use the MTD of BCNU and temozolomide with support of chemoprotected peripheral blood stem cells and perform a dose-escalation of temozolomide with O6-BG. Thus, this study will address the safety, feasibility, and tumor response of dose-intensive chemotherapy in combination with chemoprotected autologous stem cells in patients with glioblastomas. In addition, we will perform a comprehensive molecular analysis of the gene-modified cells which will provide highly relevant information for stem cell gene therapy studies. Research proposed in this study could, therefore, significantly improve the treatment and survival of patients with glioblastoma and also provide important safety and feasibility information for stem cell gene therapy applications for other diseases such as genetic disorders and AIDS.
Funding Period: 2006-08-16 - 2011-07-31
more information: NIH RePORT

Top Publications

  1. doi Temozolomide: Expanding its role in brain cancer
    M M Mrugala
    Department of Neurology and Neurosurgical Surgery, University of Washington, Seattle, Washington 98195, USA
    Drugs Today (Barc) 46:833-46. 2010
  2. pmc Extended survival of glioblastoma patients after chemoprotective HSC gene therapy
    Jennifer E Adair
    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Sci Transl Med 4:133ra57. 2012
  3. pmc The majority of CD4+ T-cell depletion during acute simian-human immunodeficiency virus SHIV89.6P infection occurs in uninfected cells
    Laura Matrajt
    Department of Medicine, University of Washington, Seattle, Washington, USA
    J Virol 88:3202-12. 2014
  4. pmc Hematopoietic stem cell expansion and gene therapy
    Korashon Lynn Watts
    Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
    Cytotherapy 13:1164-71. 2011
  5. ncbi Outside the box--novel therapeutic strategies for glioblastoma
    Maciej M Mrugala
    Department of Neurology, University of Washington, Seattle, WA, USA
    Cancer J 18:51-8. 2012
  6. ncbi A capsid-modified, conditionally replicating oncolytic adenovirus vector expressing TRAIL Leads to enhanced cancer cell killing in human glioblastoma models
    Martin E Wohlfahrt
    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109 1024, USA
    Cancer Res 67:8783-90. 2007

Scientific Experts

  • M M Mrugala
  • Hans Peter Kiem
  • Laura Matrajt
  • Jennifer E Adair
  • Korashon Lynn Watts
  • Brian C Beard
  • Martin E Wohlfahrt
  • Patrick M Younan
  • Joshua T Schiffer
  • Jason K Rockhill
  • Tobias Neff
  • Grant D Trobridge
  • Daniel L Silbergeld
  • Jennifer Adair
  • Andre Lieber

Detail Information

Publications6

  1. doi Temozolomide: Expanding its role in brain cancer
    M M Mrugala
    Department of Neurology and Neurosurgical Surgery, University of Washington, Seattle, Washington 98195, USA
    Drugs Today (Barc) 46:833-46. 2010
    ....
  2. pmc Extended survival of glioblastoma patients after chemoprotective HSC gene therapy
    Jennifer E Adair
    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Sci Transl Med 4:133ra57. 2012
    ..Thus, transplanted P140K-expressing hematopoietic stem and progenitor cells are chemoprotective, potentially maximizing the drug dose that can be administered...
  3. pmc The majority of CD4+ T-cell depletion during acute simian-human immunodeficiency virus SHIV89.6P infection occurs in uninfected cells
    Laura Matrajt
    Department of Medicine, University of Washington, Seattle, Washington, USA
    J Virol 88:3202-12. 2014
    ..Mechanisms to limit the profound indirect killing effects associated with HIV infection may be associated with immune preservation and improved long-term survival...
  4. pmc Hematopoietic stem cell expansion and gene therapy
    Korashon Lynn Watts
    Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
    Cytotherapy 13:1164-71. 2011
    ..We conclude by discussing how some of the current limitations of HSC gene therapy could be overcome by combining novel HSC expansion strategies with gene therapy...
  5. ncbi Outside the box--novel therapeutic strategies for glioblastoma
    Maciej M Mrugala
    Department of Neurology, University of Washington, Seattle, WA, USA
    Cancer J 18:51-8. 2012
    ..Lastly, alternating electric fields are being introduced to cancer therapy. This review will discuss these "nonstandard"--outside the box--modalities for therapy for malignant glioma...
  6. ncbi A capsid-modified, conditionally replicating oncolytic adenovirus vector expressing TRAIL Leads to enhanced cancer cell killing in human glioblastoma models
    Martin E Wohlfahrt
    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109 1024, USA
    Cancer Res 67:8783-90. 2007
    ..Our findings indicate that the use of a capsid-modified adenoviral vector, in combination with TRAIL expression, is a promising novel approach for gene therapy of glioblastoma...