• Department of Neurosurgery

    Brain Tumor Immunology and Immunotherapy Program

    Massachusetts General Hospital

    Harvard Medical School

     

     

  • Our Mission

    Using immunology and genomics tools, we study how the immune response to brain tumors happens. We use established preclinical models, new preclinical models we have developed, and patient-derived tissue and cells to address what T cells recognize and how antigen is presented. These studies are complemented by clinical trial efforts. Our ultimate goal is to better understand the diseases of our patients in order to develop improved therapies.

  • Select Publications

    Single-cell profiling of human dura and meningioma reveals cellular meningeal landscape and insights into meningioma immune response

      Genome Med. 2022 May 10;14(1):49. doi: 10.1186/s13073-022-01051-9

      Background: Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role. However, our understanding of the meninges largely stems from the use of pre-clinical models rather than human samples.

      Methods: Single-cell RNA sequencing of seven non-tumor-associated human dura samples and six primary meningioma tumor samples (4 matched and 2 non-matched) was performed. Cell type identities, gene expression profiles, and T cell receptor expression were analyzed. Copy number variant (CNV) analysis was performed to identify putative tumor cells and analyze intratumoral CNV heterogeneity. Immunohistochemistry and imaging mass cytometry was performed on selected samples to validate protein expression and reveal spatial localization of select protein markers.

      Results: In this study, we use single-cell RNA sequencing to perform the first characterization of both non-tumor-associated human dura and primary meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, we characterize a functionally diverse and heterogenous landscape of non-immune cells including endothelial cells and fibroblasts. Through imaging mass cytometry, we highlight the spatial relationship among immune cell types and vasculature in non-tumor-associated dura. Utilizing T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. Finally, we report copy number variant heterogeneity within our meningioma samples.

      Conclusions: Our comprehensive investigation of both the immune and non-immune cellular landscapes of human dura and meningioma at single-cell resolution builds upon previously published data in murine models and provides new insight into previously uncharacterized roles of human dura.

       

      Read more here: https://pubmed.ncbi.nlm.nih.gov/35534852/

       

      Characterization of the Genomic and Immunological Diversity of Malignant Brain Tumors Through Multi-Sector Analysis

      Cancer Discov. 2021 Oct 5:candisc.0291.2021

      Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy against primary brain malignancies such as glioblastoma (GBM). While the intratumoral heterogeneity of GBM is implicated in treatment resistance, it remains unclear whether this diversity is observed within brain metastases and to what extent cancer-cell intrinsic heterogeneity sculpts the local immune microenvironment. Here, we profiled the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through whole exome, RNA, and TCR-sequencing. Our analyses identified differences between primary and secondary malignancies with gliomas displaying more spatial heterogeneity at the genomic and neoantigen level. Additionally, this spatial diversity was recapitulated in the distribution of T cell clones where some gliomas harbored highly expanded but spatially restricted clonotypes. This study defines the immunogenomic landscape across a cohort of malignant brain tumors and contains implications for the design of targeted and immune-based therapies against intracranial malignancies.

       

      Read more here: https://pubmed.ncbi.nlm.nih.gov/34610950/

      Treatment of an Aggressive Orthotopic Murine Glioblastoma Model with Combination Checkpoint Blockade and a Multivalent Neoantigen Vaccine

      Neuro-Oncol. 2020 Mar 5;noaa050

      We characterized the microenvironment and neoantigen landscape of the aggressive CT2A GBM model in order to develop a platform to test combination checkpoint blockade and neoantigen vaccination. Whole exome DNA and RNA sequencing of the CT2A murine GBM was employed to identify expressed, somatic mutations for vaccine development. Survival analysis showed that therapeutic neoantigen vaccination with Epb4H471L, Pomgnt1R497L, and Plin2G332R, in combination with αPD-L1 treatment was superior to αPD-L1 alone. These observations provide important preclinical correlates for GBM immunotherapy trials and support further investigation into the effects of multi-modal immunotherapeutic interventions on anti-glioma immunity

       

      Read more here: https://www.ncbi.nlm.nih.gov/pubmed/32133512

      Emerging Immunotherapies for Malignant Glioma: From Immunogenomics to Cell Therapy

