Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.
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2015-03-19
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After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.
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Mitchell, Duane A, Kristen A Batich, Michael D Gunn, Min-Nung Huang, Luis Sanchez-Perez, Smita K Nair, Kendra L Congdon, Elizabeth A Reap, et al. (2015). Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature, 519(7543). pp. 366–369. 10.1038/nature14320 Retrieved from https://hdl.handle.net/10161/16099.
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Scholars@Duke
Michael Dee Gunn
Lab History
The lab started with our discovery of the lymphoid chemokines, which regulate the migration of lymphocytes and dendritic cells to and within secondary lymphoid organs. We identified the chemokine (CCL21) that mediates the entry of naïve T cells and activated dendritic cells into lymph nodes and the chemokine (CXCL13) that mediates the entry of B cells into lymphoid follicles. Our focus then shifted to understanding how specific cell types, primarily dendritic cells, and cell migration events regulate immune responses. We identified murine plasmacytoid dendritic cells; the cell type that causes pulmonary immune pathology during influenza infection; the dendritic cell type that stimulates Th1 immune responses; the cell type that induces neuronal injury in Alzheimer's disease, and the macrophage type that stimulates pulmonary hypertension. Our current work continues these basic studies while applying our findings to models of human disease.
Current Research
Development of recombinant antibodies as diagnostic reagents – Our lab has developed novel methods to generate recombinant single chain antibodies using phage display technology. We are currently using these methods to generate pathogen-specific antibodies for use in diagnostic tests for a variety of human bacterial, viral, and fungal infections. In collaboration with Duke Biomedical Engineering, we are deploying our antibodies in a novel diagnostic assay platform to develop point-of-care assays for the diagnosis of a variety of emerging pathogens. Our recently developed point-of-care assay for Ebola virus displays a sensitivity superior to PCR at a fraction of the per assay cost.
Smita K Nair
I have 22 years of experience in the field of cancer vaccines and immunotherapy and I am an accomplished T cell immunologist. Laboratory website:
https://surgery.duke.edu/immunology-inflammation-immunotherapy-laboratory
Current projects in the Nair Laboratory:
1] Dendritic cell vaccines using tumor-antigen encoding RNA (mRNA, total tumor RNA, amplified tumor mRNA)
2] Local immune receptor modulation using mRNA that encodes for antibodies, receptor-ligands, cytokines, chemokines and toll-like receptors (current target list: CTLA4, GITR, PD1, TIM3, LAG3, OX40 and 41BB)
3] Combination therapies for cancer: cytotoxic therapy (radiation, chemo and oncolytic poliovirus therapy) with dendritic cell-based vaccines and immune checkpoint blockade
4] Adoptive T cell therapy using tumor RNA-transfected dendritic cells to expand tumor-specific T cells ex vivo
5] Adoptive T cell therapy using PSMA CAR (chimeric antigen receptor) RNA-transfected T cells
6] Direct injection of tumor antigen encoding RNA (targeting antigens to dendric cells in vivo using nanoparticles and aptamers)
Annick Desjardins
Allan Howard Friedman
At the present time, I am participating in collaborative research in the areas of primary malignant brain tumors, epilepsy and subarachnoid hemorrhage.
Primary malignant brain tumors are increasing in frequency. Patients harboring glioblastoma, the most malignant primary brain tumor, have a life expectancy of less than one year. In collaboration with the Division of Neurology and the Department of Pathology, clinical and laboratory trials have been initiated to identify better treatment for this condition. At present, trials of monoclonal antibodies and novel chemotherapeutic agents are being carried out.
Although physicians have been interested in seizures since the time of Hippocrates, the origin of seizures remains obscure. At Duke University we have treated approximately thirty seizure patients a year by removing abnormal portions of brain. Tissue from these resections is being analyzed for genetics and receptor abnormalities. Positron emission tomography and magnetic resonance imaging are being used to ferret out the origin of the patient's seizures.
Approximately 28,000 patients each year suffer a ruptured intracranial aneurysm. Approximately ten percent of these patients have a genetic predisposition to forming intracranial aneurysms. In conjunction with the Division of Neurology, we are screening candidate genes searching for the cause of intracranial aneurysms.
