A peptide vaccine targeting the CMV antigen pp65 in children and young adults with recurrent high-grade glioma and medulloblastoma: a phase 1 trial.
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2025-09
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The human cytomegalovirus (CMV) antigen pp65 is expressed in high-grade glioma (HGG) and medulloblastoma but not in the adjacent brain. This single-arm phase 1 trial ( NCT03299309 ) assessed the safety and immunogenicity of a peptide vaccine (PEP-CMV) targeting pp65 in individuals (3-35 years old) with recurrent HGG or medulloblastoma. Thirty-six individuals with HGG received PEP-CMV. The mean age was 22.75 ± 9.34 years. The primary outcome, percentage of unacceptable toxicity, was met. The maximum-grade adverse events (AE) related to PEP-CMV were 17 grade 1 AEs, 15 grade 2 AEs, 1 grade 3 AE (pyramidal tract syndrome) and 1 grade 4 AE (cerebral edema). As a secondary outcome, in 21 individuals with evaluable data, T cell reactivity, measured as change in baseline interferon-γ pp65 enzyme-linked immunospot assay reactivity, had an estimated increase of 46 spots (95% confidence interval (95% CI): 8, 194) after treatment with PEP-CMV. As exploratory endpoints, the median progression-free survival was 2.5 months (95% CI: 2.2, 3.2), and median overall survival was 6.5 months (95% CI: 4.6, 8.4). PEP-CMV is well tolerated and elicits an antigen-specific immune response in individuals with multiply recurrent HGG. Only two individuals with medulloblastoma were enrolled, showing one grade 3 encephalopathy possibly related to PEP-CMV, while neither had postvaccine immune assessments due to progression-free survival and overall survival less than 2 months.
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Thompson, Eric M, David M Ashley, Katayoun Ayasoufi, Pamela Norberg, Gerald Archer, Evan D Buckley, James E Herndon, Ashley Walter, et al. (2025). A peptide vaccine targeting the CMV antigen pp65 in children and young adults with recurrent high-grade glioma and medulloblastoma: a phase 1 trial. Nature cancer, 6(9). pp. 1559–1569. 10.1038/s43018-025-00998-z Retrieved from https://hdl.handle.net/10161/34360.
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Scholars@Duke
David Michael Ashley
My career in cancer research dates more than two decades. I am credentialed in both pediatric and adult neuro-oncology practice and this has been the focus of my efforts in translational research and leadership. As evident from my publication and grant support record, my primary academic focus has been on neurologic tumors, the development of innovative therapies and approaches to care. These efforts have included basic and translational laboratory research. My experience includes moving laboratory findings in brain tumor immunology and epigenetics into early phase clinical trials. I have expertise in immuno-oncology, having developed and clinically tested dendritic cell vaccines and other immuno-therapeutics. My achievements in research have led to change in practice in the care of children and adults with brain tumors, including the introduction of new standards of practice for the delivery of systemic therapy. I am highly regarded for this work, as evidenced by numerous invitations to plenary sessions and symposia of international standing. I have been the principal investigator of a number of important national and international studies, both clinical and pre-clinical. I am recognized as a senior figure and opinion leader in neuro-oncology nationally and internationally. I have held several significant leadership roles, including Director of two major cancer centers, I served as the Chair of Medicine at Deakin University, the Program Director of Cancer Services at University Hospital Barwon Health, and Executive Director of the Western Alliance Academic Health Science Centre (Australia). I began my current position as Director of The Preston Robert Tisch Brain Tumor Center, Head, Preuss Laboratory, in March 2018. In this role, I am responsible for the clinical care, research, and educational program related to Brain Tumor Center. I am also a senior investigational neuro-oncologist within the adult brain tumor program at Duke.
Katayoun Ayasoufi
I am an assistant professor in the Department of Neurosurgery at Duke University. I am interested in mechanisms of immunosuppression following various neurological insults. I am a classically trained Immunologists. My PhD work was focused on drug-induced immunosuppression and mechanisms of immune reconstitution in mouse models of transplantation. Briefly, I discovered that a common lymphocyte depleting drug, ATG, leaves behind a population of memory CD4 T cells. These residual memory CD4 T cells are required for reconstitution of CD8 T cells and optimal thymic function to produce new T cells.
