Brain tumors with regulatory T-cells treated with EGFRvIII-specific T-cells

Summary

Principal Investigator: John H Sampson
Abstract: DESCRIPTION (provided by applicant): Malignant primary brain tumors represent the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Glioblastoma (GBM) is uniformly lethal, and current therapy is non-specific and produces a median overall survival of <15 months. In contrast, immunotherapy promises an exquisitely precise approach, and substantial evidence suggests that T-cells can eradicate large, well-established tumors in mice and humans even when tumors reside within the brain. Chimeric antigen T-cell receptors (CARs) combine the variable region of an antibody with T-cell signaling moieties to confer T-cell activation with the targeting specificiy of an antibody and are not MHC-restricted. Additionally, co-stimulatory molecules, such as CD28 and 4-1BB, can be added to these constructs to improve T-cell expansion, survival, cytokine secretion, and tumor lysis. Clinical trials utilizing CARs have demonstrated their remarkable potential. However, severe adverse events and even patient deaths have occurred when these CARs have been directed against antigens shared by normal tissues. EGFRvIII is a tumor-specific mutation of the epidermal growth factor receptor that is expressed in GBMs and several other neoplasms. We have previously shown that EGFRvIII can be recognized by highly avid antibodies, so have developed human and murine CAR vectors that specifically recognize EGFRvIII inducing cytokine secretion and in vitro and in vivo tumor lysis. We have also demonstrated that an EGFRvIII-specific peptide (PEPvIII) contains the conformational epitope for EGFRvIII-specific antibodies used in these CARs. Using this peptide, we have shown that these cognate peptides are sufficient antidotes for CARs, suggesting a novel paradigm for reducing the target-specific toxicity of less tumor-specific CARs. Despite their potency, however, CARs still require host conditioning with lymphodepletion for efficacy and are still limited by being susceptible to inhibition by host immunosuppressive factors of which regulatory T-cells (TRegs) have been most frequently implicated. Similarly, while total body irradiation or non-therapeutic chemotherapy has been applied to optimize CAR therapy, it adds additional toxicity without direct anti-tumor efficacy. Our prior experience with TMZ demonstrates that, in addition to having direct clinical benefit in GBM, TMZ can potentiate anti-tumor immune responses directly related to the rebound homeostatic proliferation it induces. To address these issues, in this proposal, we will 1) Evaluate the risk of toxicity, utility of TMZ, and the requirements for efficacy of a tumor-specific, EGFRvIII-targeted CAR in a syngeneic, immunocompetent, orthotopic murine GBM model;2) Determine if CD3-CD28-4-1BB CAR vectors naturally transfect and activate TRegs and dissect the role of CAR-secreted IL-2 in supporting the growth of intratumoral TRegs and effector T-cells;and 3) Conduct a Phase I clinical trial in TMZ-treated patients with EGFRvIII-expressing GBM to assess CAR safety, kinetics and function.
Funding Period: 2013-04-05 - 2018-03-31
more information: NIH RePORT

Top Publications

  1. pmc Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma
    Bryan D Choi
    Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Box 3050, Durham, NC 27710, USA Department of Pathology, Duke University Medical Center, Durham, NC, USA
    J Clin Neurosci 21:189-90. 2014
  2. pmc EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss
    John H Sampson
    Authors Affiliations Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery Department of Pathology The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina and Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    Clin Cancer Res 20:972-84. 2014

Research Grants

  1. Risk-Based Breast Cancer Screening in Community Settings
    Diana L Miglioretti; Fiscal Year: 2013
  2. Targeting EGFRvIII in Brain Tumors with Bispecific Antibodies
    Bryan Choi; Fiscal Year: 2013
  3. UAB / UMN SPORE in Pancreatic Cancer
    Donald J Buchsbaum; Fiscal Year: 2013
  4. Center for Molecular Imaging Research at MGH/HMS
    Ralph Weissleder; Fiscal Year: 2013
  5. WU-MDACC Inter-Institutional Molecular Imaging Center
    David Piwnica-Worms; Fiscal Year: 2013
  6. JHU ICMIC PROGRAM
    Zaver M Bhujwalla; Fiscal Year: 2013
  7. SPORE in GI Cancer
    Robert J Coffey; Fiscal Year: 2013
  8. Seattle Cancer Consortium Breast SPORE
    Peggy L Porter; Fiscal Year: 2013
  9. Augmenting Chimeric Antibody Receptor Directed T cell Therapy for Cancer
    Edmund K Moon; Fiscal Year: 2013
  10. Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium
    Julie R Palmer; Fiscal Year: 2013

Detail Information

Publications2

  1. pmc Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma
    Bryan D Choi
    Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Box 3050, Durham, NC 27710, USA Department of Pathology, Duke University Medical Center, Durham, NC, USA
    J Clin Neurosci 21:189-90. 2014
    ..Importantly, these results endorse clinical translation of this CAR in patients with EGFRvIII-expressing brain tumors. ..
  2. pmc EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss
    John H Sampson
    Authors Affiliations Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery Department of Pathology The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina and Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    Clin Cancer Res 20:972-84. 2014
    ..A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues...

