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    Cellular and Molecular Bioengineering

    (H-293) Engineer ultrasound-controllable CAR-T cells with enhanced sustainability and inducibility for solid tumor therapy

    Saturday, October 14, 2023
    9:30 AM – 10:30 AM PDT
    Location: Exhibit Hall - Row H - Poster # 293

      Presenting Author(s)

    • PH

      Peixiang He

      PhD student
      University of California San Diego, United States

      • Co-Author(s)

    • Longwei Liu (he/him/his)

      Research Assistant Professor
      University of Southern California
      Los Angeles, California, United States

    • Linshan Zhu, PhD (he/him/his)

      Postdoc researcher
      University of Southern California
      Los Angeles, California, United States

    • YQ

      Yunjia Qu, MS (she/her/hers)

      PhD Student
      Department of Bioengineering, University of California, San Diego
      LOS ANGELES, California, United States

    • CY

      Chi Woo Yoon

      Assistant research assistant
      University of Southern California, United States

    • Tianze Guo (he/him/his)

      Ph.D. Student
      University of Southern California
      Los Angeles, California, United States

    • QZ

      Qifa Zhou

      Professor in Biomedical Engineering
      University of Southern California, United States

      • Primary Investigator(s)

    • YW

      Yingxiao Wang

      Professor
      University of Southern California, United States

    Introduction:: While Chimeric Antigen Receptor (CAR) T cells demonstrate efficacy in treating leukemia, persistent challenges such as life-threatening "on-target off-tumor toxicities" and poor T cell persistence remain, which hindering its application in solid tumor treatment. The focused ultrasound (FUS)-controllable acousto-genetics approach provides an avenue for remote-controlled CAR T cell immunotherapy, offering high spatiotemporal precision to minimize the toxicity of CAR-T cells with the capacity to reach any body depth. However, the limited inducibility and short duration time of CAR-molecule after induction (less than 24 hours), especially in in vivo scenarios, limit the application of FUS-CAR T cell in clinics. In this project, we first aim to improve FUS-HS induction through optimizing of heat shock promoter we are using for CAR expression. Secondly, we will try to extend the duration of CAR expression through a novel CAR-feedback design.

    Materials and Methods::

    In this study, we employed a directed evolution approach to optimize heat shock promoters and integrated intrinsic CAR signaling to extend the CAR half-life. We constructed a library of promoter variants through site saturation mutagenesis, enhancing the likelihood of identifying variants with desirable attributes. This was followed by high-throughput in-T cell interactive heat-shock screening, allowing us to select optimal candidates. Subsequent next-generation sequencing led to the identification of a highly heat-sensitive promoter, which was employed to drive CAR expression in T cells.


    In the future, we will design a feed-back gene circuit to achieve longer CAR sustainability through CAR signaling enhancing CAR expression.

    Results, Conclusions, and Discussions::

    After directed evolution and selection, we identified a super sensitive heat-shock responsive element to FUS and its subsequent heat shock. Furthermore, some preliminary results showed that our newly developed FUS-CAR design permits more sustained CAR expression. This is a significant improvement from the initial design, which maintained expression for less than 24 hours. Moreover, the directed evolution method for heat shock element has the potential to be transplanted for improvement of other DNA enhancer elements. Besides, after futural development, this feedback design is supposed to be modular and extendable to other inducible CAR designs for various types of solid tumors or other diseases.



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