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Michael Brown

Assistant Professor in Neurosurgery
Neurosurgery, Neuro-Oncology

Selected Publications


Elucidating cellular response to treatment with viral immunotherapies in pediatric high-grade glioma and medulloblastoma.

Journal Article Transl Oncol · February 2024 HSV G207, a double-stranded, DNA virus, and the polio:rhinovirus chimera, PVSRIPO, a single positive-strand RNA virus, are viral immunotherapies being used to treat pediatric malignant brain tumors in clinical trials. The purpose of this work is to elucida ... Full text Link to item Cite

Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas.

Journal Article Nat Commun · January 25, 2024 Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX, defining molecular alterations in IDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. ... Full text Link to item Cite

Understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma.

Journal Article J Clin Invest · January 16, 2024 Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to understand and therapeutically target the STING pathway in cancer have ensued. Relative ... Full text Link to item Cite

Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens.

Journal Article Nat Genet · December 2023 Clinical response to adoptive T cell therapies is associated with the transcriptional and epigenetic state of the cell product. Thus, discovery of regulators of T cell gene networks and their corresponding phenotypes has potential to improve T cell therapi ... Full text Link to item Cite

Early enterovirus translation deficits extend viral RNA replication and elicit sustained MDA5-directed innate signaling.

Journal Article mBio · November 14, 2023 Multiple pattern recognition receptors sense vRNAs and initiate downstream innate signaling: endosomal Toll-like receptors (TLRs) 3, 7, and 8 and cytoplasmic RIG-I-like receptors (RLRs) RIG-I, and MDA5. They engage distinct signaling scaffolds: mitochondri ... Full text Link to item Cite

Polio virotherapy targets the malignant glioma myeloid infiltrate with diffuse microglia activation engulfing the CNS.

Journal Article Neuro Oncol · September 5, 2023 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 constitu ... Full text Link to item Cite

Clinical Applications of Immunotherapy for Recurrent Glioblastoma in Adults.

Journal Article Cancers (Basel) · July 31, 2023 Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Despite standard therapies, including resection and chemoradiation, recurrence is virtually inevitable. Current treatment for recurrent glioblastoma (rGBM) is rapidly evolving, ... Full text Link to item Cite

Recombinant polio-rhinovirus immunotherapy for recurrent paediatric high-grade glioma: a phase 1b trial.

Journal Article Lancet Child Adolesc Health · July 2023 BACKGROUND: Outcomes of recurrent paediatric high-grade glioma are poor, with a median overall survival of less than 6 months. Viral immunotherapy, such as the polio-rhinovirus chimera lerapolturev, is a novel approach for treatment of recurrent paediatric ... Full text Link to item Cite

Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils.

Journal Article J Immunother Cancer · April 2023 BACKGROUND: Antitumor mechanisms of CD4+ T cells remain crudely defined, and means to effectively harness CD4+ T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+ T cells hold potential to be leveraged for this purpose. Moreover, the ... Full text Link to item Cite

CD155 is a putative therapeutic target in medulloblastoma.

Journal Article Clin Transl Oncol · March 2023 BACKGROUND: Medulloblastoma is the most common pediatric malignant brain tumor, consisting of four molecular subgroups (WNT, SHH, Group 3, Group 4) and 12 subtypes. Expression of the cell surface poliovirus receptor (PVR), CD155, is necessary for entry of ... Full text Link to item Cite

Functional reprogramming of peripheral blood monocytes by soluble mediators in patients with pancreatic cancer and intraductal papillary mucinous neoplasms.

Journal Article Front Immunol · 2023 BACKGROUND: Monocytes and monocyte-derived tumor infiltrating cells have been implicated in the immunosuppression and immune evasion associated with pancreatic adenocarcinoma (PDAC). Yet, precisely how monocytes in the periphery and tumor microenvironment ... Full text Link to item Cite

Multimodality analysis confers a prognostic benefit of a T-cell infiltrated tumor microenvironment and peripheral immune status in patients with melanoma.

Journal Article Journal for immunotherapy of cancer · September 2022 BackgroundWe previously reported results from a phase 1 study testing intratumoral recombinant poliovirus, lerapolturev, in 12 melanoma patients. All 12 patients received anti-PD-1 systemic therapy before lerapolturev, and 11 of these 12 patients ... Full text Cite

PKR Binds Enterovirus IRESs, Displaces Host Translation Factors, and Impairs Viral Translation to Enable Innate Antiviral Signaling.

