Yiping Yang

Overview:

The goal of Dr. Yang’s laboratory is to understand the molecular and cellular mechanisms leading to the generation of potent and long-lasting anti-tumor immunity, and to develop effective gene immunotherapeutic strategies for treating cancer. Furthermore, rational pre-clinical approaches will be tested in clinical trials in patients with Epstein-Barr virus (EBV)-related malignancies. Specifically, we focus on the following areas:

1. Innate Immunity to Viruses. Recombinant vaccinia virus and adenovirus have been developed as potent vaccine vehicles for treating cancer and infectious diseases. Recent studies have shown that the unique potency of these viruses lies in their effective activation of the innate immune system. How these viruses activate the innate immune system remains largely unknown. We have been interested in the role of pattern-recognition receptors including Toll-like receptors (TLRs)in innate immune recognition of these viruses as well as their signaling pathways. In addition, we are investigating the role of innate immune cells such as natural killer (NK) cells in innate and adaptive immune responses to these viruses. A full understanding of these processes will help us design effective vaccine strategies.

2. T Cell Memory. Eliciting long-lived memory T cell response is an ultimate goal of vaccination to provide long-term immunity against cancer. However, it is not clear what controls the formation of long-lived memory T cells. The understanding of mechanisms underlying memory T cell formation will provide important insights into the design of effective vaccines for treating cancer.

3. Regulatory T Cell Biology. Accumulating evidence has shown that the immunosuppressive CD4+CD25+Foxp3+ regulatory T cells (TReg) play a critical role in the suppression of anti-tumor immunity. However, little is known about how TReg suppress T cell activation in vivo. Delineation of mechanisms underlying TReg-mediated suppression in vivo will help develop strategies to overcome TReg-mediated suppression in favor of boosting anti-tumor immunity.

4. Immunotherapy for EBV-associated Malignancies. Clinically, EBV-associated malignancies such as Hodgkin’s lymphoma offer a unique model to explore antigen-defined immunotherapy approaches because EBV-derived tumor antigens are specific for tumor cells only. Using this clinical model, we will test the utility of rational strategies identified in our preclinical models.

Positions:

Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Professor of Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1985

Zhejiang University (China)

Ph.D. 1993

University of Michigan at Ann Arbor

Residency, General Internal Medicine

University of Pennsylvania School of Medicine

Fellowship, Medical Oncology

Johns Hopkins University School of Medicine

Grants:

Role of hedgehog signaling in tumor-associated macrophage polarization

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

T memory stem cells in cancer

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Novel Strategies for Cancer Immunotherapy in Stem Cell Transplant

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Role of Endogenous Toll-Like Receptor Ligands in Allospecific T Cell Activation

Administered By
Surgery, Abdominal Transplant Surgery
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Role of inflammation in cancer progression

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours.

BACKGROUND: PG545 (pixatimod) is a novel immunomodulatory agent, which has been demonstrated to stimulate innate immune responses against tumours in preclinical cancer models. METHODS: This Phase I study investigated the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of PG545 monotherapy. Escalating doses of PG545 were administered to patients with advanced solid malignancies as a weekly 1-h intravenous infusion. RESULTS: Twenty-three subjects were enrolled across four cohorts (25, 50, 100 and 150 mg). Three dose-limiting toxicities (DLTs)-hypertension (2), epistaxis (1)-occurred in the 150 mg cohort. No DLTs were noted in the 100 mg cohort, which was identified as the maximum-tolerated dose. No objective responses were reported. Best response was stable disease up to 24 weeks, with the disease control rate in evaluable subjects of 38%. Exposure was proportional up to 100 mg and mean half-life was 141 h. The pharmacodynamic data revealed increases in innate immune cell activation, plasma IFNγ, TNFα, IP-10 and MCP-1. CONCLUSION: PG545 demonstrated a tolerable safety profile, proportional PK, evidence of immune cell stimulation and disease control in some subjects. Taken together, these data support the proposed mechanism of action, which represents a promising approach for use in combination with existing therapies.
Authors
Dredge, K; Brennan, TV; Hammond, E; Lickliter, JD; Lin, L; Bampton, D; Handley, P; Lankesheer, F; Morrish, G; Yang, Y; Brown, MP; Millward, M
MLA Citation
Dredge, Keith, et al. “A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours..” Br J Cancer, vol. 118, no. 8, Apr. 2018, pp. 1035–41. Pubmed, doi:10.1038/s41416-018-0006-0.
URI
https://scholars.duke.edu/individual/pub1306352
PMID
29531325
Source
pubmed
Published In
Br J Cancer
Volume
118
Published Date
Start Page
1035
End Page
1041
DOI
10.1038/s41416-018-0006-0

