9 results on '"Daniel Y Zhang"'
Search Results
2. CD8+ T-cell–Mediated Immunoediting Influences Genomic Evolution and Immune Evasion in Murine Gliomas
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Aayushi Mahajan, Junfei Zhao, Maciej S. Lesniak, Víctor A. Arrieta, Joshua Robert Kane, Li Chen, Angeliki Mela, Crismita Dmello, Craig Horbinski, Gerson Rothschild, Daniel Y Zhang, Ganesh Rao, Uttiya Basu, Takashi Tsujiuchi, Peter Canoll, Adam M. Sonabend, Raul Rabadan, Ting Xiao, Catalina Lee-Chang, Brice Laffleur, Amy B. Heimberger, and Edgar Gonzalez-Buendia
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0301 basic medicine ,Cancer Research ,education.field_of_study ,Population ,Biology ,medicine.disease ,Transplantation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Oncology ,Immunoediting ,Tumor progression ,030220 oncology & carcinogenesis ,Glioma ,medicine ,Cancer research ,Cytotoxic T cell ,education ,CD8 - Abstract
Purpose: Cancer immunoediting shapes tumor progression by the selection of tumor cell variants that can evade immune recognition. Given the immune evasion and intratumor heterogeneity characteristic of gliomas, we hypothesized that CD8+ T cells mediate immunoediting in these tumors. Experimental Design: We developed retrovirus-induced PDGF+Pten−/− murine gliomas and evaluated glioma progression and tumor immunogenicity in the absence of CD8+ T cells by depleting this immune cell population. Furthermore, we characterized the genomic alterations present in gliomas that developed in the presence and absence of CD8+ T cells. Results: Upon transplantation, gliomas that developed in the absence of CD8+ T cells engrafted poorly in recipients with intact immunity but engrafted well in those with CD8+ T-cell depletion. In contrast, gliomas that developed under pressure from CD8+ T cells were able to fully engraft in both CD8+ T-cell–depleted mice and immunocompetent mice. Remarkably, gliomas developed in the absence of CD8+ T cells exhibited increased aneuploidy, MAPK pathway signaling, gene fusions, and macrophage/microglial infiltration, and showed a proinflammatory phenotype. MAPK activation correlated with macrophage/microglia recruitment in this model and in the human disease. Conclusions: Our studies indicate that, in these tumor models, CD8+ T cells influence glioma oncogenic pathways, tumor genotype, and immunogenicity. This suggests immunoediting of immunogenic tumor clones through their negative selection by CD8+ T cells during glioma formation.
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- 2020
3. High-Affinity Chimeric Antigen Receptor With Cross-Reactive scFv to Clinically Relevant EGFR Oncogenic Isoforms
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Radhika Thokala, Zev A. Binder, Yibo Yin, Logan Zhang, Jiasi Vicky Zhang, Daniel Y. Zhang, Michael C. Milone, Guo-li Ming, Hongjun Song, and Donald M. O’Rourke
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Cancer Research ,medicine.drug_class ,EGFR ,medicine.medical_treatment ,T cell ,adoptive T cell therapy ,Monoclonal antibody ,GBM ,Antigen ,glioma ,Glioma ,medicine ,Epidermal growth factor receptor ,RC254-282 ,Original Research ,CAR T cells ,biology ,Chemistry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunotherapy ,medicine.disease ,Chimeric antigen receptor ,medicine.anatomical_structure ,Tumor Escape ,Oncology ,Cancer research ,biology.protein ,immunotherapy - Abstract
Tumor heterogeneity is a key reason for therapeutic failure and tumor recurrence in glioblastoma (GBM). Our chimeric antigen receptor (CAR) T cell (2173 CAR T cells) clinical trial (NCT02209376) against epidermal growth factor receptor (EGFR) variant III (EGFRvIII) demonstrated successful trafficking of T cells across the blood–brain barrier into GBM active tumor sites. However, CAR T cell infiltration was associated only with a selective loss of EGFRvIII+ tumor, demonstrating little to no effect on EGFRvIII- tumor cells. Post-CAR T-treated tumor specimens showed continued presence of EGFR amplification and oncogenic EGFR extracellular domain (ECD) missense mutations, despite loss of EGFRvIII. To address tumor escape, we generated an EGFR-specific CAR by fusing monoclonal antibody (mAb) 806 to a 4-1BB co-stimulatory domain. The resulting construct was compared to 2173 CAR T cells in GBM, using in vitro and in vivo models. 806 CAR T cells specifically lysed tumor cells and secreted cytokines in response to amplified EGFR, EGFRvIII, and EGFR-ECD mutations in U87MG cells, GBM neurosphere-derived cell lines, and patient-derived GBM organoids. 806 CAR T cells did not lyse fetal brain astrocytes or primary keratinocytes to a significant degree. They also exhibited superior antitumor activity in vivo when compared to 2173 CAR T cells. The broad specificity of 806 CAR T cells to EGFR alterations gives us the potential to target multiple clones within a tumor and reduce opportunities for tumor escape via antigen loss.
