Vaccine Immunotoxin and Radioimmunotherapy of Primary and Metastatic CNS Tumors

Summary

Principal Investigator: Darell D Bigner
Abstract: DESCRIPTION (provided by applicant): This is an application to the NCI from a group of senior scientists and physician/scientists with a long history of collaboration who proposes novel approaches for treatment of two of the conditions in neuro-oncology which are most refractory to treatment, neoplastic meningitis (NM) and glioblastoma multiforme (GBM). NM is characterized by the dissemination of malignant tumor cells within the leptomeningeal space and metastatic spread through the cerebrospinal fluid along the brain and spine. NM from carcinoma of the breast and lung are the most common subtypes. Prognosis of NM is grim with median survival of 2 to 6 months. Current therapy is ineffective and limited by toxicity to the CNS. GBM is the most common and most malignant primary brain tumor. Despite hundreds of clinical trials, only two agents, temozolomide and bevacizumab, have been approved for treatment by the FDA in the last decade. Less than half of patients treated with these two agents respond. Recurrence after treatment is almost universal and median survival is 15 to 18 months with few long-term survivors. Targeted immunotherapy with monoclonal antibodies (MAbs) or their fragments armed with Astatine 211 or Pseudomonas exotoxin for the treatment of NM or GBM is proposed in Projects 1 and 3. In Project 2 vaccine approaches against the ubiquitous antigens from CMV in GBM are proposed to be improved by decreasing immunosuppressive regulatory T-cells or TReg in the setting of temozolomide-induced lymphopenia by administering a specific humanized MAb reactive with the IL-2Ra receptor. Project 1, led by Michael Zaiutsky, is entitled "Targeted Radiotherapy of Neoplastic Meningitis using Monoclonal Antibodies Labeled with Alpha Particle Emitting At." Project 2, led by John Sampson, and is entitled, "Targeting Immunosuppression Pathways to Enhance Brain Tumor Immunotherapy." Project 3, led by Darell Bigner, and is entitled, "EGFRwt and EGFRvlll Dual-Specific Immunotoxin for Glioblastoma Multiforme." These three projects will be supported by an Imaging Core, Daniel Barboriak, Core Director;a Clinical Support Core for biostatistics, informatics, immune monitoring, and a brain tumor tissue biorepository, James Vredenburgh, Core Director;and an Administrative Core, Darell Bigner, Core Director.
Funding Period: 2012-07-11 - 2017-06-30
more information: NIH RePORT

Top Publications

  1. pmc SIB-DOTA: a trifunctional prosthetic group potentially amenable for multi-modal labeling that enhances tumor uptake of internalizing monoclonal antibodies
    G Vaidyanathan
    Box 3808, Radiology, Duke University Medical Center, Durham, NC 27710, USA
    Bioorg Med Chem 20:6929-39. 2012
  2. pmc Targeting breast carcinoma with radioiodinated anti-HER2 Nanobody
    Marek Pruszyński
    Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA
    Nucl Med Biol 40:52-9. 2013
  3. pmc Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma
    Bryan D Choi
    Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
    Proc Natl Acad Sci U S A 110:270-5. 2013
  4. pmc Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis
    Bryan D Choi
    Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710, United States
    J Immunol Methods 395:14-20. 2013
  5. pmc Construction of an immunotoxin, D2C7-(scdsFv)-PE38KDEL, targeting EGFRwt and EGFRvIII for brain tumor therapy
    Vidyalakshmi Chandramohan
    Preston Robert Tisch Brain Tumor Center at Duke and Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA
    Clin Cancer Res 19:4717-27. 2013
  6. pmc A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model
    Shicheng Yang
    Division of Neurosurgery, Department of Surgery, Brain Tumor Immunotherapy Program, Duke University Medical Center, 303 Research Drive, 220 Sands Building, DUMC 3050, Durham, NC, 27710, USA
    Cancer Immunol Immunother 62:1649-62. 2013
  7. pmc Improved tumor targeting of anti-HER2 nanobody through N-succinimidyl 4-guanidinomethyl-3-iodobenzoate radiolabeling
    Marek Pruszyński
    Department of Radiology, Duke University Medical Center, Durham, North Carolina
    J Nucl Med 55:650-6. 2014
  8. pmc Radiolabeling and in vitro evaluation of (67)Ga-NOTA-modular nanotransporter--a potential Auger electron emitting EGFR-targeted radiotherapeutic
    Eftychia Koumarianou
    Department of Radiology, Duke University Medical Center, Durham, NC, USA
    Nucl Med Biol 41:441-9. 2014

