SNO Basic and Translational Research Conference: Day 2 Summary
Nazanin Majd, MD, PhD
Chaired by Vinay Puduvalli, Chair and Professor of Neuro-Oncology at MD Anderson Cancer Center and Erik Sulman, Vice Chair for Research and Professor of Radiation-Oncology at New York University, the SNO led two-day Basic and Translational Science Conference was held virtually on July 15-16th, 2021, with the goal of bridging laboratory discoveries into clinical benefit for neuro-oncology patients. Below is a high-level overview of day 2 of the conference which was divided into three main sessions: Immuno-Oncology, Microenvironment, and Epigenetics.
Moderated by Shiao-Pei Weathers from MD Anderson Cancer Center, the first session of the day started with a lecture by Hideo Okada from University of California, San Francisco, titled “Use of Omics to Understand T cell Responses in Patients with Glioma.” Dr. Okada first described the use of mass cytometry to determine the phenotype of vaccine-reactive T cells (effector memory vs. exhausted T cells) in the H3.3K27M peptide vaccine trial in children with gliomas [1, 2]. Next, he highlighted findings describing the effective use of single-cell RNA sequencing, including T cell receptor (TCR) clonotype sequencing, to track vaccine-reactive T cells in the peripheral blood and tumor specimen in the poly-ICLC-associated tumor lysate vaccine trial in low grade glioma (NCT02549833, data not published). Lastly, he discussed application of a novel peptide-HLA-based T cell screening technology in site-directed biopsy samples to identify tumor-wide neoantigens and TCRs in a genetically heterogenous IDH mutant glioma human sample at diagnosis and recurrence (in collaboration with PACT Pharma, Inc). Together these studies exemplified the application of novel Omics approaches to understand T cell responses in gliomas.
Amy Heimberger from Northwestern University presented her lecture titled “The Immune Landscape of CNS Tumors: Implications for Immunotherapy.” She first reviewed her work on Immune Topographical Atlas that allows for spatial characterization of immune cells in the CNS microenvironment. She described the varying immune cell composition of glioblastoma and brain metastasis within a surgical wedge of tissue divided into the infiltrating edge, the tumor, and the necrotic core using multiplex immunohistochemistry. Given the pivotal role of STAT3 as a key hub of immunosuppression, she then discussed recently published work by her laboratory on pharmacological inhibition of STAT3 using WP1066 in combination with radiation in murine models . She demonstrated that the combination of STAT3 blockade and radiation results in CD3+ and CD11c+ cluster interactions and induction of an inflammatory environment within tumors leading to improved survival of xenograft glioma models in comparison with either therapy alone. She also shed light on the role of STING agonists to repolarize M2 immunosuppressive into M1 antitumor macrophages to turn on proinflammatory responses [4, 5]. Dr. Heimberger emphasized the need for distribution of effector immune cells uniformly within the tumor by highlighting localization of CMV T cells mainly within the perivascular space in a clinical trial of adoptive transfer of CMV-specific T cells in glioblastoma . She closed with an introduction to ultrasound blood-brain barrier (BBB) opening as an approach to improve the therapeutic impact of immune cell effectors in gliomas (unpublished data).
The first lecture in the microenvironment session, moderated by Krishna Bhat from MD Anderson Cancer Center, was by Michelle Monje from Stanford University titled “Neuronal Activity Drive Glioma Progression.” She opened her presentation highlighting the importance of understanding neuron – glia interactions to develop insights into normal gliogenesis and gliomagenesis. Using optogenetic stimulation techniques, Dr. Monje demonstrated that neuronal activity drives normal oligodendroglial cell proliferation and myelination . She then showed that neuronal activity increases proliferation of malignant glioma cells just like it does in their normal counter parts through secreted factors, BDNF and NLGN3, and that inhibition of NLGN3 release through inhibition of its sheddase, ADAM10, blocks glioma growth [8, 9]. Dr. Monje ended her lecture by describing the discovery that glioma is an electrically active tissue and engages in synaptic communication with normal neurons and that neural-glioma circuits are essential for glioma progression [10, 11].
Frank Winkler from University Hospital Heidelberg continued the microenvironment session by presenting his lecture titled “Malignant Networks in the Brain: A New View on Brain Tumors and its Clinical Implications.” Focusing on the role of tumor microenvironment in glioma growth, he demonstrated that glioma cells use tumor microtubes (TMs) as routes for brain invasion, proliferation, and to interconnect over long distances even extending to the contralateral “normal brain” . Interestingly, he showed that the more aggressive 1p19q intact astrocytomas have larger number of intracellular TMs than 1p19q codeleted oligodendrogliomas and are proficient in expression of neurogenesis pathways. In addition, Dr. Winkler highlighted that TMs convey resistance to both temozolomide and radiotherapy . Lastly, he explained the discovery that neuron-glioma synapses activate TM networks and drive glioma progression and introduced clinical trials of parampanel and meclofenamate, inhibitors of TM functional networks, to tackle treatment resistance in human gliomas [14, 15].
