A5037165527- CAR-T cell therapy research
- Immunotherapy and Immune Responses
- Glioma Diagnosis and Treatment
- Immune cells in cancer
- Nanowire Synthesis and Applications
- Cancer Immunotherapy and Biomarkers
- Virus-based gene therapy research
- Neuroinflammation and Neurodegeneration Mechanisms
- Advancements in Semiconductor Devices and Circuit Design
- Advances in Oncology and Radiotherapy
- Single-cell and spatial transcriptomics
- Cancer, Hypoxia, and Metabolism
- Hepatitis Viruses Studies and Epidemiology
- Innovations in Medical Education
- Advanced Radiotherapy Techniques
- Lung Cancer Treatments and Mutations
- Cancer, Stress, Anesthesia, and Immune Response
- Acute Lymphoblastic Leukemia research
- Immune Cell Function and Interaction
- Multiple and Secondary Primary Cancers
- Cancer Research and Treatments
- Nanoplatforms for cancer theranostics
- Inflammatory mediators and NSAID effects
- Brain Metastases and Treatment
University of California, San Francisco
2017-2022
Neurological Surgery
2017-2022
Parker Institute for Cancer Immunotherapy
2021
Broad Center
2021
UCSF Helen Diller Family Comprehensive Cancer Center
2017-2020
Cancer Research Center
2017-2020
City College of San Francisco
2017
Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 are among first genetic alterations observed during development of lower-grade glioma (LGG). LGG-associated IDH mutations confer gain-of-function activity by converting α-ketoglutarate to oncometabolite R-2-hydroxyglutarate (2HG). Clinical samples gene expression data from The Cancer Genome Atlas (TCGA) demonstrate reduced cytotoxic T lymphocyte-associated IFN-γ-inducible chemokines, including CXCL10, IDH-mutated (IDH-MUT) tumors...
Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack ideal target antigens that are both absolutely tumor specific and homogeneously expressed. We show multi-antigen prime-and-kill recognition circuits provide flexibility precision to overcome these challenges in context glioblastoma. A synNotch recognizes a priming antigen, such as heterogeneous but tumor-specific glioblastoma neoantigen epidermal growth factor splice variant III (EGFRvIII) or...
The median overall survival for children with diffuse intrinsic pontine glioma (DIPG) is less than one year. majority of midline gliomas, including more 70% DIPGs, harbor an amino acid substitution from lysine (K) to methionine (M) at position 27 histone 3 variant (H3.3). From a CD8+ T cell clone established by stimulation HLA-A2+ cells synthetic peptide encompassing the H3.3K27M mutation, complementary DNA receptor (TCR) α- and β-chains were cloned into retroviral vector. TCR-transduced...
Glioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought determine what extent this evasion due intrinsic properties of the tumor cells versus specialized context brain, and if it can be reversed.
Background Long-term prognosis of WHO grade II, isocitrate dehydrogenase (IDH)-mutated low-grade glioma (LGG) is poor due to high risks recurrence and malignant transformation into high-grade glioma. Immunotherapy strategies are attractive given the relatively intact immune system patients with LGG slow tumor growth rate. However, accumulation oncometabolite D-2-hydroxyglutarate (D-2HG) in IDH-mutated gliomas leads suppression inflammatory pathways microenvironment, thereby contributing...
Rigorous preclinical studies of chimeric antigen receptor (CAR) immunotherapy will require large quantities consistent and high-quality CAR-transduced T (CART) cells that can be used in syngeneic mouse glioblastoma (GBM) models. To this end, we developed a novel transgenic (Tg) strain with fully murinized CAR targeting epidermal growth factor variant III (EGFRvIII).We first established the version EGFRvIII-CAR validated its function using retroviral vector (RV) C57BL/6J mice bearing SB28 GBM...
Children with high-grade gliomas (pHGGs) represent a clinical population in substantial need of new therapeutic options given the inefficacy and toxicity current standard-of-care modalities. Although immunotherapy has emerged as promising modality, it yet to elicit significant survival benefit for pHGG patients. While preclinical studies address variety underlying challenges, translational trial design management also reflect most updated progress lessons from field.The authors will focus...
ABSTRACT Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack target antigens that are both tumor-specific and homogeneously expressed. We show multiantigen prime-and-kill recognition circuits have flexibility precision to overcome these challenges in attacking glioblastoma. A synNotch recognizes a specific priming – heterogeneous glioblastoma neoantigen EGFRvIII or brain tissue-specific used locally induce expression CAR, enabling thorough but...