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- 2021
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4. Activation of 4-1BBL+ B cells with CD40 agonism and IFNγ elicits potent immunity against glioblastoma
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Ignacio Jusué-Torres, Irina V. Balyasnikova, Rachel A. Burga, Ting Xiao, Peng Zhang, Aida Rashidi, Víctor A. Arrieta, Yu Han, David Hou, Adam M. Sonabend, Catalina Lee-Chang, Craig Horbinski, Roger Stupp, Maciej S. Lesniak, Aurora Lopez-Rosas, Jason Miska, and Daniel Y Zhang
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Tumor Immunology ,medicine.medical_treatment ,Immunology ,CD8-Positive T-Lymphocytes ,Cancer Vaccines ,B7-H1 Antigen ,Article ,Interferon-gamma ,Mice ,Neuroinflammation ,Antigen ,Immunity ,Cell Line, Tumor ,Glioma ,medicine ,Animals ,Immunology and Allergy ,CD40 Antigens ,B cell ,Mice, Knockout ,B-Lymphocytes ,CD40 ,biology ,business.industry ,Neoplasms, Experimental ,Immunotherapy ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Blockade ,4-1BB Ligand ,medicine.anatomical_structure ,Cancer research ,biology.protein ,Glioblastoma ,business ,CD8 ,Neuroscience - Abstract
Lee-Chang et al. explore the B cell–based vaccine as immunotherapy to treat deadly tumors, including glioblastoma. Their approach utilizes 4-1BBL+ B cells as a cellular platform to promote antitumor immunity., Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With the goal of exploring ways to boost anti-GBM immunity, we developed a B cell–based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNγ stimulation. BVax migrates to key secondary lymphoid organs and is proficient at antigen cross-presentation, which promotes both the survival and the functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This treatment elicited immunological memory that prevented the growth of new tumors upon subsequent reinjection in cured mice. GBM patient–derived BVax was successful in activating autologous CD8+ T cells; these T cells showed a strong ability to kill autologous glioma cells. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic., Graphical Abstract
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- 2020
5. Ultrasound-mediated delivery of paclitaxel for glioma: a comparative study of distribution, toxicity and efficacy of albumin-bound versus cremophor formulations
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Roger Stupp, Alexandre Carpentier, Aneta Baran, Edgar Gonzalez-Buendia, Miguel Muzzio, Crismita Dmello, J. Robert Kane, Lisa P. Magnusson, Michael Canney, Li Chen, Daniel Y Zhang, Adam M. Sonabend, C. David James, Víctor A. Arrieta, Carole Desseaux, and Craig Horbinski
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Male ,Cancer Research ,Biodistribution ,Paclitaxel ,Drug Compounding ,Drug delivery to the brain ,Mice, Nude ,Pharmacology ,Article ,Polyethylene Glycols ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Drug Delivery Systems ,Glioma ,Albumins ,medicine ,Animals ,Tissue Distribution ,Fluorescein ,Ultrasonography ,Microbubbles ,business.industry ,computer.file_format ,medicine.disease ,Xenograft Model Antitumor Assays ,Survival Rate ,Oncology ,chemistry ,Tolerability ,Blood-Brain Barrier ,030220 oncology & carcinogenesis ,Toxicity ,Nanoparticles ,Female ,ABX test ,business ,computer ,030217 neurology & neurosurgery - Abstract
Purpose: Paclitaxel shows little benefit in the treatment of glioma due to poor penetration across the blood–brain barrier (BBB). Low-intensity pulsed ultrasound (LIPU) with microbubble injection transiently disrupts the BBB allowing for improved drug delivery to the brain. We investigated the distribution, toxicity, and efficacy of LIPU delivery of two different formulations of paclitaxel, albumin-bound paclitaxel (ABX) and paclitaxel dissolved in cremophor (CrEL-PTX), in preclinical glioma models. Experimental Design: The efficacy and biodistribution of ABX and CrEL-PTX were compared with and without LIPU delivery. Antiglioma activity was evaluated in nude mice bearing intracranial patient-derived glioma xenografts (PDX). Paclitaxel biodistribution was determined in sonicated and nonsonicated nude mice. Sonications were performed using a 1 MHz LIPU device (SonoCloud), and fluorescein was used to confirm and map BBB disruption. Toxicity of LIPU-delivered paclitaxel was assessed through clinical and histologic examination of treated mice. Results: Despite similar antiglioma activity in vitro, ABX extended survival over CrEL-PTX and untreated control mice with orthotropic PDX. Ultrasound-mediated BBB disruption enhanced paclitaxel brain concentration by 3- to 5-fold for both formulations and further augmented the therapeutic benefit of ABX. Repeated courses of LIPU-delivered CrEL-PTX and CrEL alone were lethal in 42% and 37.5% of mice, respectively, whereas similar delivery of ABX at an equivalent dose was well tolerated. Conclusions: Ultrasound delivery of paclitaxel across the BBB is a feasible and effective treatment for glioma. ABX is the preferred formulation for further investigation in the clinical setting due to its superior brain penetration and tolerability compared with CrEL-PTX.