James Emmett Herndon
Current research interests have application to the design and analysis of cancer clinical trials. Specifically, interests include the use of time-dependent covariables within survival models, the design of phase II cancer clinical trials which minimize some of the logistical problems associated with their conduct, and the analysis of longitudinal studies with informative censoring (in particular, quality of life studies of patients with advanced cancer).
Roger Edwin McLendon
Brain tumors are diagnosed in more than 20,000 Americans annually. The most malignant neoplasm, glioblastoma, is also the most common. Similarly, brain tumors constitute the most common solid neoplasm in children and include astrocytomas of the cerebellum, brain stem and cerebrum as well as medulloblastomas of the cerebellum. My colleagues and I have endeavored to translate the bench discoveries of genetic mutations and aberrant protein expressions found in brain tumors to better understand the processes involved in the etiology, pathogenesis, and treatment of brain tumors. Using the resources of the Preston Robert Brain Tumor Biorepository at Duke, our team, consisting of Henry Friedman, Allan Friedman, and Hai Yan and lead by Darell Bigner, have helped to identify mutations in Isocitrate Dehydrogenase (IDH1 and IDH2) as a marker of good prognosis in gliomas of adults. This test is now offered at Duke as a clinical test. Working with the Molecular Pathology Laboratory at Duke, we have also brought testing for TERT promoter region mutations as another major test for classifying gliomas in adults. Our collaboration with the Toronto Sick Kids Hospital has resulted in prognostic testing for childhood medulloblastomas, primitive neuroectodermal tumors, and ependymomas at Duke.
Darell Doty Bigner
The Causes, Mechanisms of Transformation and Altered Growth Control and New Therapy for Primary and Metastatic Tumors of the Central Nervous System (CNS).
There are over 16,000 deaths in the United States each year from primary brain tumors such as malignant gliomas and medulloblastomas, and metastatic tumors to the CNS and its covering from systemic tumors such as carcinoma of the lung, breast, colon, and melanoma. An estimated 80,000 cases of primary brain tumors were expected to be diagnosed last year. Of that number, approximately 4,600 diagnosed will be children less than 19 years of age. During the last 20 years, however, there has been a significant increase in survival rates for those with primary malignant brain tumors.
For the last 44 years my research has involved the investigation of the causes, mechanism of transformation and altered growth control, and development of new methods of therapy for primary brain tumors and those metastasizing to the CNS and its coverings. In collaboration with my colleagues in the Preston Robert Tisch Brain Tumor Center, new drugs and those not previously thought to be active against CNS tumors have been identified. Overcoming mechanisms of drug resistance in primary brain tumors are also being pursued.
As the founding Director of the Preston Robert Tisch Brain Tumor Center, I help coordinate the research activities of all 37 faculty members in the Brain Tumor Center. These faculty members have projects ranging from very basic research into molecular etiology, molecular epidemiology, signal transduction; translational research performing pre-clinical evaluation of new therapies, and many clinical investigative efforts. I can describe any of the Brain Tumor Center faculty member’s research to third year students and then direct them to specific faculty members with whom the students would like a discussion.
We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain. These include EGFRwt, EGFRvIII, and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate. We raised conventional and fully human monoclonal antibodies against most of these targets as well as having developed single fragment chain molecules from naïve human libraries.
