• Potential therapy may boost chemoimmunot

    From ScienceDaily@1:317/3 to All on Mon Mar 28 22:30:40 2022
    Potential therapy may boost chemoimmunotherapy response in bladder
    cancer

    Date:
    March 28, 2022
    Source:
    Cedars-Sinai Medical Center
    Summary:
    Adding an anti-inflammatory medication to immunotherapy and standard
    chemotherapy drugs may provide long-term suppression of aggressive
    bladder tumor growth, according to a proof-of-concept study.



    FULL STORY ========================================================================== Adding an anti-inflammatory medication to immunotherapy and standard chemotherapy drugs may provide long-term suppression of aggressive
    bladder tumor growth, according to a proof-of-concept study led by
    Cedars-Sinai Cancerinvestigators. The findings, made in laboratory mice,
    were published TK in the peer-reviewed journal Nature Communications.


    ==========================================================================
    The researchers' previous work, led by Cedars-Sinai scientist Keith
    Syson Chan, PhD -- the study's corresponding author -- found that the
    combined use of the chemotherapy drugs gemcitabine and cisplatin is
    unable to activate a patient's own immune response to cancer. They also
    found that chemotherapy prompts the overwhelming release of an inhibitory signal, or brake, that suppresses an immune response by counteracting "go" signals. When the investigators added the anti-inflammatory drug celecoxib
    to gemcitabine to remove the brake, they were able to shift the balance
    toward the "go" signals, improving the immune response in laboratory mice.

    Building on those findings, the researchers discovered a mechanism that
    may drive the immune-dampening effect of chemotherapy and determined how
    to counteract it, therefore activating a longer-lasting immune response.

    "These results are significant because the novel drug combination
    of an anti- inflammatory medication like celecoxib, chemotherapy and immunotherapy potentially can increase the chemoimmunotherapy response in patients with muscle-invasive bladder cancer," said Fotis Nikolo, PhD,
    a project scientist at Cedars-Sinai Cancer and first co-author of the
    study. "We're also hopeful that our findings will be relevant to other
    cancer types." Muscle-invasive bladder cancer is aggressive and more
    likely to spread to other parts of the body, according to the Urology
    Care Foundation. Each year, more than 83,000 new U.S. cases of bladder
    cancer are diagnosed in men and women.

    About one quarter of those newly diagnosed have the muscle-invasive type.

    Past and Present Treatments Since the 1940s, the main treatment
    for killing cancer cells has involved chemotherapy drugs, which kill
    the cells directly. But many of the current drugs fail to induce the
    most efficient form of cell death, known as immunogenic cell death,
    which activates the release of a protein that instructs the patients'
    own immune cells to kill the invading cancer cells. This "go" signal
    prompts immune cells -- called dendritic cells -- to activate T cells to eradicate tumors. Instead, most current chemotherapies for pancreatic,
    bladder, breast and ovarian cancers not only are non-immunogenic, they
    suppress the immune system.



    ==========================================================================
    In recent years, immunotherapy drugs have been added to cancer treatment regimens to help a patient's own immune cells attack cancer, but the
    response rate is low. Currently, about 70% to 80% of patients taking immunotherapy drugs fail to respond to them, Nikolo said.

    Unlocking the Puzzle The researchers may have discovered why the
    combination of chemotherapy and immunotherapy often fails. In their
    current study, the investigators found that chemotherapy induced a
    remarkable release of prostaglandin E2, a bioactive lipid associated with inflammation and cancer. Called an inhibitory damage- associated molecular pattern, or iDAMP, prostaglandin E2 blocks dendritic cells from maturing
    and fighting cancer, explained Kazukuni Hayashi, PhD, a study co- author.

    To counteract that effect, the researchers added to the chemoimmunotherapy
    the drug celecoxib. The anti-inflammatory medication targets the
    protein COX-2, which promotes the release of prostaglandin E2,Hayashi explained. This drug combination allows killer T cells to infiltrate
    the tumor core and kill the tumor cells.

    "The addition of the celecoxib not only worked well with chemotherapy,
    it also sensitized bladder tumors toward chemoimmunotherapy, providing
    a long-lasting response," Hayashi said.



    ========================================================================== Next, the researchers plan to test the efficacy of the new treatment in randomized, placebo-controlled human trials in collaboration with their
    Cedars- Sinai Cancer and Mount Sinai clinical colleagues, including
    those researching new treatments for colon and pancreatic cancer.

    "Harnessing the patients' immune system to attack tumor cells has become
    an important tool for physicians treating cancer," said Dan Theodorescu,
    MD, PhD, director of Cedars-Sinai Cancer and a study co-author. "With
    these findings, patients who don't respond to chemotherapy and
    immunotherapy have the potential for better outcomes in the future."
    Additional Cedars-Sinai Cancer co-authors include Xen Ping Hoi; Mark
    Alonzo; Armine Kasabyan; Hideki Furuya, PhD; Charles Rosser, MD; Dolores
    Di Vizio, MD, PhD; and Jlenia Guarnerio, PhD. Collaborators at Mt. Sinai,
    NCI, and Moffitt Cancer Center also contributed to the study.

    Research reported in this study was supported in part by theNational
    Cancer Institute under award numbers R01CA255609-01A1, F31CA247257, T32GM088129, and the U.S. Department of Defense, under award numbers
    CA181002, CA200750, and CA210889.


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


    ========================================================================== Journal Reference:
    1. Fotis Nikolos, Kazukuni Hayashi, Xen Ping Hoi, Mark Ellie Alonzo,
    Qianxing Mo, Armine Kasabyan, Hideki Furuya, Jane Trepel,
    Dolores Di Vizio, Jlenia Guarnerio, Dan Theodorescu, Charles
    Rosser, Andrea Apolo, Matthew Galsky, Keith Syson Chan. Cell
    death-induced immunogenicity enhances chemoimmunotherapeutic
    response by converting immune-excluded into T-cell inflamed
    bladder tumors. Nature Communications, 2022; 13 (1) DOI:
    10.1038/s41467-022-29026-9 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220328090017.htm

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