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- 2019
6. CD8+ T-cell-mediated immunoediting influences genomic evolution and immune evasion in murine gliomas
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Víctor A. Arrieta, Angeliki Mela, Brice Laffleur, Li Chen, Amy B. Heimberger, Edgar Gonzalez-Buendia, Peter Canoll, Uttiya Basu, Maciej S. Lesniak, Joshua Robert Kane, Adam M. Sonabend, Raul Rabadan, Craig Horbinski, Crismita Dmello, Catalina Lee-Chang, Daniel Y Zhang, Gerson Rothschild, Takashi Tsujiuchi, Junfei Zhao, Ganesh Rao, Ting Xiao, and Aayushi Mahajan
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0303 health sciences ,education.field_of_study ,Population ,biochemical phenomena, metabolism, and nutrition ,Biology ,medicine.disease ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immunoediting ,Tumor progression ,Immunity ,030220 oncology & carcinogenesis ,Glioma ,medicine ,Cancer research ,bacteria ,Cytotoxic T cell ,education ,030304 developmental biology - Abstract
Cancer immunoediting shapes tumor progression by the selection of tumor cell variants that can evade immune recognition. Given the immune evasion and intra-tumor heterogeneity intrinsic to gliomas, we hypothesized that CD8+ T-cells mediate immunoediting in these tumors. We evaluated glioma progression in the absence of CD8+ T-cells by depleting this immune cell population in transgenic murine gliomas. Upon transplantation, gliomas that developed in the absence of CD8+ T-cells engrafted poorly in recipients with intact immunity but engrafted well in those with CD8+ T-cell depletion. Gliomas developed in absence of CD8+ T-cells exhibited increased chromosomal instability, MAPK signaling, gene fusions, and macrophage/microglial infiltration. MAPK activation correlated with macrophage/microglial recruitment in this model and in the human disease. Our results indicate that CD8+ T-cells mediate immunoediting during gliomagenesis, influencing the genomic stability of glioma and its microenvironment, leading to immune evasion.SignificanceImmune evasion renders cancer resistant to anti-tumoral immunity. Therapeutic intervention often fails for gliomas because of the plasticity of tumor cell variants that resist immune surveillance. Our results demonstrate a mechanism of immune evasion in gliomas that derives from CD8+ T-cells during the development and progression of this disease.
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- 2019
7. A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter- and Intra-tumoral Heterogeneity
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Dmitriy Petrov, Di-ao Liu, H. Isaac Chen, Deeksha Saxena, Phuong T.T. Nguyen, Xuyu Qian, MacLean Nasrallah, Radhika Thokala, Samuel Zheng Hao Wong, Timothy H. Lucas, Jay F. Dorsey, Fadi Jacob, Donald M. O'Rourke, Steven Brem, Ryan D Salinas, Kimberly M. Christian, Guo Li Ming, Hongjun Song, Jordan G. Schnoll, Daniel Y. Zhang, Stefan Prokop, Saad Sheikh, and Zev A. Binder
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Adult ,Male ,medicine.medical_treatment ,Cell Culture Techniques ,Mice, Nude ,Biology ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Organoid ,Animals ,Humans ,Aged ,Biological Specimen Banks ,030304 developmental biology ,Aged, 80 and over ,0303 health sciences ,Translational bioinformatics ,Reproducibility of Results ,Immunotherapy ,Middle Aged ,medicine.disease ,Key features ,Xenograft Model Antitumor Assays ,Biobank ,Chimeric antigen receptor ,Organoids ,Cancer research ,Treatment strategy ,Female ,Glioblastoma ,030217 neurology & neurosurgery - Abstract
Summary Glioblastomas exhibit vast inter- and intra-tumoral heterogeneity, complicating the development of effective therapeutic strategies. Current in vitro models are limited in preserving the cellular and mutational diversity of parental tumors and require a prolonged generation time. Here, we report methods for generating and biobanking patient-derived glioblastoma organoids (GBOs) that recapitulate the histological features, cellular diversity, gene expression, and mutational profiles of their corresponding parental tumors. GBOs can be generated quickly with high reliability and exhibit rapid, aggressive infiltration when transplanted into adult rodent brains. We further demonstrate the utility of GBOs to test personalized therapies by correlating GBO mutational profiles with responses to specific drugs and by modeling chimeric antigen receptor T cell immunotherapy. Our studies show that GBOs maintain many key features of glioblastomas and can be rapidly deployed to investigate patient-specific treatment strategies. Additionally, our live biobank establishes a rich resource for basic and translational glioblastoma research.
