Polio virotherapy targets the malignant glioma myeloid infiltrate with diffuse microglia activation engulfing the CNS.
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2023-09
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Abstract
Background
Malignant gliomas commandeer dense inflammatory infiltrates with glioma-associated macrophages and microglia (GAMM) promoting immune suppression, evasion, and tumor progression. Like all cells in the mononuclear phagocytic system, GAMM constitutively express the poliovirus receptor, CD155. Besides myeloid cells, CD155 is widely upregulated in the neoplastic compartment of malignant gliomas. Intratumor treatment with the highly attenuated rhino:poliovirus chimera, PVSRIPO, yielded long-term survival with durable radiographic responses in patients with recurrent glioblastoma (Desjardins et al. New England Journal of Medicine, 2018). This scenario raises questions about the contributions of myeloid versus neoplastic cells to polio virotherapy of malignant gliomas.Methods
We investigated PVSRIPO immunotherapy in immunocompetent mouse brain tumor models with blinded, board-certified neuropathologist review, a range of neuropathological, immunohistochemical, and immunofluorescence analyses, and RNAseq of the tumor region.Results
PVSRIPO treatment caused intense engagement of the GAMM infiltrate associated with substantial, but transient tumor regression. This was accompanied by marked microglia activation and proliferation in normal brain surrounding the tumor, in the ipsilateral hemisphere and extending into the contralateral hemisphere. There was no evidence for lytic infection of malignant cells. PVSRIPO-instigated microglia activation occurred against a backdrop of sustained innate antiviral inflammation, associated with induction of the Programmed Cell Death Ligand 1 (PD-L1) immune checkpoint on GAMM. Combining PVSRIPO with PD1/PD-L1 blockade led to durable remissions.Conclusions
Our work implicates GAMM as active drivers of PVSRIPO-induced antitumor inflammation and reveals profound and widespread neuroinflammatory activation of the brain-resident myeloid compartment by PVSRIPO.Type
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Yang, Yuanfan, Michael C Brown, Gao Zhang, Kevin Stevenson, Malte Mohme, Reb Kornahrens, Darell D Bigner, David M Ashley, et al. (2023). Polio virotherapy targets the malignant glioma myeloid infiltrate with diffuse microglia activation engulfing the CNS. Neuro-oncology, 25(9). pp. 1631–1643. 10.1093/neuonc/noad052 Retrieved from https://hdl.handle.net/10161/32183.
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Scholars@Duke
Michael Brown
Dr. Brown’s research focuses on leveraging intratumor innate immunity for cancer immunotherapy, particularly in the context of malignant brain tumors. Dr. Brown's lab uses mouse cancer models, ex vivo human tumor slice culture assays, and clinical trial associated specimens to decode mechanisms by which intratumor innate immune cells control cancer immune surveillance and develop novel in situ vaccine approaches that engage endogenous antitumor T cells. The Brown lab also collaborates with clinicians and other research groups to facilitate the translation of novel therapies, define determinants of successful immunotherapy, and elucidate mechanisms explaining immune dysfunction in patients with cancer.
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.
Giselle Yvette López
I am a physician scientist with a clinical focus on neuropathology, and a research interest in brain tumors. Originally from Maryland, I completed my undergraduate training at the University of Maryland, completing degrees in Physiology and Neurobiology as well as Spanish Language and Literature. I subsequently came to Duke for my MD and PhD, and discovered a passion for brain tumor research, and quickly realized that this was my life's calling. Clinically, I specialize in neuropathology. While I have active projects and collaborations on many kinds of brain tumors, my lab's primary focus is oligodendroglioma, a kind of infiltrative brain tumor that impacts adults. Our goal is to identify new ways to treat these tumors and improve the lives of patients with oligodendrogliomas and other kinds of brain tumors. By blending together computational approaches with wet lab approaches, we use the strengths inherent in different research modalities to excel in identifying unexplored pathways and thinking outside the box to identify new ways to target this brain tumor. We do this through research in an inclusive, multidisciplinary lab environment that strives for excellence in research while creating well-rounded, thriving scientists ready for the next step in their careers.
Research Opportunities
We currently have opportunities in the laboratory for one-year projects (ideal for post-bac fellows or third year med student research experiences). These projects are centered on identifying and testing novel therapeutic approaches for oligodendroglioma using in vitro and in vivo model systems. Please reach out if you are interested and would like to hear more about my mentoring philosophy, lab culture, and opportunities to be at the cutting edge of science.
Matthias Gromeier
I am a classically trained virologist with a focus on molecular mechanisms of RNA virus pathogenesis. My career is dedicated to unraveling RNA virus:host relations and devising methods of exploiting them for cancer immunotherapy and vaccine design. My background is in translation regulation and mRNA metabolism, viral RNA sensing and innate immunity, and cancer immunology and immunotherapy. Basic mechanistic research in my laboratory is supporting an ambitious clinical translational research program with active multi-center clinical trials in several cancer indications.
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