Showing papers by "Hong Jiang published in 2017"

Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance

Abstract: Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms of resistance remain incompletely understood. To address this, we recently studied a cohort of melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) and identified immune markers of response and resistance. Building on these studies, we performed deep molecular profiling including T cell receptor sequencing and whole-exome sequencing within the same cohort and demonstrated that a more clonal T cell repertoire was predictive of response to PD-1 but not CTLA-4 blockade. Analysis of CNAs identified a higher burden of copy number loss in nonresponders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was nonredundant, suggesting the potential utility of a combinatorial biomarker to optimize patient care with checkpoint blockade therapy.

Oncolytic adenovirus and tumor-targeting immune modulatory therapy improve autologous cancer vaccination

Abstract: Oncolytic viruses selectively lyse tumor cells, disrupt immunosuppression within the tumor, and reactivate antitumor immunity, but they have yet to live up to their therapeutic potential Immune checkpoint modulation has been efficacious in a variety of cancer with an immunogenic microenvironment, but is associated with toxicity due to nonspecific T-cell activation Therefore, combining these two strategies would likely result in both effective and specific cancer therapy To test the hypothesis, we first constructed oncolytic adenovirus Delta-24-RGDOX expressing the immune costimulator OX40 ligand (OX40L) Like its predecessor Delta-24-RGD, Delta-24-RGDOX induced immunogenic cell death and recruit lymphocytes to the tumor site Compared with Delta-24-RGD, Delta-24-RGDOX exhibited superior tumor-specific activation of lymphocytes and proliferation of CD8+ T cells specific to tumor-associated antigens, resulting in cancer-specific immunity Delta-24-RGDOX mediated more potent antiglioma activity in immunocompetent C57BL/6 but not immunodeficient athymic mice, leading to specific immune memory against the tumor To further overcome the immune suppression mediated by programmed death-ligand 1 (PD-L1) expression on cancer cells accompanied with virotherapy, intratumoral injection of Delta-24-RGDOX and an anti-PD-L1 antibody showed synergistic inhibition of gliomas and significantly increased survival in mice Our data demonstrate that combining an oncolytic virus with tumor-targeting immune checkpoint modulators elicits potent in situ autologous cancer vaccination, resulting in an efficacious, tumor-specific, and long-lasting therapeutic effect Cancer Res; 77(14); 3894-907 ©2017 AACR

Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma

Abstract: Appreciation for genomic and immune heterogeneity in cancer has grown though the relationship of these factors to treatment response has not been thoroughly elucidated. To better understand this, we studied a large cohort of melanoma patients treated with targeted therapy or immune checkpoint blockade (n = 60). Heterogeneity in therapeutic responses via radiologic assessment was observed in the majority of patients. Synchronous melanoma metastases were analyzed via deep genomic and immune profiling, and revealed substantial genomic and immune heterogeneity in all patients studied, with considerable diversity in T cell frequency, and few shared T cell clones (<8% on average) across the cohort. Variables related to treatment response were identified via these approaches and through novel radiomic assessment. These data yield insight into differential therapeutic responses to targeted therapy and immune checkpoint blockade in melanoma, and have key translational implications in the age of precision medicine.

Rare GCH1 heterozygous variants contributing to Parkinson’s disease

Abstract: 1 Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China 2 National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan, P.R. China 3 State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, P.R. China 4 Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, P.R. China 5 Parkinson’s Disease Center of Beijing Institute for Brain Disorders, Beijing, P.R. China 6 Collaborative Innovation Center for Brain Science, Shanghai, P.R. China 7 Collaborative Innovation Center for Genetics and Development, Shanghai, P.R. China

Toward Understanding Non-coding RNA Roles in Intracranial Aneurysms and Subarachnoid Hemorrhage.

