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Haopeng Wang, PhDAssociate Professor

Tel:

Email: wanghp@@shanghaitech.edu.cn

Fax: 86-21-20685-22

Add: 393 Middle Huaxia Road, Pudong, Shanghai

Faculty KMS Profile

中文信息English
T Cell Signaling and Engineering

Principal investigator

Name:

Haopeng WangAssociate Professor , PhD, Associate Professor

Position:

Affiliation:

School of Life Science and Technology

Honor:

Education Background:
  • 1999/09-2003/07, Nanjing University, B.S. in Biochemistry
  • 2004/01-2009/07, St Jude Children’s Research Hospital/University of Tennessee Health Science Center,Dario Vignali Lab, Ph. D. in Immunology
Working Experience:
  • 2009/08-2015/07, University of California, San Francisco, Arthur Weiss Lab, Postdoctoral Fellow
  • 2015/07-2021/05, School of Life Science and Technology, ShanghaiTech University, Assistant Professor (TENURE-TRACK)
  • 2021/05-Now, School of Life Science and Technology, ShanghaiTech University, Associate Professor (TENURED)

Group Introduction

Research Area:
Cancer immunity, CAR-T, TCR-T, Immune checkpoints
Research Interests:

Recently, significant breakthroughs have been made in cancer immunotherapy. Immunologists have successfully cured cancer patients by using biologic (e.g., checkpoint blockade) and cellular drugs (e.g., TCR-T and CAR-T) to enhance the anti-cancer ability of patients' own T cells. The major goal of our laboratory is to explore the regulatory mechanism of T cell anti-tumor ability and develop new cancer immunotherapies by combining proteomic, CRISPR screen, and mouse genetics.


Engineered T cell therapies, mainly CAR-T and TCR-T, have become the new frontier of cancer treatment. CAR-T and TCR-T therapies differ in many aspects, including cell persistence and toxicity, leading to different therapeutic outcomes. Both TCR and CAR recognize antigens and trigger T-cell mediated antitumor response, but they have distinct molecular structures and signaling properties.



The antitumor response in the engineered T cells can be conceptually divided into three stages: i. The sensors on the T cell membrane, e.g., TCR and CAR, scan the surrounding environment and recognize tumor antigens on tumor cells; ii. The information is transduced and amplified through a signal transduction network to activate T cells; iii. An array of effector molecules are activated or produced to execute antitumor responses (see the Figure below and our review published in Trends in Cancer, 2021). The sensors, transducers, and effectors are the essential components of the antitumor response of engineered T cells. Positive and negative feedback loops are also involved in enabling these three components to induce a potent and durable antitumor response. TCR-T and CAR-T exhibit several distinct clinical features, including in vivo persistence of transferred T cells, the number of T cells transferred to the patients and the efficacy against solid tumors. These differences are contributed, at least partially, by the distinct features of sensors and transducers of TCR-T and CAR-T cells. Understanding how engineered T cells sense the tumor antigens and how signaling networks control T cell antitumor activities will help us develop next-generation engineered T cell therapy. Collectively, in my eyes, the primary function of the egineered T cells is to serve as an information processor, where inputs are recongized and sorted,followed by the activated effector mechanisms. Thus, our laboratory is focusing on the optimizing the sensors and transducers, as well as the effector molecules, that regulate T cell antitumor function.





Group Website:

Research Achievement

1. Develop new CAR-T therapies using synthetic immunology approaches (Immunity 2020, Cover article)

CAR-T therapy is a type of cancer immunotherapy that recognizes and kills tumor cells in vivo by expressing chimeric antigen receptors (Chimeric Antigen Receptor, CAR) on a patient's own T cells. CAR-T therapy has shown remarkable efficacy in hematological cancers and is approved for the treatment of acute B lymphocytic leukemia and certain types of non-Hodgkin's lymphoma. However, as a new treatment, CAR-T therapy also has its limitations. More and more clinical data shows that up to 30%-50% of patients treated with CAR-T therapy might experience tumor recurrence, and most of these patients will experience recurrence within one year after receiving CAR-T therapy. There are several reasons for tumor recurrence, of which the in vivo persistence of CAR-T cells (the length of time that CAR-T cells survive in the patient) is a decisive factor. In clinical studies of acute lymphocytic leukemia and chronic lymphocytic leukemia, it has been found that the efficacy of CAR-T therapy is positively correlated with the in vivo persistence of CAR-T cells. Therefore, exploring the regulation mechanism of the in vivo persistence of CAR-T cells has become a current research hotspot.

Our team and collaborators published a research paper titled Chimeric Antigen Receptor Designed to Prevent Ubiquitination and Downregulation Showed Durable Anti-tumor Efficacy on Immunity (Cover article). By studying the regulation mechanism of CAR-receptor trafficking in CAR-T cells, a new type of recyclable CAR was designed, which significantly improved the in vivo persistence and anti-tumor effect of CAR-T cells, providing a new strategy for preventing tumor recurrence after CAR T therapy. The technology transfer was successfully completed at the end of 2020 and clinical trials related to recyclable CAR-T are expected to be launched in 2021.