Research Grants30

  1. Risk-Based Breast Cancer Screening in Community Settings
    Diana L Miglioretti; Fiscal Year: 2013
    ..The program represents an integrated effort to improve screening with the overall aim of averting deaths from breast cancer while minimizing harms. ..
  2. Targeting EGFRvIII in Brain Tumors with Bispecific Antibodies
    Bryan Choi; Fiscal Year: 2013
    ..This work has the potential to improve the clinical management of patients with GBM by generating a novel therapeutic. ..
  3. UAB / UMN SPORE in Pancreatic Cancer
    Donald J Buchsbaum; Fiscal Year: 2013
    ..The application has strong institutional support from UAB and UMN, excellent pancreatic cancer populations and concurrence with federal guidelines. ..
  4. Center for Molecular Imaging Research at MGH/HMS
    Ralph Weissleder; Fiscal Year: 2013
    ....
  5. WU-MDACC Inter-Institutional Molecular Imaging Center
    David Piwnica-Worms; Fiscal Year: 2013
    ..Our Molecular Imaging Center also provides a pilot project program for new investigators and a multidisciplinary training program for students, post-docs, and fellows. ..
  6. JHU ICMIC PROGRAM
    Zaver M Bhujwalla; Fiscal Year: 2013
    ..The Career Development Component is structured with the purpose of creating independently funded investigators who will, in the future, become leaders in the field. ..
  7. SPORE in GI Cancer
    Robert J Coffey; Fiscal Year: 2013
    ..Administrative Core B. Translational Pathology &Imaging Core C. Biostatistics &Bioinformatics Career Development Program Developmental Research Program ..
  8. Seattle Cancer Consortium Breast SPORE
    Peggy L Porter; Fiscal Year: 2013
    ..abstract_text> ..
  9. Augmenting Chimeric Antibody Receptor Directed T cell Therapy for Cancer
    Edmund K Moon; Fiscal Year: 2013
    ..June have mentored over 100 trainees. In addition, an advisory committee of distinguished scientists will provide experimental assistance, intellectual guidance, and career advice throughout the duration of this award. ..
  10. Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium
    Julie R Palmer; Fiscal Year: 2013
    ..By pooling our data, specimens, and importantly, expertise to investigate these synergist hypotheses, we will elucidate much of the etiology of aggressive, early onset breast cancers in AA women. ..
  11. Overcoming resistance to BRAF(V600E) targeted therapies in melanoma
    David E Fisher; Fiscal Year: 2013
    ..abstract_text> ..
  12. Adoptive Immunotherapy of Cancer with IL-12 Secreting Tumor-Targeted T cells
    RENIER JOSEPH BRENTJENS; Fiscal Year: 2013
    ..The goal of this project is to improve the function of these cells to make them better suited to treat patients with persistent cancer after chemotherapy. ..
  13. Therapeutic Opportunities for Pediatric Astrocytoma
    Rosalind A Segal; Fiscal Year: 2013
    ..The three projects interact with one another and are further unified by economies of scale enabled by an Innovative Neuropathology (INP) core. ..
  14. MIXED HEMATOPOIETIC CHIMERISM AFTER STEM CELL ALLOGRAFTS
    Rainer F Storb; Fiscal Year: 2013
    ..This is especially important since median ages at diagnosis of patients with most candidate diseases range from 65 to 70 years, which is beyond the age range of inclusion in conventional myeloablative HCT regimens. ..
  15. Normal &Neoplastic Growth in the Brain
    Suzanne J Baker; Fiscal Year: 2013
    ..Integrated analyses within the group will identify common and unique signal transduction pathways in pediatric brain tumorigenesis. ..
  16. Directing Tumor-specific T cells to Tumors
    Pawel Kalinski; Fiscal Year: 2013
    ..abstract_text> ..
  17. Optimized ex vivo expansion of anti-tumor Th1 and Tc1 for adoptive immunotherapy
    Mary L Disis; Fiscal Year: 2013
    ..We will also assess whether these culture methods increase epitope spreading. ..
  18. Vaccine Immunotoxin and Radioimmunotherapy of Primary and Metastatic CNS Tumors
    Darell D Bigner; Fiscal Year: 2013
    ..abstract_text> ..
  19. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
    ..We also want to understand why the immune system destroys hypocretin neurons in narcolepsy and to prevent/cure it. ..