Journal Article mBio · June 28, 2022 For RNA virus families except Picornaviridae, viral RNA sensing includes Toll-like receptors and/or RIG-I. Picornavirus RNAs, whose 5' termini are shielded by a genome-linked protein, are predominately recognized by MDA5. This has important ramifications f ... Full text Link to item Cite

Predictive factors of neoadjuvant immune checkpoint blockade in melanoma.

Journal Article Hum Vaccin Immunother · May 31, 2022 This review describes the current body of literature and ongoing clinical trials examining neoadjuvant immune checkpoint inhibitors (ICI) for patients with resectable stage III and IV melanoma. Based on prior success in treating metastatic melanoma and as ... Full text Link to item Cite

Engaging Pattern Recognition Receptors in Solid Tumors to Generate Systemic Antitumor Immunity.

Journal Article Cancer Treat Res · 2022 Malignant tumors frequently exploit innate immunity to evade immune surveillance. The priming, function, and polarization of antitumor immunity fundamentally depends upon context provided by the innate immune system, particularly antigen presenting cells. ... Full text Link to item Cite

Elucidating cellular response to treatment with viral immunotherapies in pediatric high-grade glioma and medulloblastoma.

Journal Article Transl Oncol · February 2024 HSV G207, a double-stranded, DNA virus, and the polio:rhinovirus chimera, PVSRIPO, a single positive-strand RNA virus, are viral immunotherapies being used to treat pediatric malignant brain tumors in clinical trials. The purpose of this work is to elucida ... Full text Link to item Cite

Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas.

Journal Article Nat Commun · January 25, 2024 Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX, defining molecular alterations in IDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. ... Full text Link to item Cite

Understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma.

Journal Article J Clin Invest · January 16, 2024 Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to understand and therapeutically target the STING pathway in cancer have ensued. Relative ... Full text Link to item Cite

Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens.

Journal Article Nat Genet · December 2023 Clinical response to adoptive T cell therapies is associated with the transcriptional and epigenetic state of the cell product. Thus, discovery of regulators of T cell gene networks and their corresponding phenotypes has potential to improve T cell therapi ... Full text Link to item Cite

Early enterovirus translation deficits extend viral RNA replication and elicit sustained MDA5-directed innate signaling.

Journal Article mBio · November 14, 2023 Multiple pattern recognition receptors sense vRNAs and initiate downstream innate signaling: endosomal Toll-like receptors (TLRs) 3, 7, and 8 and cytoplasmic RIG-I-like receptors (RLRs) RIG-I, and MDA5. They engage distinct signaling scaffolds: mitochondri ... Full text Link to item Cite

Polio virotherapy targets the malignant glioma myeloid infiltrate with diffuse microglia activation engulfing the CNS.

Journal Article Neuro Oncol · September 5, 2023 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 constitu ... Full text Link to item Cite

Clinical Applications of Immunotherapy for Recurrent Glioblastoma in Adults.

Journal Article Cancers (Basel) · July 31, 2023 Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Despite standard therapies, including resection and chemoradiation, recurrence is virtually inevitable. Current treatment for recurrent glioblastoma (rGBM) is rapidly evolving, ... Full text Link to item Cite

Recombinant polio-rhinovirus immunotherapy for recurrent paediatric high-grade glioma: a phase 1b trial.

Journal Article Lancet Child Adolesc Health · July 2023 BACKGROUND: Outcomes of recurrent paediatric high-grade glioma are poor, with a median overall survival of less than 6 months. Viral immunotherapy, such as the polio-rhinovirus chimera lerapolturev, is a novel approach for treatment of recurrent paediatric ... Full text Link to item Cite

Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils.

Journal Article J Immunother Cancer · April 2023 BACKGROUND: Antitumor mechanisms of CD4+ T cells remain crudely defined, and means to effectively harness CD4+ T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+ T cells hold potential to be leveraged for this purpose. Moreover, the ... Full text Link to item Cite

CD155 is a putative therapeutic target in medulloblastoma.

Journal Article Clin Transl Oncol · March 2023 BACKGROUND: Medulloblastoma is the most common pediatric malignant brain tumor, consisting of four molecular subgroups (WNT, SHH, Group 3, Group 4) and 12 subtypes. Expression of the cell surface poliovirus receptor (PVR), CD155, is necessary for entry of ... Full text Link to item Cite

Functional reprogramming of peripheral blood monocytes by soluble mediators in patients with pancreatic cancer and intraductal papillary mucinous neoplasms.