Wentao Li, Shizhen Qiu, Jian Chen, Shutan Jiang, Wendong Chen, Jingwei Jiang, Fei Wang, Wen Si, Yilai Shu, Ping Wei, Gaofeng Fan, Ruijun Tian, Haitao Wu, Chenqi Xu, Haopeng WangChimeric Antigen Receptor Designed to Prevent Ubiquitination and Downregulation Showed Durable Antitumor Efficacy. Immunity. 2020.

Immunity invited Prof. Stephen Gottschalk and Prof. Hongbo Chi to write a preview for our article.



2. Apply a genome-wide CRISPR genetic screen to map T cell functional regulatory networks (PNAS2018)

As an essential part of the human immune system, T cells play a vital role in immune monitoring and killing tumor cells. However, tumor cells can inhibit the anti-tumor activity of T cells via multiple mechanisms, thereby escaping from the body's immune system attack. Therefore, tumors can be treated by increasing the activity of T cells in the clinic. At present, T cell-based tumor immunotherapy has achieved remarkable success in clinical practice and has broad application prospects. However, the existing treatments are only effective for a fraction of cancer patients, and there are considerable side effects. Therefore, further investigation on the regulation mechanism of T cell activation will contribute to developing new tumor immunotherapies to improve the efficacy and benefit more patients.

In cooperation with Arthur Weiss lab at UCSF and Lai Wei's group at Sun Yat-sen University, our research team published a research paper titled A genome-wide CRISPR screen identifies FAM49B as a key regulator of actin dynamics and T cell activation in PNAS. In the previous studies from our laboratory, a gene-editing toolbox for studying T cells has been established. This project used a genome-wide CRISPR genetic screen to systematically study the molecular mechanism of T cell activation and illustrate a regulatory map of human T cell functions. It is worth mentioning that this study is the FIRST reported genome-wide CRISPR screen on T cells.


Dr. Lawerence Samelson, associate director of the Center for Cancer Research at the National Cancer Institute, gave a high appraisal of this work: Shang et al by reporting a genome-wide CRISPRscreen in Jurkat T cells have performed an important service for the immunologycommunity. The lists of activating and inhibitory molecules that they havereported will be of great use to many investigators. This is an excellent studyand important contribution to those studying lymphocyte activation and signaltransduction in general.

Shen Chi, Arthur Weiss, Haopeng WangA CRISPR-based toolbox for studying T cell signal transduction. BioMed Research. 2016.

Wanjing Shang, Yong Jiang, Michael Boettcher, Kang Ding, Marianne Mollenauer, Zhongyi Liu, Xiaofeng Wen, Chang Liu, Piliang Hao, Suwen Zhao, Michael T McManus, Lai Wei, Arthur Weiss, Haopeng Wang.Genome-wide CRISPR screen identifies FAM49B as a key regulator of actin dynamics and T cell activation.PNAS. 2018



3. Establish CAR-T therapies for T-cell lymphoma (National Key R&D Program)

CAR-T therapy has achieved remarkable results in the treatment of B cell-derived leukemia and lymphoma. But for T cell tumors that are also hemolymphatic tumors, CAR-T therapy has not been a suitable treatment plan. This is mainly due to the following fact: in vitro generated CAR-T cells, the patient's T cell tumor, and the T cells in the patient, all three of which are T lymphocytes by definition, and it is logically difficult to find a surface target to effectively distinguish these three types of cells (see the graph below). Our team cooperates with the first-line clinical team to develop a CAR-T therapy that can effectively treat T cell tumors. We expect to launch a clinical trial in early 2022.


Representative Publications (*First Author, # Corresponding Author)

Monograph

Patent

Funding

Awards

  • 1. 2011-2014, American Rheumatoid Arthritis Foundation Postdoctoral Scholarship
  • 2. 2014-2015, National Institutes of Health T32 Scholarship
  • 3. 2018, Roche Sponsored Research Funding
  • 4. 2018, Young Scholar, Center for Excellence and Innovation in Molecular and Cellular Sciences, Chinese Academy of Sciences
  • 5. 2019, National Key Research and Development Program of China

Research Achievement

Group Member and Photo

  • Name:Li Li
    Position:Engineer
    Duration:2018/09-Now
    Email:lili2@@shanghaitech.edu.cn
  • Name:Wentao Li
    Position:Doctoral Student
    Duration:2014/09-Now
    Email:liwt@@shanghaitech.edu.cn
  • Name:Shizhen Qiu
    Position:Doctoral Student
    Duration:2017/09-Now
    Email:qiushzh@shanghaitech.edu.cn
  • Name:Fei Wang
    Position:Doctoral Student
    Duration:2015/09-Now
    Email:wangfei1@@shanghaitech.edu.cn
  • Name:Yong Jiang
    Position:Doctoral Student
    Duration:2016/09-Now
    Email:jiangyong2@@shanghaitech.edu.cn
  • Name:Jingwei Jiang
    Position:Doctoral Student
    Duration:2016/09-Now
    Email:jiangjw@@shanghaitech.edu.cn
  • Name:Anran Dai
    Position:Doctoral Student
    Duration:2017/09-Now
    Email:Daiar@shanghaitech.edu.cn
  • Name:Kun Wang
    Position:Doctoral Student
    Duration:2019/09-Now
    Email:wangkun@@shanghaitech.edu.cn

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