• Programming the immune system to superch

    From ScienceDaily@1:317/3 to All on Wed Mar 16 22:30:42 2022
    Programming the immune system to supercharge cancer cell therapies
    Genome-wide approaches to engineer more effective anti-cancer
    immunotherapy

    Date:
    March 16, 2022
    Source:
    New York Genome Center
    Summary:
    Scientists have developed a genetic screening platform to identify
    genes that can enhance immune cells to make them more persistent
    and increase their ability to eradicate tumor cells.



    FULL STORY ==========================================================================
    The first FDA-approved gene therapies are living drugs: immune cells
    taken from cancer patients engineered to target tumor cells. However, for
    many patients, these advanced therapies do not result in a long-lasting remission. Now, scientists at the New York Genome Center and New York University have developed a genetic screening platform to identify genes
    that can enhance immune cells to make them more persistent and increase
    their ability to eradicate tumor cells.


    ==========================================================================
    In the journal Nature, the researchers describe the discovery of synthetic
    gene programs that profoundly rewire a specific kind of immune cell
    called T cells, making them more effective at finding and fighting cancer cells. The research team, led by Neville Sanjana, PhD, Core Faculty Member
    at the New York Genome Center, Assistant Professor of Biology at New
    York University, and Assistant Professor of Neuroscience and Physiology
    at NYU Grossman School of Medicine, profiled the impact of nearly 12,000 different genes in multiple T cell subsets from human donors. The goal
    of this large-scale genetic screen was to identify precisely those genes
    that enable T cells to proliferate and to understand how those genes
    impact other aspects of immune cell function relevant to fighting cancer.

    Previous efforts to engineer T cells have focused on the targeting of
    specific tumor types by careful selection of cancer or tissue-specific
    proteins (antigens). Since first developed more than 30 years ago,
    chimeric antigen receptor (CAR)-T cell therapy has proven highly effective
    in targeting blood cancer cells, resulting in multiple FDA-approved
    CAR-T therapies. CAR-T cells have antigen receptors on their surface
    that recognize specific proteins present on cancer cells to target and
    destroy them. Some patients are cancer free even a decade after their
    CAR-T cell therapy, as the T cells introduced years earlier are still
    doing their job. But one of the major challenges facing biomedical
    science is to understand why a large majority of cancer patients who
    receive CAR-T cells fail to achieve lasting remission.

    Dr. Sanjana, senior author of the study, explained, "To date, genetic engineering of T cells has been focused on finding new antigens or new
    CARs. We took a radically different approach: Instead of changing the
    antibody, we thought why not try adding genes that transform T cells
    into more aggressive cancer fighters? These modifier genes worked very
    well in blood cancers, and we believe they will likely work for multiple antigens and in solid tumors." By combining modifier genes identified
    in the screen with existing CARs, the researchers were able to engineer T
    cells that were more effective at eliminating tumor cells. One particular modifier gene, lymphotoxin beta receptor (LTBR), acts like a molecular
    fountain of youth: with LTBR, T cells multiply, have a greater proportion
    of younger, more stem cell-like cells and resist becoming exhausted
    over time. Adding LTBR also caused T cells to secrete more cytokines,
    which are vital for the anti-tumor activity of T cells.

    Cytokines play an essential role in enabling T cells to better communicate
    with other immune cells in the body and launch coordinated attacks on
    the cancer.

    Interestingly, LTBR is not normally expressed in T cells, which
    highlights the power of the genome-scale screen to find genes that
    activate completely new cellular programs.