Journal Article Front Immunol · 2023 BACKGROUND: Monocytes and monocyte-derived tumor infiltrating cells have been implicated in the immunosuppression and immune evasion associated with pancreatic adenocarcinoma (PDAC). Yet, precisely how monocytes in the periphery and tumor microenvironment ... Full text Link to item Cite

Multimodality analysis confers a prognostic benefit of a T-cell infiltrated tumor microenvironment and peripheral immune status in patients with melanoma.

Journal Article Journal for immunotherapy of cancer · September 2022 BackgroundWe previously reported results from a phase 1 study testing intratumoral recombinant poliovirus, lerapolturev, in 12 melanoma patients. All 12 patients received anti-PD-1 systemic therapy before lerapolturev, and 11 of these 12 patients ... Full text Cite

PKR Binds Enterovirus IRESs, Displaces Host Translation Factors, and Impairs Viral Translation to Enable Innate Antiviral Signaling.

Journal Article mBio · June 28, 2022 For RNA virus families except Picornaviridae, viral RNA sensing includes Toll-like receptors and/or RIG-I. Picornavirus RNAs, whose 5' termini are shielded by a genome-linked protein, are predominately recognized by MDA5. This has important ramifications f ... Full text Link to item Cite

Predictive factors of neoadjuvant immune checkpoint blockade in melanoma.

Journal Article Hum Vaccin Immunother · May 31, 2022 This review describes the current body of literature and ongoing clinical trials examining neoadjuvant immune checkpoint inhibitors (ICI) for patients with resectable stage III and IV melanoma. Based on prior success in treating metastatic melanoma and as ... Full text Link to item Cite

Engaging Pattern Recognition Receptors in Solid Tumors to Generate Systemic Antitumor Immunity.

Journal Article Cancer Treat Res · 2022 Malignant tumors frequently exploit innate immunity to evade immune surveillance. The priming, function, and polarization of antitumor immunity fundamentally depends upon context provided by the innate immune system, particularly antigen presenting cells. ... Full text Link to item Cite

739 Intratumor childhood vaccine-specific CD4+ T cell recall helps antitumor CD8 T cells

Conference Journal for ImmunoTherapy of Cancer · November 2021 BackgroundPVSRIPO, a recombinant poliovirus derived from the live-attenuated Sabin oral polio vaccine strain, is being tested in multi-institutional phase II clinical trials for recurrent glioblastoma ( Full text Cite

Enterovirus 2Apro Cleavage of the YTHDF m6A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling.

Journal Article mBio · April 13, 2021 Enteroviruses (EV) deploy two proteases that mediate viral polyprotein cleavage and host cell manipulation. Here, we report that EV 2A proteases cleave all three members of the YTHDF protein family, cytosolic N6-methyladenosine (m6A) "readers" that regulat ... Full text Link to item Cite

Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling.

Journal Article Nat Commun · March 25, 2021 Activating intra-tumor innate immunity might enhance tumor immune surveillance. Virotherapy is proposed to achieve tumor cell killing, while indirectly activating innate immunity. Here, we report that recombinant poliovirus therapy primarily mediates antit ... Full text Link to item Cite

Aryl Hydrocarbon Receptor Signaling Controls CD155 Expression on Macrophages and Mediates Tumor Immunosuppression.

Journal Article J Immunol · March 15, 2021 Crosstalk between costimulatory and coinhibitory ligands are a prominent node of immune cell regulation. Mounting evidence points toward a critical role for CD155, the poliovirus receptor, in suppressing T cell function, particularly in cancer. However, re ... Full text Link to item Cite

Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.

Journal Article Nat Commun · January 13, 2021 Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10-20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunother ... Full text Open Access Link to item Cite

Harnessing virus tropism for dendritic cells for vaccine design.

Journal Article Curr Opin Virol · October 2020 Dendritic cells (DCs) are pivotal stimulators of T cell responses. They provide essential signals (epitope presentation, proinflammatory cytokines, co-stimulation) to T cells and prime adaptive immunity. Therefore, they are paramount to immunization strate ... Full text Link to item Cite

Genetically stable poliovirus vectors activate dendritic cells and prime antitumor CD8 T cell immunity.

Journal Article Nat Commun · January 27, 2020 Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses can provide a context optimal for generating antigen-specific CD8 T cells, as they have natural tropism for dendrit ... Full text Link to item Cite

Oncolytic poliovirus immunotherapy for breast cancer

Conference JOURNAL OF IMMUNOLOGY · 2020 Cite

The Emerging Role of Surgery for Patients With Advanced Melanoma Treated With Immunotherapy.

