• A new toolkit to engineer safe and effic

    From ScienceDaily@1:317/3 to All on Friday, April 15, 2022 22:30:40
    A new toolkit to engineer safe and efficient therapeutic cells

    Date:
    April 15, 2022
    Source:
    Gladstone Institutes
    Summary:
    Researchers undertook a systematic analysis of the molecular
    building blocks used to engineer therapeutic cells. Their work
    resulted in a comprehensive rule book for the design of therapeutic
    cells with improved specificity and safety, and for the eventual
    customization of cell-based therapies.



    FULL STORY ========================================================================== Therapies based on engineered immune cells have recently emerged as a
    promising approach in the treatment of cancer. Compared to traditional
    drugs, engineered immune cells are more precise and sophisticated in
    their ability to detect and eliminate cancer cells.


    ==========================================================================
    But despite their promise, cell-based therapies still face important limitations, including toxicity and the possibility that they could
    attack healthy cells. In addition, scientists don't have a good handle
    on how to modify existing therapeutic cells to expand their applications
    or better control their activity.

    To overcome these limitations, researchers at Gladstone Institutes and
    UC San Francisco (UCSF) undertook a systematic analysis of the molecular building blocks used to engineer therapeutic cells. Their work, reported
    in the journal Cell, resulted in a comprehensive rule book for the design
    of therapeutic cells with improved specificity and safety, and for the
    eventual customization of cell-based therapies.

    "We have identified principles that should greatly facilitate the
    engineering of therapeutic cells with greater sensitivity, accuracy, and
    safety than was possible before," says Kole Roybal, PhD, an associate
    professor in the Department of Microbiology and Immunology at UCSF, an affiliate investigator at Gladstone Institutes and core member of the Gladstone-UCSF Institute of Genomic Immunology, a Parker Institute for
    Cancer Immunotherapy investigator, and the study's senior author. "Our
    work will provide biomedical researchers with a toolkit for directing
    a range of cell-based therapies to their intended targets and for
    programming their therapeutic activities." Building a Better Receptor
    At the core of most therapeutic cells is a molecule called a receptor.

    Receptors are large proteins that straddle the cell's outer
    membrane. Their outer portion recognizes a specific target (for instance
    a protein on the surface of a cancer cell) and their inner portion tells
    the cell what to do upon recognizing this target. One way to engineer a therapeutic cell is to insert in a cell -- often an immune cell called
    a T cell -- a synthetic receptor made by piecing together fragments of
    known receptors.



    ==========================================================================
    This approach was used to create CAR-T cells, which have proven very
    effective at eliminating some types of blood cancers. CAR-T cells harbor
    a "chimeric antigen receptor" (CAR) that is based on a receptor normally
    found in T cells.

    Starting with a different backbone, Roybal previously developed a
    receptor called synNotch that can direct T cells to better recognize
    and kill solid tumors. Since this early stage research, Roybal's lab
    has shown how synNotch can be used in combination with CARs to develop next-generation cell therapies for ovarian cancer and mesothelioma. The synNotch receptor allows scientists to precisely control when and where
    the therapeutic T cell is active.

    "These smart cell therapies can unleash potent therapeutic activity
    precisely at the site of disease, improving the efficacy of the therapy
    and reducing the chance of life-threatening toxicities seen in patients,"
    says Roybal.

    However, the original synNotch receptor is difficult to deploy for
    cell-based therapy in humans. For one thing it is bulky, which makes it difficult to insert into human cells. For another, some of its parts
    come from mouse, yeast, and viruses instead of human receptors, which
    could lead to immune rejection of the engineered cells once introduced
    in a patient.

    To understand what they could keep and remove from the synNotch receptor without losing its desirable features, the Roybal team systematically
    swapped out various portions of the receptor. After inserting the
    modified receptors in human T cells, the scientists tested their ability
    to recognize their intended targets and activate the expected response.



    ==========================================================================
    "A challenging but fun feat was figuring out how different parts of known receptors function, so that we could take those pieces apart and put
    them back together in novel ways to meet our design specifications,"
    says Raymond Liu, PhD, a first author of the study and postdoctoral
    fellow in Roybal's lab.

    In the end, the team produced a catalog of receptors they dubbed SNIPRs,
    which are small enough for cost-effective engineering into human
    cells. They are also made exclusively from human receptor fragments
    and can detect and respond to even small amounts of their targets. In
    addition, the activity of SNIPRs can be adapted so that cells that harbor
    them don't just kill target cells, but can also deliver specific molecules
    to precise disease locations.

    "Understanding the rules of receptor design allowed us to build receptors
    that are more effective and also better suited for clinical translation,"
    says Iowis Zhu, a graduate student in the Roybal Lab and the other first
    author of the new study.

    A Platform for Next-Generation Cell Therapy The researchers next assessed
    the ability of these optimized receptors to clear tumors in mouse models
    of leukemia, mesothelioma, and ovarian cancer.

    To reduce the chances of killing non-target cells, they combined a SNIPR designed to recognize one molecule on the tumor with a CAR receptor
    tuned to another tumor molecule. Moreover, they made the production of
    the CAR receptor dependent on the activation of the SNIPR receptor. This
    way, only cells carrying the targets of both the synNotch and the CAR
    receptors would be killed, while cells carrying only one target would not.

    In each of the three cancer types they tested, this two-step targeting
    strategy led to more selective elimination of cancer cells than could
    be achieved with either receptor alone, highlighting the promise of this approach to reduce off- target toxicity of cell therapies.

    Cell therapies based on SNIPRs are now being optimized for the treatment
    of ovarian cancer, renal cancer, prostate cancer, and glioblastoma in
    both the academic setting and a company called Arsenal Bio, co-founded
    by Roybal.

    And cancer may not be the only condition that could be treated with
    SNIPR-based cell therapy.

    This receptor system is also amenable to enhancing the anti-inflammatory activity of immune cells for the treatment of autoimmunity. In addition,
    SNIPRs could be used to target stem cells or other cell types to detect
    tissue damage and induce tissue repair or the reversal of fibrosis.

    "Engineered cells have the potential to operate as much smarter
    therapeutics than traditional small molecules and biologics," says
    Roybal. "We're hoping our new receptor system will serve as a technology platform enabling scientists and clinicians to design safer, targeted,
    and more effective cell-based therapies against cancer and many other diseases."

    ========================================================================== Story Source: Materials provided by Gladstone_Institutes. Original
    written by Stacie Dodgson and Franc,oise Chanut. Note: Content may be
    edited for style and length.


    ========================================================================== Journal Reference:
    1. Iowis Zhu, Raymond Liu, Julie M. Garcia, Axel Hyrenius-Wittsten,
    Dan I.

    Piraner, Josef Alavi, Divya V. Israni, Bin Liu, Ahmad S. Khalil,
    Kole T.

    Roybal. Modular design of synthetic receptors for programmed
    gene regulation in cell therapies. Cell, 2022; 185 (8): 1431 DOI:
    10.1016/ j.cell.2022.03.023 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220415124718.htm

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