Within the epigenetic session moderated by Houtan Noushmehr from the Henry Ford Cancer Institute, Joe Costello from University of California, San Francisco presented his lecture titled “Epigenetic Mechanisms and Their Role in Brain Tumors” focused on epigenetic mechanisms in gliomas including DNA methylation and demethylation, histone modifications, and chromatin remodeling. Importantly, he explained the interaction between genetic alterations and epigenetics in gliomas and how every known category of epigenetic modifier has been identified as a frequently mutated gene in human cancers, particular in brain tumors (i.e. DNA methylation/DNMT3A, Hydromethylation/IDH1, chromatin remodelers/ATRX). He concluded his lecture by emphasizing a novel perspective into these genetic and epigenetic interactions stating that somatic mutations are the cause of gliomas and the ensuing epigenetic reprograming is the mechanism by which genetic modifications lead to varying cancer phenotypes.
Vinay Puduvalli closed the epigenetics session discussing therapeutic opportunities to target the epigenome in his lecture titled “Clinical Targeting of the Epigenome in Brain Tumors.” He first appraised negative clinical trials of HDAC inhibitors in gliomas and elaborated on mechanisms of resistance while emphasizing the need for combination studies to optimize targeting HDACs and resistance pathways. Additionally, Dr. Puduvalli reviewed ongoing clinical and preclinical studies focusing on demethylation agents, inhibitors of protein arginine methyltransferase and BET bromodomain inhibitors. He concluded his lecture by highlighting the challenges involved in the development of CNS tumor specific epigenetic therapies including BBB penetration of the drugs, target relevance, and toxicity profile.
The half-day conference was concluded by a panel discussion involving speakers and moderators from all the sessions above, pharmaceutical leaders including Sharon Tamir from Karyopharm Therapeutics and Kyle Holen from AbbVie, and Kirk Tanner from the National Brain Tumor Society. The panel further discussed challenges and strategies to translate preclinical breakthroughs into clinical benefit with an emphasis on fostering collaborations amongst basic scientists, clinicians, and pharmaceutical leaders for the benefit of brain tumor patients.
- Mueller, S., et al., Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma. J Clin Invest, 2020. 130(12): p. 6325-6337.
- Chheda, Z.S., et al., Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy. J Exp Med, 2018. 215(1): p. 141-157.
- Ott, M., et al., Radiation with STAT3 Blockade Triggers Dendritic Cell-T cell Interactions in the Glioma Microenvironment and Therapeutic Efficacy. Clin Cancer Res, 2020. 26(18): p. 4983-4994.
- Ohkuri, T., et al., STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Cancer Immunol Res, 2014. 2(12): p. 1199-208.
- Corrales, L., et al., Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Rep, 2015. 11(7): p. 1018-30.
- Weathers, S.P., et al., Glioblastoma-mediated Immune Dysfunction Limits CMV-specific T Cells and Therapeutic Responses: Results from a Phase I/II Trial. Clin Cancer Res, 2020. 26(14): p. 3565-3577.
- Gibson, E.M., et al., Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science, 2014. 344(6183): p. 1252304.
- Pan, Y., et al., NF1 mutation drives neuronal activity-dependent initiation of optic glioma. Nature, 2021. 594(7862): p. 277-282.
- Venkatesh, H.S., et al., Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion. Cell, 2015. 161(4): p. 803-16.
- Venkatesh, H.S., et al., Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma. Nature, 2017. 549(7673): p. 533-537.
- Venkatesh, H.S., et al., Electrical and synaptic integration of glioma into neural circuits. Nature, 2019. 573(7775): p. 539-545.
- Osswald, M., et al., Brain tumour cells interconnect to a functional and resistant network. Nature, 2015. 528(7580): p. 93-8.
- Weil, S., et al., Tumor microtubes convey resistance to surgical lesions and chemotherapy in gliomas. Neuro Oncol, 2017. 19(10): p. 1316-1326.
- Venkataramani, V., et al., Synaptic input to brain tumors: clinical implications. Neuro Oncol, 2021. 23(1): p. 23-33.
- Schneider, M., et al., Meclofenamate causes loss of cellular tethering and decoupling of functional networks in glioblastoma. Neuro Oncol, 2021.