Abstract: Subarachnoid hemorrhage (SAH) is a common and frequently life-threatening cerebrovascular disease, which is mostly related with a ruptured intracranial aneurysm Its complications include rebleeding, early brain injury, cerebral vasospasm, delayed cerebral ischemia, chronic hydrocephalus, and also non neurological problems Non-coding RNAs (ncRNAs), comprising of microRNAs (miRNAs), small interfering RNAs (siRNAs) and long non-coding RNAs (lncRNAs), play an important role in intracranial aneurysms and SAH Here, we review the non-coding RNAs expression profile and their related mechanisms in intracranial aneurysms and SAH Moreover, we suggest that these non-coding RNAs function as novel molecular biomarkers to predict intracranial aneurysms and SAH, and may yield new therapies after SAH in the future

TIE2 associates with caveolae and regulates caveolin-1 to promote their nuclear translocation

Abstract: DNA repair pathways are aberrant in cancer, enabling tumor cells to survive standard therapies-chemotherapy and radiotherapy. Our group previously reported that, upon irradiation, the membrane-bound tyrosine kinase receptor TIE2 translocates into the nucleus and phosphorylates histone H4 at Tyr51, recruiting ABL1 to the DNA repair complexes that participate in the nonhomologous end-joining pathway. However, no specific molecular mechanisms of TIE2 endocytosis have been reported. Here, we show that irradiation or ligand-induced TIE2 trafficking is dependent on caveolin-1, the main component of caveolae. Subcellular fractionation and confocal microscopy demonstrated TIE2/caveolin-1 complexes in the nucleus, and using inhibitor or small interfering RNAs (siRNAs) against caveolin-1 or Tie2 inhibited their trafficking. TIE2 was found in caveolae and directly phosphorylated caveolin-1 at Tyr14 in vitro and in vivo This modification regulated the generation of TIE2/caveolin-1 complexes and was essential for TIE2/caveolin-1 nuclear translocation. Our data further demonstrate that the combination of TIE2 and caveolin-1 inhibitors resulted in significant radiosensitization of malignant glioma cells, which will guide the development of combinatorial treatment with radiotherapy for patients with glioblastoma.

Novel mutations in ADSL for Adenylosuccinate Lyase Deficiency identified by the combination of Trio-WES and constantly updated guidelines.

Abstract: Whole-exome sequencing (WES), one of the next-generation sequencing (NGS), has become a powerful tool to identify exonic variants. Investigating causality of the sequence variants in human disease becomes an important part in NGS for the research and clinical applications. Recently, important guidelines on them have been published and will keep on updating. In our study, two Chinese families, with the clinical diagnosis of “Epilepsy”, which presented with seizures, psychomotor retardation, hypotonia and etc. features, were sequenced by Trio-WES (including the proband and the unaffected parents), and a standard interpretation of the identified variants was performed referring to the recently updated guidelines. Finally, we identified three novel mutations (c.71 C > T, p.P24L; c.1387-1389delGAG, p.E463-; c.134 G > A, p.W45*; NM_000026) in ADSL in the two Chinese families, and confirmed them as the causal variants to the disease-Adenylosuccinate Lyase Deficiency. Previous reported specific therapy was also introduced to the patients after our refined molecular diagnosis, however, the effect was very limited success. In summary, our study demonstrated the power and advantages of WES in exploring the etiology of human disease. Using the constantly updated guidelines to conduct the WES study and to interpret the sequence variants are a necessary strategy to make the molecular diagnosis and to guide the individualized treatment of human disease.

Mutation screening of the PRRT2 gene for benign epilepsy with centrotemporal spikes in Chinese mainland population

Abstract: Proline-rich transmembrane protein 2 gene (PRRT2) mutations are reported to cause common paroxysmal neurological disorders and show a remarkable pleiotropy. Benign epilepsy with centrotemporal spikes (BECTS) is considered to be the most common epilepsy syndrome in childhood. It is placed among the idiopathic localization related epilepsies. Recently, it was reported that a girl with a PRRT2 mutation c.649_650insC developed infantile focal epilepsy with bilateral spikes which resembled the rolandic spikes. Hereby we performed a comprehensive genetic mutation screening of PRRT2 gene in a cohort of 53 sporadic BECTS patients. None of the 53 sporadic BECTS patients and other 250 controls carried mutations including c.649_650insC in PRRT2. Our data indicated that the PRRT2 mutations might most likely not be associated with BECTS in Chinese mainland population.

