A5077751908- Immunotherapy and Immune Responses
- Cancer Research and Treatments
- vaccines and immunoinformatics approaches
- RNA Interference and Gene Delivery
- Cancer Immunotherapy and Biomarkers
- CAR-T cell therapy research
- Glioma Diagnosis and Treatment
- Monoclonal and Polyclonal Antibodies Research
- Immune Cell Function and Interaction
- Cancer Genomics and Diagnostics
- Ferroptosis and cancer prognosis
- T-cell and B-cell Immunology
- Brain Metastases and Treatment
- Single-cell and spatial transcriptomics
- Immune cells in cancer
- RNA modifications and cancer
- Mathematical Biology Tumor Growth
- Radiopharmaceutical Chemistry and Applications
- Neuroinflammation and Neurodegeneration Mechanisms
- Nanoplatforms for cancer theranostics
- Radiomics and Machine Learning in Medical Imaging
- Salmonella and Campylobacter epidemiology
- Meningioma and schwannoma management
- Melanoma and MAPK Pathways
- Lung Cancer Treatments and Mutations
Washington University in St. Louis
2016-2025
Alvin J. Siteman Cancer Center
2017-2023
Barnes-Jewish Hospital
2017-2022
Jewish Hospital
2017-2022
Neurological Surgery
2017-2020
University of Minnesota, Duluth
2011
University of Minnesota
2005-2010
Pediatrics and Genetics
2009
Twin Cities Orthopedics
2006
Purpose: T-cell dysfunction is a hallmark of glioblastoma (GBM). Although anergy and tolerance have been well characterized, exhaustion remains relatively unexplored. Exhaustion, characterized in part by the upregulation multiple immune checkpoints, known contributor to failures amid checkpoint blockade, strategy that has lacked success thus far GBM. This study among first examine, credential as bona fide, T cells infiltrating human murine GBM.Experimental Design: Tumor-infiltrating...
We present the case of a patient with left frontal glioblastoma primitive neuroectodermal tumor features and hypermutated genotype in setting POLE germline alteration. During standard-of-care chemoradiation, developed cervical spine metastasis was subsequently treated pembrolizumab. Shortly thereafter, an additional metastatic spinal lesion. Using whole-exome DNA sequencing clonal analysis, we report changes subclonal architecture throughout treatment. Furthermore, persistently high...
The pathogenesis of persistent infection is dictated by the balance between opposing immune activation and suppression signals. Herein, virulent Salmonella was used to explore role potential importance Foxp3-expressing regulatory T cells in dictating natural progression bacterial infection. Two distinct phases are identified. In first 3–4 weeks after infection, progressively increasing burden associated with delayed effector cell activation. Reciprocally, at later time points reductions were...
Abstract The “cancer immunogenomics” paradigm has facilitated the search for tumor-specific antigens over last 4 years by applying comprehensive cancer genomics to tumor antigen discovery. We applied this methodology identify “neoantigens” in C57BL/6-derived GL261 and VM/Dk-derived SMA-560 models. Following DNA whole-exome RNA sequencing, high-affinity candidate neoepitopes were predicted screened immunogenicity ELISPOT tetramer analyses. harbored 4,932 2,171 nonsynonymous exome mutations,...
Recent clinical trials have highlighted the limited efficacy of T cell-based immunotherapy in patients with glioblastoma (GBM). To better understand characteristics tumor-infiltrating lymphocytes (TIL) GBM, we performed cellular indexing transcriptomes and epitopes by sequencing single-cell RNA paired V(D)J sequencing, respectively, on TILs from two cohorts totaling 15 high-grade glioma, including GBM or astrocytoma, IDH-mutant, grade 4 (G4A). Analysis CD8+ TIL landscape reveals an...
Although clinical trials testing immunotherapies in glioblastoma (GBM) have yielded mixed results, new strategies targeting tumor-specific somatic coding mutations, termed "neoantigens," represent promising therapeutic approaches. We characterized the microenvironment and neoantigen landscape of aggressive CT2A GBM model order to develop a platform test combination checkpoint blockade vaccination.Flow cytometric analysis was performed on intracranial GL261 tumor-infiltrating lymphocytes...
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 have previously reported use an immunogenomics pipeline to identify candidate neoantigens preclinical models GBM. Here, we report application same and guide screening neoantigen-specific T cell responses a patient with GBM treated synthetic long peptide following autologous tumor lysate DC...