A mouse model for cancer immunoediting with renal cell carcinoma to explore mechanisms of immune escape

Authors
Bigger, E; Quigley, M; Yang, Y
MLA Citation
Bigger, Elizabeth, et al. “A mouse model for cancer immunoediting with renal cell carcinoma to explore mechanisms of immune escape.” Journal of Clinical Oncology, vol. 31, no. 15, AMER SOC CLINICAL ONCOLOGY, 2013.
URI
https://scholars.duke.edu/individual/pub1081748
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Published Date

Targeting co-stimulatory pathways in gene therapy.

Gene therapy with recombinant viral vectors such as adenovirus and adenovirus-associated virus holds great promise in treating a wide range of diseases because of the high efficiency with which the viruses transfer their genomes into host cells in vivo. However, the activation of the host immune responses remains a major hurdle to successful gene therapy. Studies in the past two decades have elucidated the important role co-stimulation plays in the activation of both T and B cells. This review summarizes our current understanding of T cell co-stimulatory pathways, and strategies targeting these co-stimulatory pathways in gene therapy applications as well as potential future directions.
Authors
MLA Citation
Huang, Xiaopei, and Yiping Yang. “Targeting co-stimulatory pathways in gene therapy..” Front Microbiol, vol. 2, 2011. Pubmed, doi:10.3389/fmicb.2011.00202.
URI
https://scholars.duke.edu/individual/pub822444
PMID
22046171
Source
pubmed
Published In
Frontiers in Microbiology
Volume
2
Published Date
Start Page
202
DOI
10.3389/fmicb.2011.00202

Direct action of type I IFN on NK cells is required for their activation in response to vaccinia viral infection in vivo.

Type I IFN plays an important role in the activation of NK cells. However, the mechanism underlying type I IFN-dependent NK cell activation remains largely unknown. A recent report suggested that type I IFN acted on accessory dendritic cells, leading to IL-15 production, and that subsequent trans-presentation of IL-15 was required for NK cell activation upon stimulation with synthetic TLR ligands. It is not clear how type I IFN regulates NK cell activation in response to live pathogens. Using a murine model of infection with vaccinia virus (VV), we previously demonstrated a critical role for type I IFN in the innate immune control of VV infection. In this study, we first showed that type I IFN did not directly protect L929 cells from VV infection in vitro and that type I IFN-dependent innate immune control of VV infection in vivo was mediated by activated NK cells. We further demonstrated that direct action of type I IFN on NK cells, but not on dendritic cells, is required for the activation of NK cells in response to VV infection both in vitro and in vivo, leading to efficient VV clearance. Our findings may help design effective strategies for the control of poxviral infections in vivo.
Authors
Martinez, J; Huang, X; Yang, Y
MLA Citation
Martinez, Jennifer, et al. “Direct action of type I IFN on NK cells is required for their activation in response to vaccinia viral infection in vivo..” J Immunol, vol. 180, no. 3, Feb. 2008, pp. 1592–97. Pubmed, doi:10.4049/jimmunol.180.3.1592.
URI
https://scholars.duke.edu/individual/pub777572
PMID
18209055
Source
pubmed
Published In
The Journal of Immunology
Volume
180
Published Date
Start Page
1592
End Page
1597
DOI
10.4049/jimmunol.180.3.1592

Recombinant adeno-associated virus for muscle directed gene therapy.