Adenovirus and immunomodulator combination therapy

Abstract: Certain embodiments include the enhancement of effectiveness for an adenoviral cancer therapy.

Abstract 4565: Forced expression of GITRL in cancer cells enhances adenovirus-mediated in situ vaccination

Abstract: Our approach involves a platform of killing cancer using more potent oncolytic viruses-based immunotherapy strategies. These replication competent adenoviruses are targeted to the Rb pathway to generate tumor-selectivity. The second generation of these therapeutic agents, Delta-24-RGD, was successfully translated to the clinical setting and is currently been tested in Phase I studies in several institutions in the USA and in Europe for the treatment of patients suffering from recurrent gliomas. Preliminary data from these clinical trials showed that 10 to 15% of Delta-24-RGD-treated tumors undergo complete regression. Agonistic treatments targeting co-stimulatory tumor necrosis factor receptor superfamily (TNFRSF), such as GITR (CD357), have been shown to enhance the proliferation and activation of T cells. Moreover, in preclinical tumor efficacy studies, these agonistic signals have shown potent tumoricidal activity. Different from antibodies, co-stimulatory ligands can be easily incorporated into replication competent oncolytic adenoviruses. Infection of cancer cells with these armed viruses will lead to the expression in their cell membranes of the co-stimulatory molecule that will directly interact with the tumor infiltrating lymphocytes to amplify and enhance the anti-tumor T-cell activity. In this study, we have developed an armed Delta-24-RGD carrying the cDNA of the mouse GITRL, Delta-24-GREAT. Treatment of glioma-bearing mice with intracranial injection of Delta-24-GREAT increased mice survival (P Citation Format: Yisel A. Rivera-Molina, Francisco Puerta Martinez, Teresa Nguyen, Hong Jiang, Xuejun Fan, Rehnuma Shifat, Mohammad Belayat Hossain, Verlene K. Henry, Caroline C. Carrillo, Candelaria Gomez-Manzano, Juan Fueyo. Forced expression of GITRL in cancer cells enhances adenovirus-mediated in situ vaccination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4565. doi:10.1158/1538-7445.AM2017-4565

Abstract 3668: Oncolytic adenoviruses expressing OX40L or GITRL immune modulators show antitumor effect on immune-competent mouse breast cancer models

Abstract: Metastasis of advanced stage cancers remains as the main cause of morbidity and mortality in oncologic patients. Metastatic cancers, especially those that metastasize to the brain, are generally resistant to conventional therapies. Thus, more innovative and efficacious therapies are urgently needed. Therapeutic goals are the specific targeting of malignant cells, shrinkage of stablished tumors, prevention and/or eradication of metastases and, ultimately, induction of a specific anti-tumor immune response. In this study we tested the efficiency of a treatment regimen consisting of oncolytic adenoviruses combined with specific immune regulators to prevent tumor progression and metastasis. In order to do so, mouse metastatic breast cancer cells 4T1 or 66c14, were orthotopically implanted in female BALB/c mice. The resulting primary tumors were treated with multiple doses of third generation adenoviruses targeting different immune checkpoints, such as, OX40/OX40L and GITR/GITRL pathways in the immune synapse. The treatment with these adenoviral constructs resulted in T cells activation and reduction of the metastases in 50% of the mice. In addition, the size and number of the metastases detected in lungs were significantly lower comparing with those observed in the control groups. Survival rates were also significantly different (P Citation Format: Francisco W. Puerta Martinez, Yisel A. Rivera, Teresa Nguyen, Xuejun Fan, Jared M. Henderson, Shifat Rehnuma, Mohammad B. Hossain, Hong Jiang, Juan Fueyo, Candelaria Gomez Manzano. Oncolytic adenoviruses expressing OX40L or GITRL immune modulators show antitumor effect on immune-competent mouse breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3668. doi:10.1158/1538-7445.AM2017-3668