Abstract Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy against primary malignancies such as glioblastoma (GBM). Although the intratumoral heterogeneity of GBM is implicated treatment resistance, it remains unclear whether this diversity observed within metastases and to what extent cancer cell–intrinsic sculpts local immune microenvironment. Here, we profiled immunogenomic state 93 spatially distinct regions from 30...
Abstract Background Preclinical studies and early clinical trials have shown that targeting cancer neoantigens is a promising approach towards the development of personalized immunotherapies. DNA vaccines can be rapidly efficiently manufactured integrate multiple simultaneously. We therefore sought to optimize design polyepitope test optimized neoantigen in preclinical models translation. Methods developed vaccine platform target neoantigens. The was first using model antigens vitro vivo....
Neoantigens are tumor-specific peptide sequences resulting from sources such as somatic DNA mutations. Upon loading onto major histocompatibility complex (MHC) molecules, they can trigger recognition by T cells. Accurate neoantigen identification is thus critical for both designing cancer vaccines and predicting response to immunotherapies. Neoantigen prioritization relies on correctly whether the presenting sequence successfully induce an immune response. Because most mutations...
Abstract Purpose: Outcomes for patients with glioblastoma (GBM) remain poor despite multimodality treatment surgery, radiation, and chemotherapy. There are few immunotherapy options due to the lack of tumor immunogenicity. Several clinical trials have reported promising results cancer vaccines. To date, studies used data from a single site identify targetable antigens, but this approach limits antigen pool is antithetical heterogeneity GBM. We implemented multisector sequencing increase...
Abstract The Foxp3-expressing subset of regulatory CD4+ T cells have defined Ag specificity and play essential roles in maintaining peripheral tolerance by suppressing the activation self-reactive cells. Similarly, during chronic infection, pathogen-specific expand actively suppress effector Herein, we used MHC class II tetramers Foxp3gfp knockin mice to track kinetics magnitude whereby Foxp3+CD4+ Foxp3−CD4+ are primed after acute infection with recombinant Listeria monocytogenes (Lm)...
BRAF V600E mutations have been successfully treated with targeted therapy in melanoma, non–small cell lung cancer, and thyroid cancer. Interestingly, these also identified a subset of pediatric adult brain tumors, several cases reportedly responding to therapy. However, reports limited single-agent inhibitor recurrent disease. Herein, we report dramatic clinical radiographic responses combination dabrafenib (BRAF inhibitor) trametinib (MEK 2 adults high-grade gliomas (HGGs), 1 patient the...
We aimed to evaluate the clinical outcomes of molecular glioblastoma (mGBM) as compared histological GBM (hGBM) and determine prognostic impact TERT mutation, EGFR amplification, CDKN2A/B deletion on isocitrate dehydrogenase (IDH)-wildtype GBM.IDH-wildtype patients treated with radiation therapy (RT) between 2012 2019 were retrospectively analyzed. mGBM was defined grade II-III IDH-wildtype astrocytoma without features but one following alterations: or combination whole chromosome 7 gain 10...
The blood-brain barrier (BBB) is a major limiting factor for drug delivery in brain tumors. Laser interstitial thermal therapy (LITT) disrupts the peritumoral BBB. In this study, we examine survival patients with recurrent glioblastoma (GBM) treated LITT followed by low-dose doxorubicin, potent anti-neoplastic poor BBB permeability.Forty-one GBM were enrolled; thirty evaluable. Participants underwent 6 weekly doxorubicin treatments starting within one week (Early Arm) or at 6-8 weeks (Late...
Gliomas are the most common primary brain tumor in adults. Current treatments involve surgery, radiation, and temozolomide (TMZ) chemotherapy; however, prognosis remains poor new approaches required. Circadian medicine aims to maximize treatment efficacy and/or minimize toxicity by timed delivery of medications accordance with daily rhythms patient. We published a retrospective study showing greater anti-tumor for morning, relative evening, administration TMZ patients glioblastoma. conducted...
The central nervous system (CNS) antigen-presenting cell (APC) that primes antitumor CD8+ T-cell responses remains undefined. Elsewhere in the body, conventional dendritic 1 (cDC1) performs this role. However, steady-state brain parenchyma cDC1 are extremely rare; cDCs localize to choroid plexus and dura. Thus, whether play a function presenting antigen derived from parenchymal sources tumor setting unknown. Using preclinical glioblastoma (GBM) models cDC1-deficient mice, we explored...