Browsing by Author "Bao, Xuhui"
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Item Open Access Bacterial‐Mediated Tumor Therapy: Old Treatment in a New Context(Advanced Science) Liu, Yao; Niu, Lili; Li, Nannan; Wang, Yang; Liu, Mingyang; Su, Xiaomin; Bao, Xuhui; Yin, Bo; Shen, ShunItem Open Access Immunotoxin Monotherapy and Combinatorial Therapy With Immune Checkpoint Inhibitors for Malignant Brain Tumors(2016) Bao, XuhuiGlioblastoma is the most common and aggressive malignant brain tumor among all primary brain and central nervous system (CNS) tumors. The median survival time for glioblastoma patients given the current standard of care treatment (surgery, radiation, and chemotherapy) is less than 15 months. Medulloblastoma is another major malignant brain tumor that most frequently occurs in children. Although recent advances in surgery, radiotherapy, and chemotherapy have led to an increase in 5-year survival rates of medulloblastoma patients, treatment-related toxicity often has a major impact on long-term quality of survival.
As a result, there is an urgent need to develop more efficient and novel therapeutic approaches that specifically target tumor cells while preserving the surrounding normal CNS to improve the poor survival and quality of life of patients with malignant brain tumors. To address this need, we have developed two novel targeted immunotoxins (ITs), D2C7-(scdsFv)-PE38KDEL (D2C7-IT) and NZ-1-(scdsFv)-PE38KDEL (NZ-1-IT). D2C7-IT was developed by fusing the single-chain variable fragment (scFv) of the D2C7 monoclonal antibody (mAb) with domains II and III of Pseudomonas exotoxin A (PE38KDEL), and NZ-1-IT was developed by fusing the scFv of the NZ-1 mAb with PE38KDEL. D2C7-IT reacts with both the wild-type epidermal growth factor receptor (EGFRwt) and the EGFR variant III (EGFRvIII), two overexpressed proteins in glioblastomas. NZ-1-IT reacts with podoplanin (PDPN), a protein that has a high expression in glioblastomas and medulloblastomas.
In vitro cytotoxicity data shows that both ITs effectively inhibited protein synthesis in a variety of epitope-expressing glioblastoma and medulloblastoma xenograft cells and human tumor cell lines. Furthermore, the direct anti-tumor efficacy of D2C7-IT was examined in orthotopic glioma models in immunocompromised mice, while the direct anti-tumor efficacy of NZ-1-IT was observed in medulloblastoma xenograft-bearing immunocompromised mice. Both immunotoxins showed a robust anti-tumor efficacy in the preclinical brain tumor models. D2C7-IT was first investigated in the subsequent studies to accelerate its translation to the clinic. The preclinical toxicity of intracerebral D2C7-IT infusion was subsequently determined in normal Sprague-Dawley (SD) rats. The maximum tolerated dose (MTD) of D2C7-IT was determined to be between a total dose of 0.10 and 0.35 μg, and the no-observed-adverse-effect level (NOAEL) of D2C7-IT was a total dose of 0.05 μg in SD rats. Both the MTD and NOAEL were utilized as references for the D2C7-IT clinical trial design.
In addition to direct tumor cell killing, immunotoxin monotherapy has been shown to induce a secondary anti-tumor immune response through the engagement of T cells. Therefore, the D2C7-IT-induced secondary anti-tumor immune response was investigated using syngeneic mouse glioma models in immunocompetent mice. Moreover, previous studies have demonstrated that immune checkpoint inhibitors have a robust anti-tumor efficacy by augmenting the T cell response to the tumor cells. Thus, immune checkpoint inhibitors were combined with D2C7-IT in order to enhance the immunotoxin-induced anti-tumor immune response to eliminate residual tumor cells and prevent tumor recurrence in the long term. Meanwhile, studies with NZ-1-IT remain preliminary; thus, this IT will not be as robustly discussed as D2C7-IT throughout this text.
Item Open Access Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations.(Journal for immunotherapy of cancer, 2019-05-29) Chandramohan, Vidyalakshmi; Bao, Xuhui; Yu, Xin; Parker, Scott; McDowall, Charlotte; Yu, Yen-Rei; Healy, Patrick; Desjardins, Annick; Gunn, Michael D; Gromeier, Matthias; Nair, Smita K; Pastan, Ira H; Bigner, Darell DBackground
D2C7-IT is a novel immunotoxin (IT) targeting wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins in glioblastoma. In addition to inherent tumoricidal activity, immunotoxins induce secondary immune responses through the activation of T cells. However, glioblastoma-induced immune suppression is a major obstacle to an effective and durable immunotoxin-mediated antitumor response. We hypothesized that D2C7-IT-induced immune response could be effectively augmented in combination with αCTLA-4/αPD-1/αPD-L1 therapies in murine models of glioma.Methods
To study this, we overexpressed the D2C7-IT antigen, murine EGFRvIII (dmEGFRvIII), in established glioma lines, CT-2A and SMA560. The reactivity and therapeutic efficacy of D2C7-IT against CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII cells was determined by flow cytometry and in vitro cytotoxicity assays, respectively. Antitumor efficacy of D2C7-IT was examined in immunocompetent, intracranial murine glioma models and the role of T cells was assessed by CD4+ and CD8+ T cell depletion. In vivo efficacy of D2C7-IT/αCTLA-4/αPD-1 monotherapy or D2C7-IT+αCTLA-4/αPD-1 combination therapy was evaluated in subcutaneous unilateral and bilateral CT-2A-dmEGFRvIII glioma-bearing immunocompetent mice. Further, antitumor efficacy of D2C7-IT+αCTLA-4/αPD-1/αPD-L1/αTim-3/αLag-3/αCD73 combination therapy was evaluated in intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII glioma-bearing mice. Pairwise differences in survival curves were assessed using the generalized Wilcoxon test.Results
D2C7-IT effectively killed CT-2A-dmEGFRvIII (IC50 = 0.47 ng/mL) and SMA560-dmEGFRvIII (IC50 = 1.05 ng/mL) cells in vitro. Treatment of intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII tumors with D2C7-IT prolonged survival (P = 0.0188 and P = 0.0057, respectively), which was significantly reduced by the depletion of CD4+ and CD8+ T cells. To augment antitumor immune responses, we combined D2C7-IT with αCTLA-4/αPD-1 in an in vivo subcutaneous CT-2A-dmEGFRvIII model. Tumor-bearing mice exhibited complete tumor regressions (4/10 in D2C7-IT+αCTLA-4 and 5/10 in D2C7-IT+αPD-1 treatment groups), and combination therapy-induced systemic antitumor response was effective against both dmEGFRvIII-positive and dmEGFRvIII-negative CT-2A tumors. In a subcutaneous bilateral CT-2A-dmEGFRvIII model, D2C7-IT+αCTLA-4/αPD-1 combination therapies showed dramatic regression of the treated tumors and measurable regression of untreated tumors. Notably, in CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII intracranial glioma models, D2C7-IT+αPD-1/αPD-L1 combinations improved survival, and in selected cases generated cures and protection against tumor re-challenge.Conclusions
These data support the development of D2C7-IT and immune checkpoint blockade combinations for patients with malignant glioma.Item Open Access Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside(Signal Transduction and Targeted Therapy) Bao, Xuhui; Liang, Yongjun; Chang, Hanman; Cai, Tianji; Feng, Baijie; Gordon, Konstantin; Zhu, Yuekun; Shi, Hailian; He, Yundong; Xie, LiyiAbstractProprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9’s aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.