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- 2020
8. IMMU-42. CD8+ T-CELLS MEDIATE IMMUNOEDITING, AND INFLUENCE GENOTYPE, TUMOR ONCOGENIC PATHWAYS AND MICROENVIRONMENT DURING PROGRESSION OF MURINE GLIOMAS
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Li Chen, Peter Canoll, Víctor A. Arrieta, Aayushi Mahajan, Ganesh Rao, Adam M. Sonabend, Gerson Rothschild, Craig Horbinski, Catalina Lee-Chang, Angeliki Mela, Daniel Y Zhang, Maciej S. Lesniak, Raul Rabadan, Takashi Tsujiuchi, Ting Xiao, Junfei Zhao, Crismita Dmello, Uttiya Basu, J. Robert Kane, Brice Laffleur, and Amy B. Heimberger
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Cancer Research ,Immunology ,Cancer ,Biology ,medicine.disease ,Fusion gene ,Oncology ,Immunoediting ,Tumor progression ,Chromosome instability ,Glioma ,Genotype ,Cancer research ,medicine ,Cytotoxic T cell ,Neurology (clinical) - Abstract
Cancer immunoediting shapes tumor progression by the immunological selection of tumor cell variants that can evade immune recognition. Given the immune evasive cellular diversity of glioblastoma, we hypothesized that CD8+ T-cells mediate immunoediting in this tumor. We evaluated tumor progression in the absence of CD8+ T-cells by depleting this immune cell population in a transgenic murine glioma model. Tumors generated in the absence of CD8+ T-cells developed poorly in recipients with intact immunity, implying a more immunogenic profile. These tumors demonstrated increased chromosomal instability, gene fusions, MAPK signaling, and macrophage infiltration. These observations were stochastic, suggesting variability in the mode of tumor evolution in the absence of this immune effector. MAPK activation was correlated with macrophage recruitment in two transgenic murine models and the human disease. Our results indicate that CD8+ T-cells mediate a strong immunoediting selection in glioblastoma that protect against the hallmarks of cancer and drive immune evasion.
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- 2019
9. Optical Principles of Fluorescence-Guided Brain Tumor Surgery: A Practical Primer for the Neurosurgeon
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Sunil Singhal, Daniel Y. Zhang, and John Y K Lee
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medicine.medical_specialty ,Brain tumor ,Neuroimaging ,Neurosurgical Procedures ,Resection ,03 medical and health sciences ,0302 clinical medicine ,Surgical oncology ,medicine ,Humans ,Medical physics ,Intraoperative imaging ,Brain tumor surgery ,Fluorescent Dyes ,business.industry ,Brain Neoplasms ,Optical Imaging ,medicine.disease ,Clinical trial ,Neurosurgeons ,Surgery, Computer-Assisted ,Novel agents ,030220 oncology & carcinogenesis ,Surgery ,Neurology (clinical) ,Neurosurgery ,business ,030217 neurology & neurosurgery - Abstract
Fluorescence-guided surgery is a rapidly growing field that has produced some of the most important innovations in surgical oncology in the past decade. These intraoperative imaging technologies provide information distinguishing tumor tissue from normal tissue in real time as the surgery proceeds and without disruption of the workflow. Many of these fluorescent tracers target unique molecular or cellular features of tumors, which offers the opportunity for identifying pathology with high precision to help surgeons achieve their primary objective of a maximal safe resection. As novel fluorophores and fluorescent probes emerge from preclinical development, a practical understanding of the principles of fluorescence remains critical for evaluating the clinical utility of these agents and identifying opportunities for further innovation. In this review, we provide an "in-text glossary" of the fundamental principles of fluorescence with examples of direct applications to fluorescence-guided brain surgery. We offer a detailed discussion of the various advantages and limitations of the most commonly used intraoperative imaging agents, including 5-aminolevulinic acid, indocyanine green, and fluorescein, with a particular focus on the photophysical properties of these specific agents as they provide a framework through which to understand the new agents that are entering clinical trials. To this end, we conclude with a survey of the fluorescent properties of novel agents that are currently undergoing or will soon enter clinical trials for the intraoperative imaging of brain tumors.
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- 2017
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