Abstract Brain cancers are the leading cause of cancer related mortality in children and young adults with median overall survival 9-10 months hence represents a significant unmet medical need. Genome-wide sequencing efforts pediatric gliomas have identified recurrent shared missense mutation gene encoding replication-independent variant histone 3, H3.3. Approximately 70% diffuse intrinsic pontine (DIPG) 50% thalamic other midline harbor amino acid substitution from lysine (K) to methionine...
The median overall survival for children with diffuse intrinsic pontine glioma (DIPG) is less than a year. majority of midline gliomas, including over 70% DIPG, harbor an amino-acid substitution from lysine (K) to methionine (M) at position 27 histone 3 variant 3.3. As predicted by the NetMHC3.4 peptide binding algorithm, competitive inhibition assay demonstrated that 10-mer encompassing K27M mutation (H3.3K27M hereafter), but not corresponding non-mutant peptide, has excellent affinity...
Myeloid Derived Suppressor Cells (MDSCs) are present in most solid tumors, including glioblastoma (GBM), where they can block the activation of tumor-reactive T-cells and support tumor growth. Our lab others have demonstrated important roles cyclooxygenase (COX)-2 as well its enzymatic product, prostaglandin E2 (PGE2), MDSC development, accumulation, function. PGE2 mediates cellular responses through receptors, EP1-EP4, which EP4 is known to play an role anti-tumor immune responses. We...
Heterogeneous expression of target antigens can allow tumor escape from chimeric antigen receptor-transduced T-cell (CART) therapy targeting a single antigen. While epidermal growth factor receptor (EGFR)vIII represents glioblastoma (GBM)-specific antigen, its is heterogeneous within the tumor. On other hand, most expressed more uniformly in GBMs are non-mutated, glioma-associated (GAAs), such as EphA2. Although these GAAs not normal brain, they at low levels organs. As way to safely without...
Abstract Heterogeneous expression of target antigens allows tumor escape from chimeric antigen receptor-transduced T-cell (CART) therapy targeting a single antigen. While epidermal growth factor receptor (EGFR)vIII represents glioblastoma (GBM)-specific antigen, its is heterogeneous within the tumor. On other hand, most expressed more uniformly in GBMs are non-mutated, glioma-associated (GAAs), such as EphA2. Although these GAAs not normal brain, they at low levels organs. As way to safely...
Abstract The lack of conventional lymphatic drainage to and from the brain parenchyma restricts capacity peripheral immune system recognize respond glioma antigens. In some solid tumor types central nervous autoimmunity, spontaneous development tertiary lymphoid structures (TLS) with varying degrees organization have been observed in human patients mice following chronic inflammation. cancer setting, presence TLS are generally associated improved prognosis, especially when they characterized...
Abstract Treatment of solid cancers with chimeric antigen receptor (CAR) T-cells is challenging because a lack target antigens that are both tumor-specific and homogenously expressed. While epidermal growth factor (EGFR)vIII represents glioblastoma (GBM)-specific antigen, its expression heterogeneous within the tumor resulting in escape. In contrast, more expressed GBM-associated (GAA), such as EphA2, non-ideal other normal organs, yielding potential cross-reactive toxicity. As way to safely...
Abstract Recent studies have demonstrated the impacts of 2-HG on anti-tumor immune response in isocitrate dehydrogenase (IDH)-mutant gliomas. Our laboratory has reported that mutant IDH1 (IDH1R132H) suppresses STAT1, master regulator IFN-responses and IFN-inducible chemokines, thereby contributing to “cold” tumor environment. data also indicated inhibition production, through use a small molecular inhibitor IDH, can restore immunity. As IDH1R132H mutation been shown elicit CD4+ T-cell human...
ABSTRACT Background Rigorous preclinical studies of chimeric antigen receptor (CAR) immunotherapy will require large quantities consistent and high-quality CAR-transduced T (CART)-cells that can be used in syngeneic mouse glioblastoma (GBM) models. To this end, we developed a novel transgenic (Tg) strain with fully murinized CAR targeting epidermal growth factor variant III (EGFRvIII). Methods We first established the version EGFRvIII-CAR validated its function using retroviral vector (RV)...
Abstract The absence of conventional lymphatic access to the brain parenchyma restricts capacity peripheral immune system recognize and elicit durable responses against glioma antigens. In some solid tumor types autoimmune diseases such as multiple sclerosis, spontaneous development tertiary lymphoid structures (TLS) with varying degrees organization have been observed in human patients mice experiencing chronic inflammation. presence TLS context cancer is generally associated improved...