As a postdoc, I was fascinated by the neuroimmune connections in brain cancer and during other brain injuries. My expertise in mechanisms of immunosuppression and immune reconstitution allowed me to study neurological-injury induced immunosuppression. Both acute and chronic neurological diseases induce severe peripheral immunosuppression including low CD4 T cell count, immune organ atrophy, and lower MHCII expression on APCs. For example, GBM patients have CD4 T cell counts as low as AIDS patients. Yet, the mechanisms of such profound immunosuppression remains unknown. During my postdoc, I was able to determine hallmark features of peripheral immunosuppression described in patients also occur in mice using novel mouse models. We determined that soluble actors released during brain injury mediate most hallmark features of immunosuppression using parabiosis. These included low CD4 T cells count, MHCII downregulation, and thymic involution. We further discovered that serum-derived non-steroidal factors with molecular weights larger than 100kDa are responsible for the peripheral immunosuppression in mouse models of GBM. Similar soluble factor mediated immunosuppression was in play in other non-cancerous brain injuries as well.
I am continuing this line of work and investigating the identity of soluble factors involved in mediating peripheral immunosuppression in GBM and other brain injuries in my independent laboratory. GBM is incurable and associated with severe immunosuppression systemically. Most immune-modulating therapies will fail in the presence of severe immunosuppression. Our goal is to determine what causes peripheral immunosuppression and devise strategies to reverse it. This is the first step in developing novel therapeutics for GBM patients. Our work is also relevant to other neurological diseases and will be applicable to a large cohort of patients with acute and chronic neurological diseases.
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).
Kristin M. Schroeder
I have a strong belief that all children diagnosed with cancer should have the same chance of cure regardless of where they live. Since 2014, i have spent six or more months per year in Mwanza, Tanzania, at the Bugando Medical Centre as part of the Duke Global Cancer Program. In addition to developing capacity for pediatric cancer care, my research focuses on creating interventions to improve outcomes and reducing treatment abandonment in low resource settings.
As a trained pediatric neuro-oncologist, I am also involved in neuro-oncology capacity development in Sub-Saharan Africa, and am collaborating with a multidisciplinary team in Tanzania to establish diagnostic and treatment opportunities for patients.
Annick Desjardins
Margaret Johnson
I am a neuro-oncologist, neurologist, and palliative care physician at the Preston Robert Tisch Brain Tumor Center. I also provide neuro-oncology expertise for the National Tele-Oncology Program and National Precision Oncology Program at the Veteran's Health Administration. My clinical and research interests encompass supportive care and palliative care with a special interest in older adults with brain tumors. The incidence of malignant brain tumors like glioblastoma and non-malignant tumors like meningioma affect aging populations and it is crucial to be able to provide better care for these patients.
Katherine Barnett Peters
Katy Peters, MD, PhD, FAAN is a professor of neurology and neurosurgery at the Preston Robert Tisch Brain Tumor Center (PRTBTC) at Duke. Her academic medical career started at Stanford University School of Medicine, receiving an MD and Ph.D. in Cancer Biology. After completing a neurology residency at Johns Hopkins University and a fellowship in cognitive neurosciences, Katy joined the PRTBTC as a neuro-oncology fellow. In 2009, she became a faculty member at PRTBTC. With a fantastic team of nursing and advanced practice providers, she actively sees and cares for patients with primary brain tumors. Her research interests include supportive care for brain cancer patients, cognitive dysfunction in cancer patients, and physical function and activity of brain cancer patients. While she runs clinical trials to treat primary brain tumors, her key interest is on clinical trials that focus on improving brain tumor patients' quality of life and cognition. In 2019, the PRTBTC designated her as the Director of Supportive Care, thus furthering the PRTBTC and her committee to better the quality of life for brain tumor patients. She is active in teaching medical school students, residents, fellows, and advanced practice providers and is the Program Director of the PRTBRC neuro-oncology fellowship. She is board certified by the American Board of Psychiatry and Neurology and the United Council of Neurologic Subspecialties for neuro-oncology.
Mustafa Khasraw
I am a physician-scientist with a background in medical oncology and neuro-oncology, with affiliations to multiple departments, research, and training programs at Duke.