Research Grants

  1. NEW MODALITIES FOR TREATMENT OF PAIN AND DRUG ABUSE
    Victor J Hruby; Fiscal Year: 2013
  2. Comparative Mechanisms of Cancer Chemoprevention
    Roderick H Dashwood; Fiscal Year: 2013

Detail Information

Publications8

  1. pmc SIB-DOTA: a trifunctional prosthetic group potentially amenable for multi-modal labeling that enhances tumor uptake of internalizing monoclonal antibodies
    G Vaidyanathan
    Box 3808, Radiology, Duke University Medical Center, Durham, NC 27710, USA
    Bioorg Med Chem 20:6929-39. 2012
    ..These results suggest that SIB-DOTA warrants further evaluation as a residualizing agent for labeling internalizing mAbs including those targeted to EGFRvIII...
  2. pmc Targeting breast carcinoma with radioiodinated anti-HER2 Nanobody
    Marek Pruszyński
    Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA
    Nucl Med Biol 40:52-9. 2013
    ..This provided motivation for the generation of HER2-specific 5F7GGC Nb, its radioiodination and evaluation for targeting HER2 expressing tumors...
  3. pmc Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma
    Bryan D Choi
    Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
    Proc Natl Acad Sci U S A 110:270-5. 2013
    ..Finally, bscEGFRvIIIxCD3 represents a unique advancement in BiTE technology given its exquisite tumor specificity, which enables precise elimination of cancer without the risk of autoimmune toxicity...
  4. pmc Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis
    Bryan D Choi
    Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710, United States
    J Immunol Methods 395:14-20. 2013
    ....
  5. pmc Construction of an immunotoxin, D2C7-(scdsFv)-PE38KDEL, targeting EGFRwt and EGFRvIII for brain tumor therapy
    Vidyalakshmi Chandramohan
    Preston Robert Tisch Brain Tumor Center at Duke and Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA
    Clin Cancer Res 19:4717-27. 2013
    ....
  6. pmc A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model
    Shicheng Yang
    Division of Neurosurgery, Department of Surgery, Brain Tumor Immunotherapy Program, Duke University Medical Center, 303 Research Drive, 220 Sands Building, DUMC 3050, Durham, NC, 27710, USA
    Cancer Immunol Immunother 62:1649-62. 2013
    ..ACT using the ex vivo ttRNA-DC-T platform in conjunction with a cytokine cocktail generated potent CD62Lhigh anti-tumor T cells and imposes a novel T cell-based therapeutic with the potential to treat brain tumors and other cancers...
  7. pmc Improved tumor targeting of anti-HER2 nanobody through N-succinimidyl 4-guanidinomethyl-3-iodobenzoate radiolabeling
    Marek Pruszyński
    Department of Radiology, Duke University Medical Center, Durham, North Carolina
    J Nucl Med 55:650-6. 2014
    ..The aim of the present study was to evaluate the tumor-targeting potential of anti-HER2 5F7GGC Nanobody after radioiodination with the residualizing agent N-succinimidyl 4-guanidinomethyl 3-(125/131)I-iodobenzoate (*I-SGMIB)...
  8. pmc Radiolabeling and in vitro evaluation of (67)Ga-NOTA-modular nanotransporter--a potential Auger electron emitting EGFR-targeted radiotherapeutic
    Eftychia Koumarianou
    Department of Radiology, Duke University Medical Center, Durham, NC, USA
    Nucl Med Biol 41:441-9. 2014
    ..Hence their conjugation to Auger electron emitters, can cause severe cell killing, by nuclear localization. Herein we evaluate the use of MNT as a platform for targeted radiotherapy with (67)Ga...

Research Grants30

  1. NEW MODALITIES FOR TREATMENT OF PAIN AND DRUG ABUSE
    Victor J Hruby; Fiscal Year: 2013
    ....
  2. Comparative Mechanisms of Cancer Chemoprevention
    Roderick H Dashwood; Fiscal Year: 2013
    ..This application is innovative and timely in bridging basic mechanisms, preclinical models, and human studies of epigenetics and diet. ..