My personal research focuses on molecularly targeted therapies of primary and metastatic CNS tumors with monoclonal antibodies and their fragments. Our study we conducted was with a molecule we discovered many years ago, the extracellular matrix molecule, Tenascin. We have treated over 150 malignant brain tumor patients with excellent results with a radiolabeled antibody we developed against Tenascin. We are collaborating with Dr. Ira Pastan at NIH to develop tumor-targeted therapies by fusing single fragment chain molecules from monoclonal antibodies or from naïve human libraries to the truncated fragment of pseudomonas exotoxin A. One example of this is the pseudomonas exotoxin conjugated to a single fragment chain antibody that reacts with wild type EGFR and EGFRvIII, two overexpressed proteins on glioblastoma. The immunotoxin, called D2C7-IT, is currently being investigated in an FDA dose-escalation study, in which patients undergoing treatment of this investigational new drug are showing positive responses. My laboratory is also working with Matthias Gromeier, creator of the oncolytic poliovirus - a re-engineered poliovirus that is lethal to cancer cells, but not lethal to normal cells. The oncolytic poliovirus therapeutic approach has shown such promising results in patients with glioblastoma, that it was recently featured on a on a special two-segment program of 60 Minutes. The next clinical step will be to combine both the virus and the immunotoxin with anti-PD1, an immune checkpoint blockade inhibitor and with anti-CD40, a fully human monoclonal antibody which converts tumor stimulant macrophages into tumor suppressive macrophages. We believe that regional tumor-targeted cytotoxic therapies, such as oncolytic poliovirus and the D2C7 immunotoxin, not only specifically target and destroy tumor cells, but in the process, initiate immune events that promote an in situ vaccine effect. That immune response can be amplified by human checkpoint blockade to engender a long-term systemic immune response that effectively eliminates recurrent and disseminated GBM cells. Ultimately, all three agents may be used together, providing different antigenic targets and cytotoxicity mechanisms.
We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain. These include glycoprotein non-metastatic B (GPNMB), a molecule shared with malignant melanoma; MRP3, a member of the multidrug resistant family; and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate. We are raising conventional monoclonal antibodies against all of these targets as well as developing single fragment chain molecules from naïve human libraries. When necessary, affinity maturation in vitro is carried out and the antibodies and fragments are armed either with radioactive iodine, radioactive lutetium, or radioactive Astatine-211. Other constructs are evaluated for unarmed activity and some are armed with Pseudomonas exotoxin. After development of the constructs, they are evaluated in human malignant glioma xenograft systems and then all studies necessary for Investigational New Drug Permits from the Food and Drug Administration are carried out prior to actual clinical trial.
I was senior author on a New England Journal of Medicine paper that was the first to show markedly increased survival in low to intermediate grade gliomas with an isocitrate dehydrogenase mutation.
The first fully funded Specialized Research Center on Primary and Metastatic Tumors to the CNS funded by the National Institutes of Health, of which I was Principal Investigator, was funded for 30 years at which time the type of grant was discontinued. My NCI MERIT Award, which ranked in the upper 1.2 percentile of all NIH grants at the time of its last review, is currently in its 40th year of continuous funding. It is one of the few MERIT awards awarded three consecutive times, and it is the longest continually funded grant of the NCI Division of Cancer Diagnosis and Treatment. My last NCI Award was an Outstanding Investigator Award from 2014 to 2022.
In addition to the representative publications listed, I have made national presentations and international presentations during the past year.
My laboratory has trained over 50 third year medical students, residents, Ph.D. students, and postdoctoral fellows and I have a great deal of experience in career development with some students having advanced all the way from fellowship status to endowed professorships. A major goal with third year medical students is to perform work that can be presented in abstract form at national or international meetings and to obtain publication in major peer-reviewed journals.
John Howard Sampson
Current research activities involve the immunotherapeutic targeting of a tumor-specific mutation in the epidermal growth factor receptor. Approaches used to target this tumor-specific epitope include unarmed and radiolabeled antibody therapy and cell mediated approaches using peptide vaccines and dendritic cells. Another area of interest involves drug delivery to brain tumors. Translational and clinical work is carried out in this area to formulate the relationship between various direct intratumoral infusion parameters and drug distribution within brain tumors and normal brain.
The Duke Brain Tumor Immunotherapy Program (BTIP) has an emphasis on translational research in Neuro-Oncology. There are two main areas of study. The first is novel mechanisms of delivery of large molecular weight molecules, such as monoclonal antibodies, throughout brain intersitial space using novel intracerebral infusion techniques developed by this laboratory. Studies exploring this technology are undertaken in both small and large laboratory animals and patients with brain tumors.
The other focus of the BTIP is translational immunotherapy. In this line of work, dendritic cell vaccination strategies and adoptive T-cell strategies have been developed to target novel and well-characterized tumor-specific antigens in patients with brain tumors. The BTIP integrates well with and works closely with the Preston Robert Tisch Brain Tumor Center at Duke. The BTIP is well funded and currently holds seven NIH grants, including a SPORE in Brain Cancer grant. There are a large number of investigators at various levels so that students will get exposure to various levels of research and mentorship.
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