    "Our goal was to take existing immunotherapies and make them better. We
    were astonished that LTBR so significantly potentiates CAR therapies. It
    is an important step forward towards the development of next-generation
    CAR-T cell therapy," said the study's first author Mateusz Legut, PhD,
    a postdoctoral fellow in the Sanjana Lab. The research team found that
    adding LTBR rewires the genome of T cell, triggering expression of many
    other genes that potentiate T cell function. The team was able to quickly understand the effects of LTBR and similar modifier genes by combining
    gene overexpression screens with single- cell genomics. The new method
    that they developed -- OverCITE-seq -- allowed the researchers to test
    the impact of different modifier genes on the cellular states of T cells,
    which includes the expression of every gene, the proteins decorating the
    cell surface, and the unique T cell receptors expressed by each cell (clonotype). OverCITE-seq gave the researchers a detailed picture of
    how each modifier gene boosts T cell activity and did so for all of the top-ranked genes in one single-cell experiment. For LTBR, this yielded
    an early clue that a large number of genes were changing, leading
    the researchers to further identify a well-studied modulator of gene
    expression called NF-kB driving many of these changes. This LTBR-driven profound reprogramming was also seen in so- called unconventional T
    cells such as ?? T cells, which are present at a lower abundance than conventional T cells but can target a more diverse set of tumors.

    "The most exciting aspect is the demonstration that LTBR and other
    highly ranked genes improved the antigen-specific responses of chimeric
    antigen receptor T cells and ?? T cells. If validated in vitro and in
    clinical testing, this may have profound implication for future CAR-T
    cell therapies in both lymphoid malignancies and other cancers." said
    study co-author Catherine Diefenbach, MD, an Associate Professor in
    the Department of Medicine at the Grossman NYU School of Medicine and
    the Director of the Clinical Lymphoma Program at NYU's Perlmutter
    Cancer Center. The team also combined several top- ranked genetic
    modifiers with CARs similar to two existing FDA-approved therapies for
    blood cancers: tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta). Virtually all modifiers tested boosted CAR-T responses,
    including LTBR. Since T cells from cancer patients tend to be in poor
    condition compared to T cells from healthy donors, the researchers wanted
    to also test LTBR's ability to rejuvenate cancer patient T cells. They
    added LTBR together with a CAR to dysfunctional T cells from patients
    diagnosed with diffuse large B cell lymphoma, a blood cancer, and found
    a similar boost in T cell function, suggesting that the technology could
    work as an optimized therapy in the clinic.

    Andrew Sewell, PhD, an expert in T cells and immunotherapy from Cardiff University's School of Medicine who was not involved in the study noted,
    "Gain- of-function screening in T cells has great potential to uncover how
    to make immunotherapies more successful -- especially in solid cancers
    where current CAR T cell therapies do not work well." The research team
    also showed that T cells enhanced with modifier genes were better able
    to eradicate not only leukemia but also pancreatic cancer cells. Those
    results are encouraging not only to develop a larger panel of enhanced
    CAR-T therapies for blood cancers, but for the key role they could play
    in targeting solid tumors, a field in which establishing efficient CAR-T immunotherapy has been more challenging.

    In addition to Drs. Legut, Diefenbach and Sanjana, the research team
    included co-authors from the Sanjana lab, the NYGC Technology Innovation
    Lab, and the lab of Teresa Davoli, PhD, at the NYU Grossman School
    of Medicine. The Sanjana Lab has been focused on developing new gene
    editing and functional genomic technologies to reduce the high failure
    of current immunotherapies and build next-generation therapeutics. Since
    the newly-characterized modifier genes like LTBR can work hand in hand
    with already approved CAR-T therapies, this research has clear potential
    to move from bench to bedside and improve outcomes for cancer patients
    around the world.

    Video: https://vimeo.com/687951684

    ========================================================================== Story Source: Materials provided by New_York_Genome_Center. Note:
    Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Mateusz Legut, Zoran Gajic, Maria Guarino, Zharko Daniloski,
    Jahan A.

    Rahman, Xinhe Xue, Congyi Lu, Lu Lu, Eleni P. Mimitou, Stephanie
    Hao, Teresa Davoli, Catherine Diefenbach, Peter Smibert, Neville
    E. Sanjana. A genome-scale screen for synthetic drivers of T cell
    proliferation.

    Nature, 2022; DOI: 10.1038/s41586-022-04494-7 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220316132655.htm

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