Journal Article J Surg Res · April 2019 BACKGROUND: The emergence of immune checkpoint inhibitors (ICIs) has improved survival for patients with metastatic melanoma. The types of disease-response patterns to ICI therapy can be more complex relative to traditional chemotherapy and include mixed r ... Full text Link to item Cite

Engineered Oncolytic Poliovirus PVSRIPO Subverts MDA5-Dependent Innate Immune Responses in Cancer Cells.

Journal Article J Virol · October 1, 2018 We are pursuing cancer immunotherapy with a neuro-attenuated recombinant poliovirus, PVSRIPO. PVSRIPO is the live attenuated type 1 (Sabin) poliovirus vaccine carrying a heterologous internal ribosomal entry site (IRES) of human rhinovirus type 2 (HRV2). I ... Full text Link to item Cite

Poliovirus Receptor (CD155) Expression in Pediatric Brain Tumors Mediates Oncolysis of Medulloblastoma and Pleomorphic Xanthoastrocytoma.

Journal Article J Neuropathol Exp Neurol · August 1, 2018 Poliovirus oncolytic immunotherapy is a putatively novel approach to treat pediatric brain tumors. This work sought to determine expression of the poliovirus receptor (PVR), CD155, in low-grade and malignant pediatric brain tumors and its ability to infect ... Full text Link to item Cite

Abstract LB-302: Oncolytic poliovirus-mediated inflammation and immunity in breast cancer

Conference Cancer Research · July 1, 2018 AbstractBreast cancer is the most common malignancy among women in the United States and the second leading cause of cancer deaths in women. Disease prognosis, local recurrence rates and response to therapy ... Full text Cite

Regulation of Hypoxia-Inducible Factor 1α during Hypoxia by DAP5-Induced Translation of PHD2.

Journal Article Mol Cell Biol · June 1, 2018 Death-associated protein 5 (DAP5) is an atypical isoform of the translation initiation scaffolds eukaryotic initiation factor 4GI (eIF4GI) and eIF4GII (eIF4GI/II), which recruit mRNAs to ribosomes in mammals. Unlike eIF4GI/II, DAP5 binds eIF2β, a subunit o ... Full text Link to item Cite

XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype.

Journal Article Cancer Res · April 1, 2018 Hyperactivation of the NFκB pathway is a distinct feature of inflammatory breast cancer (IBC), a highly proliferative and lethal disease. Gene expression studies in IBC patient tissue have linked EGFR (EGFR/HER2)-mediated MAPK signaling to NFκB hyperactivi ... Full text Link to item Cite

Chemotherapy enhances oncolytic recombinant poliovirus efficacy

Conference JOURNAL FOR IMMUNOTHERAPY OF CANCER · November 7, 2017 Link to item Cite

PVSRIPO is an interferon-resistant, immunotherapeutic oncolytic virus

Conference JOURNAL FOR IMMUNOTHERAPY OF CANCER · November 7, 2017 Link to item Cite

Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of dendritic cells and tumor antigen-specific CTLs.

Journal Article Sci Transl Med · September 20, 2017 Tumors thrive in an immunosuppressive microenvironment that impedes antitumor innate and adaptive immune responses. Thus, approaches that can overcome immunosuppression and engage antitumor immunity are needed. This study defines the adjuvant and cancer im ... Full text Link to item Cite

MNK Controls mTORC1:Substrate Association through Regulation of TELO2 Binding with mTORC1.

Journal Article Cell Rep · February 7, 2017 The mechanistic target of rapamycin (mTOR) integrates numerous stimuli and coordinates the adaptive response of many cellular processes. To accomplish this, mTOR associates with distinct co-factors that determine its signaling output. While many of these c ... Full text Link to item Cite

MNK inversely regulates TELO2 vs. DEPTOR to control mTORC1 signaling.

Journal Article Mol Cell Oncol · 2017 mTORC1 is the major homeostatic nutrient sensor for the cell. As such, it is integrated into diverse signaling networks and co-factor interactions that determine its activity. Our recent work implicates the mTORC1 co-factor and PI3K-related Kinase (PIKK) s ... Full text Link to item Cite

Recombinant oncolytic poliovirus, PVSRIPO, has potent cytotoxic and innate inflammatory effects, mediating therapy in human breast and prostate cancer xenograft models.