      Neuro Oncol. 2020 Jul 2: noaa154

      As immunotherapy assumes a central role in the management of many cancers, ongoing work is directed at understanding whether immune-based treatments will be successful in patients with glioblastoma (GBM). Despite several large studies conducted in the last several years, there remain no FDA-approved immunotherapies in this patient population. Nevertheless, there are a range of exciting new approaches being applied to GBM, all of which may not only allow us to develop new treatments but also help us understand fundamental features of the immune response in the central nervous system. In this review, we summarize new developments in the application of immune checkpoint blockade, from biomarker-driven patient selection to the timing of treatment. Moreover, we summarize novel work in personalized immune-oncology by reviewing work in cancer immunogenomics–driven neoantigen vaccine studies. Finally, we discuss cell therapy efforts by reviewing the current state of chimeric antigen receptor T-cell therapy.

       

      Read more here: https://www.ncbi.nlm.nih.gov/pubmed/32615600

      Detection of Neoantigen-specific T Cells Following a Personalized Vaccine in a Patient with Glioblastoma

      Oncoimmunology, 2019 Jan 25;8(4):e1561106

      Neoantigens represent promising targets for personalized cancer vaccine strategies. However, the feasibility of this approach in lower mutational burden tumors like glioblastoma (GBM) remains unknown. We report the application a cancer immunogenomics pipeline to identify candidate neoantigens and guide screening for neoantigen-specific T cell responses in a patient with GBM treated with a personalized synthetic long peptide vaccine. Following vaccination, reactivity to 3 HLA class I- and 5 HLA class II-restricted candidate neoantigens were detected. These data demonstrate the feasibility and translational potential of a therapeutic neoantigen-based vaccine approach in patients with primary CNS tumors.

       

      Read more here: https://www.ncbi.nlm.nih.gov/pubmed/30906654

      Targeting Neoantigens in Glioblastoma: An Overview of Cancer Immunogenomics and Translational Implications

      Neurosurgery. 2017 Sep 1;64(CN_suppl_1):165-176

      Recent interest has been focused on the identification of tumor-specific mutations, termed neoantigens, which can serve as immunodominant targets for antitumor immune effector cells to maximize “on-tumor” effect and minimize “off-tumor” toxicities. In this review, we discuss: (1) the current perspective on CNS immunosurveillance, (2) the process of neoantigen identification focusing on the cancer immunogenomics approach, and (3) how this strategy can be used to target GBM specifically.

       

      Read more here: https://www.ncbi.nlm.nih.gov/pubmed/28899059

      Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy

      Cancer Discov. 2016 Nov;6(11):1230-1236.

      We present the case of a patient with a left frontal glioblastoma with primitive neuroectodermal tumor features and hypermutated genotype in the setting of a POLE germline alteration. Using whole-exome DNA sequencing and clonal analysis, we report changes in the subclonal architecture throughout treatment. Furthermore, a persistently high neoantigen load was observed within all tumors. Interestingly, following initiation of pembrolizumab, brisk lymphocyte infiltration was observed in the subsequently resected metastatic spinal lesion and an objective radiographic response was noted in a progressive intracranial lesion, suggestive of active central nervous system (CNS) immunosurveillance following checkpoint blockade therapy.

       

      Read more here: https://www.ncbi.nlm.nih.gov/pubmed/27683556

      Endogenous Neoantigen-Specific CD8 T Cells Identified in Two Glioblastoma Models Using a Cancer Immunogenomics Approach

      Cancer Immunol Res. 2016 Dec;4(12):1007-1015

      We applied a cancer immunogenomics approach to identify tumor-specific "neoantigens" in the C57BL/6-derived GL261 and VM/Dk-derived SMA-560 tumor models. Following DNA whole-exome and RNA sequencing, high-affinity candidate neoepitopes were predicted and screened for immunogenicity by ELISPOT and tetramer analyses. We confirmed H-2Db-restricted endogenous tumor-specific neoantigens that are functionally immunogenic. By establishing the immunogenicities of predicted high-affinity neoepitopes in these models, we extend the immunogenomics-based neoantigen discovery pipeline to glioblastoma models and provide a tractable system to further study the mechanism of action of T cell-activating immunotherapeutic approaches in preclinical models of glioblastoma

       

      Read more here: https://www.ncbi.nlm.nih.gov/pubmed/27799140

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