I lead a Tumor Immunology Lab where we use various wet and dry lab techniques to understand the interactions between tumors and the immune system. Our goal is to identify vulnerabilities that can be targeted for novel therapies.
I serve as the Deputy Director of the Center for Cancer Immunotherapy at the Duke Cancer Institute where we are tasked to facilitate clinical research and translate promising discoveries made by scientists across various departments and cancer types at Duke, particularly in the field of immune and T cell-based therapies.
My team and our laboratory operate in an environment that enables the transition from bench-side basic scientific discoveries to clinical trials, and back to the bench ensuring the evaluation of new treatments for cancer patients.
Henry Seth Friedman
Overview: Our laboratory is pursuing a comprehensive analysis of the biology and therapy of adult and childhood central nervous system malignancies, particularly high-grade medulloblastoma, glioma, and ependymoma.
Laboratory Studies: Active programs, using human adult and pediatric CNS tumor continuous cell lines, transplantable xenografts growing subcutaneously and intracranially in athymic nude mice and rats, and as well as in the subarachnoid space of the athymic nude rats, and patients tumor specimens, are defining:
1) the chemotherapeutic profile of medulloblastoma, adult and childhood glioma and ependymoma
2) mechanisms of resistance to classical bifunctional alkylators, nitrosoureas and methylators operational in malignant glioma and medulloblastoma, particularly DNA adduct and crosslink repair, O6-alkylguanine-DNA alkyltransferase elevation and DNA mismatch repair deficiency.
3) modulations designed to over come or circumvent specific mechanisms of resistance
4) the activity of signal pathway inhibitors of EGFR, m-tor and other targets
5) the therapeutic advantages of intrathecal and intratumoral drug delivery in the treatment of neoplastic meningitis and intracranial malignancies, respectively.
The results of the therapeutic studies to date have demonstrated the marked activity of alkylating agents, particularly melphalan and cyclophosphamide and the role of glutathione, AGT glutathione-S-transferase, abnormal drug transport and alterations in formation and repair of DNA-DNA crosslinks in modulating cytotoxicity of these agents. Modulations shown to be effective in enhancing alkylator activity/reversing alkylator resistance include BSO-mediated glutathione depletion, inhibition of DNA-DNA crosslink repair and inhibition of 06-alkylguanine-DNA alkyltransferase by 06-benzylguanine. Recent studies have demonstrated profound activity of temozolomide, CPT-11 topotecan, irofulven, and karenitecin as well as the combination of CPT-11 or topotecan plus BCNU or temozolomide. Successful treatment of neoplastic meningitis in nude rats with intrathecal 4-hydroperoxycyclophosphamide, melphalan, temozolomide and busulfan, and intracranial glioma in nude rats with intratumoral temozolomide has also been demonstrated. More recent studies have revealed cyclophosphamide resistance secondary to DNA interstrand crosslink repair. Additional studies have shown that cyclophosphamide crosslinks are formed at the 1,3 N7 position, serving as the basis for construction of a defined crosslink in a plasmid vector to assay for crosslink repair and allowing demonstration of the lack of a role of nucleotide excision repair. Mismatch repair deficiency has been shown as a mechanism mediating acquired methylator (procarbazine and temozolomide) resistance in an adult glioblastoma xenograft.
Clinical Studies: Clinical investigations are designed to translate laboratory programs into successful treatment for adults and children with malignant brain tumors, particularly medulloblastoma. Clinical trials for adults include phase II trials of temozolomide, ZD1839 (Iressa), karenitecin, and temozolomide plus O6-BG as well as phase I trials of topotecan plus BCNU, CPT-11 plus temozolomide, and PTK787 ± temozolomide or CCNU. Studies are in progress in children evaluating the activity CPT-11 plus temozolomide, intrathecal busulfan and cyclophosphamide/melphalan or cyclophosphamide/busulfan plus autologous bone marrow support . Extension of these studies to a larger cohort of patients is being performed nationally under the auspices of the Pediatric Brain Tumor Consortium (Henry S. Friedman -- Head of New Agents Committee).
Future studies will address the role of agents designed to decrease repair of interstrand crosslinks when given in combination with alkylating agents, as well as newer signal pathway inhibitors such as RAD001, PKI166, and DB-67.
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.
Daniel Bryce Landi
Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.