Journal Article Oncotarget · November 29, 2016 Intratumoral inoculation of viruses with tumor-selective cytotoxicity may induce cancer cell death and, thereby, shrink neoplastic lesions. It is unlikely, however, that viral tumor cell killing alone could produce meaningful, durable clinical responses, a ... Full text Link to item Cite

Abstract A157: Oncolytic poliovirus mediated immune events

Journal Article Cancer Immunology Research · January 1, 2016 AbstractIntroduction: Tumor-targeted therapies that efficiently eliminate malignant cells and in the process engage the innate and adaptive immune system are desirable for preventing cancer recurrence. We ha ... Full text Cite

Cytotoxic and immunogenic mechanisms of recombinant oncolytic poliovirus.

Journal Article Curr Opin Virol · August 2015 An oncolytic virus (OV) based on poliovirus (PV), the highly attenuated polio/rhinovirus recombinant PVSRIPO, may deliver targeted inflammatory cancer cell killing; a principle that is showing promise in clinical trials for recurrent glioblastoma (GBM). Th ... Full text Link to item Cite

Oncolytic immunotherapy through tumor-specific translation and cytotoxicity of poliovirus.

Journal Article Discov Med · May 2015 Achieving tumor-specific, robust, and durable effector cytotoxic immune responses is key to successful immunotherapy. This has been accomplished with adoptive cell transfer of ex vivo-expanded autologous tumor-infiltrating or engineered T cells, or with im ... Link to item Cite

Autoimmunity to the alpha 3 chain of type IV collagen in glomerulonephritis is triggered by 'autoantigen complementarity'.

Journal Article J Autoimmun · May 2015 'Autoantigen complementarity' is a theory proposing that the initiator of an autoimmune response is not necessarily the autoantigen or its molecular mimic, but may instead be a peptide that is 'antisense/complementary' to the autoantigen. We investigated w ... Full text Link to item Cite

Oncolytic polio virotherapy of cancer.

Journal Article Cancer · November 1, 2014 Recently, the century-old idea of targeting cancer with viruses (oncolytic viruses) has come of age, and promise has been documented in early stage and several late-stage clinical trials in a variety of cancers. Although originally prized for their direct ... Full text Link to item Cite

Induction of viral, 7-methyl-guanosine cap-independent translation and oncolysis by mitogen-activated protein kinase-interacting kinase-mediated effects on the serine/arginine-rich protein kinase.

Journal Article J Virol · November 2014 UNLABELLED: Protein synthesis, the most energy-consuming process in cells, responds to changing physiologic priorities, e.g., upon mitogen- or stress-induced adaptations signaled through the mitogen-activated protein kinases (MAPKs). The prevailing status ... Full text Link to item Cite

Mitogen-activated protein kinase-interacting kinase regulates mTOR/AKT signaling and controls the serine/arginine-rich protein kinase-responsive type 1 internal ribosome entry site-mediated translation and viral oncolysis.

Journal Article J Virol · November 2014 UNLABELLED: Translation machinery is a major recipient of the principal mitogenic signaling networks involving Raf-ERK1/2 and phosphoinositol 3-kinase (PI3K)-mechanistic target of rapamycin (mTOR). Picornavirus internal ribosomal entry site (IRES)-mediated ... Full text Link to item Cite

T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation.

Journal Article Proc Natl Acad Sci U S A · April 8, 2014 Endotoxemia is caused by excessive inflammation, but the immune system has various mechanisms to avoid collateral organ damage in endotoxemia. A handful of reports have shown that innate immune responses are suppressed by the adaptive immune system. Howeve ... Full text Link to item Cite

Mitotic phosphorylation of eukaryotic initiation factor 4G1 (eIF4G1) at Ser1232 by Cdk1:cyclin B inhibits eIF4A helicase complex binding with RNA.

Journal Article Mol Cell Biol · February 2014 During mitosis, global translation is suppressed, while synthesis of proteins with vital mitotic roles must go on. Prior evidence suggests that the mitotic translation shift involves control of initiation. Yet, no signals specifically targeting translation ... Full text Link to item Cite

Anti-LAMP-2 antibodies are not prevalent in patients with antineutrophil cytoplasmic autoantibody glomerulonephritis.

Journal Article J Am Soc Nephrol · March 2012 Lysosomal membrane protein 2 (LAMP-2) is a target of antineutrophil cytoplasmic autoantibodies (ANCA) in addition to the more commonly known targets proteinase 3 and myeloperoxidase. The prevalence of anti-LAMP-2 antibodies and their relationship to diseas ... Full text Link to item Cite