Although gene transfer with adeno-associated virus (AAV) vectors has typically been low, transduction can be enhanced in the presence of adenovirus gene products through the formation of double stranded, non-integrated AAV genomes. We describe the unexpected finding of high level and stable transgene expression in mice following intramuscular injection of purified recombinant AAV (rAAV). The rAAV genome is efficiently incorporated into nuclei of differentiated muscle fibers where it persists as head-to-tail concatamers. Fluorescent in situ hybridization of muscle tissue suggests single integration sites. Neutralizing antibody against AAV capsid proteins does not prevent readministration of vector. Remarkably, no humoral or cellular immune responses are elicited to the neoantigenic transgene product E. coli beta-galactosidase. The favorable biology of rAAV in muscle-directed gene therapy described in this study expands the potential of this vector for the treatment of inherited and acquired diseases.
Authors
Fisher, KJ; Jooss, K; Alston, J; Yang, Y; Haecker, SE; High, K; Pathak, R; Raper, SE; Wilson, JM
MLA Citation
Fisher, K. J., et al. “Recombinant adeno-associated virus for muscle directed gene therapy..” Nat Med, vol. 3, no. 3, Mar. 1997, pp. 306–12.
URI
https://scholars.duke.edu/individual/pub807234
PMID
9055858
Source
pubmed
Published In
Nature Medicine
Volume
3
Published Date
Start Page
306
End Page
312

Research Areas:

Acute Disease
Adaptive Immunity
Adenoviridae
Adenoviridae Infections
Adenovirus E1A Proteins
Adenovirus E1B Proteins
Adenoviruses, Human
Adjuvants, Immunologic
Adoptive Transfer
Aged
Alternative Splicing
Antibody Formation
Antigen Presentation
Antigens, CD4
Antigens, CD8
Antigens, Neoplasm
Antigens, Viral
Antineoplastic Agents
Autoantigens
Autoimmune Diseases
Autoimmunity
Blotting, Western
CD4 Antigens
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Cell Proliferation
Chaperonins
Chloride Channels
Coculture Techniques
Combined Modality Therapy
Cyclic AMP
Cystic Fibrosis Transmembrane Conductance Regulator
Cytokines
Cytotoxicity, Immunologic
DNA, Viral
Dendritic Cells
Dependovirus
Disease Models, Animal
Electric Conductivity
Endoplasmic Reticulum
Endosomes
Extracellular Signal-Regulated MAP Kinases
Female
Flow Cytometry
Gene Deletion
Gene Knock-In Techniques
Gene Transfer Techniques
Gene therapy
Genes, Bacterial
Genes, Viral
Genetic Therapy
Germinal Center
Glucose
Graft vs Host Disease
Growth Inhibitors
HLA Antigens
HLA-C Antigens
Heat-Shock Proteins
Hemagglutinins
Hematologic Neoplasms
Hematopoietic Stem Cell Transplantation
Heparitin Sulfate
Histocompatibility
Histocompatibility Testing
Humans
Immune System
Immune Tolerance
Immunity, Cellular
Immunity, Innate
Immunologic Memory
Immunosuppressive Agents
Immunotherapy
Influenza A virus
Interferon Type I
Interferon-beta
Interleukin-10
Interleukin-12
Interleukin-13
Interleukin-2
Interleukin-6
Killer Cells, Natural
Luciferases
Lung Neoplasms
Lymphocyte Activation
Lymphocyte Depletion
Lymphocyte Transfusion
Lymphocytes
Lymphoma
Lymphopenia
Macrophages
Male
Membrane Glycoproteins
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Knockout
Mice, Mutant Strains
Mice, Nude
Mice, Transgenic
Microsomes
Middle Aged
Mitosis
Molecular Sequence Data
Myelodysplastic Syndromes
Myeloid Cells
Myeloid Differentiation Factor 88
NK Cell Lectin-Like Receptor Subfamily K
Neoplasms
North Carolina
Oocytes
Peripheral Blood Stem Cell Transplantation
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
RNA, Messenger
Receptors, Cell Surface
Receptors, Interleukin-1
Receptors, KIR
Recombinant Proteins
Retrospective Studies
Reverse Transcriptase Polymerase Chain Reaction
Risk Factors
STAT1 Transcription Factor
Sequence Deletion
Stem Cell Transplantation
Survival Rate
T-Cell Antigen Receptor Specificity
T-Lymphocytes
T-Lymphocytes, Cytotoxic
T-Lymphocytes, Regulatory
Toll-Like Receptor 2
Toll-Like Receptor 4
Toll-Like Receptor 8
Toll-Like Receptor 9
Toll-Like Receptors
Transfection
Transgenes
Transplantation Conditioning
Transplantation, Homologous
Tumor Escape
Vaccines
Vaccinia
Vaccinia virus
Virus Diseases
Viruses
Xenopus
beta-Galactosidase