• New graft strategy may improve outcomes

    From ScienceDaily@1:317/3 to All on Mon Jan 10 21:30:38 2022
    New graft strategy may improve outcomes for blood stem cell recipients


    Date:
    January 10, 2022
    Source:
    University of Pittsburgh
    Summary:
    Removing one type of T cell from donor blood used for stem
    cell grafts could greatly reduce a serious complication called
    graft-versus-host disease in patients with leukemia, according to
    a new study.



    FULL STORY ========================================================================== Removing one type of T cell from donor blood used for stem cell grafts
    could greatly reduce a serious complication called graft-versus-host
    disease in patients with leukemia, according to a new study.


    ========================================================================== Published today in the Journal of Clinical Oncology, the study reports
    that only 7% of leukemia patients who received stem cell transplants
    depleted of nai"ve T cells developed chronic graft-versus-host disease,
    or GVHD, as compared to the 30% to 60% rate with standard of care
    treatment. About 70% of these patients developed the acute form of GVHD,
    but disease was typically mild and responsive to first-line corticosteroid agents.

    "It's quite remarkable that we were able to reduce chronic GVHD so
    dramatically with this graft engineering strategy," said senior author
    Warren Shlomchik, M.D., director of the Hematopoietic Stem Cell Transplant
    and Cell Therapy program at UPMC Hillman Cancer Center, and professor
    of medicine and immunology at the University of Pittsburgh School of
    Medicine. "It's also striking that we saw almost no steroid-refractory
    acute graft-versus-host disease in our patients." For patients with
    leukemia and other blood diseases, transplantation of hematopoietic
    stem cells -- progenitor cells that can turn into any type of blood
    cell -- from a healthy donor can rebuild the body's blood manufacturing
    system. But this life-saving treatment also comes with risks. Stem cell
    grafts, which are collected from either the bone marrow or circulating
    blood, contain T cells that can cause GVHD by attacking host tissues.

    Acute GVHD typically occurs within 100 days after transplantation and
    tends to affect the skin, liver and gastrointestinal tract. Most patients respond to corticosteroid drugs, but a substantial fraction require
    additional immunosuppression. Chronic GVHD usually develops later than
    the acute form and can affect many organs. This persistent version of
    the disease can be more difficult to treat, often requiring prolonged immunosuppression and reducing patient quality of life or causing death.

    Removing all T cells from a graft prior to transplantation can reduce
    GVHD, but this approach is a double-edged sword. Previous studies found
    that patients were at higher risk of leukemia relapse or death because T
    cells also are important for killing cancer cells and fighting infections.



    ========================================================================== Shlomchik and colleagues' new strategy reduces these negative side effects
    by depleting grafts of inexperienced, nai"ve T cells but retaining memory
    T cells, which protect against previously encountered pathogens.

    "We are trying to find the balance between leaving all T cells in and
    risking GVHD and removing all T cells and making patients vulnerable to infections and cancer relapse," said first author Marie Bleakley, M.D.,
    Ph.D., associate professor of pediatrics at University of Washington
    School of Medicine and Fred Hutchinson Cancer Research Center. "This
    technique of reducing nai"ve T cells works better than most competing approaches." Led by Bleakley, who holds the Gerdin Family Endowed Chair
    of Leukemia Research at Fred Hutch, the team recruited 138 leukemia
    patients, including both adults and children, across three phase II
    clinical trials. They collected circulating blood from healthy donors
    who were immunologically matched to each patient and used a reagent to
    remove nai"ve T cells. After chemotherapy and irradiation to kill cancer
    cells and make space for the transplant, patients received the nai"ve
    T cell-depleted graft.

    According to Shlomchik, the most striking finding was that just 7% of
    patients developed chronic GVHD compared with previously reported rates
    of 30% to 60%.

    "Bench-to-bedside is almost a cliche', but we've taken this work from
    mouse studies in the lab all the way to patients in the clinic,"
    said Shlomchik, who also holds the Pittsburgh Foundation chair in
    cancer immunology. "Our patients are doing exceedingly well compared
    to those who received different treatment approaches reported in other
    studies, suggesting that nai"ve T cell depletion could be a broadly
    applicable strategy to reduce GVHD and improve outcomes." "However,
    randomized trials comparing our approach to standard approaches are
    needed to definitively determine which are best," he continued. "But
    even without randomized trials, we are confident that nai"ve T cell
    depletion reduces chronic GVHD." Importantly, nai"ve T cell depletion
    did not appear to increase rates of leukemia relapse or fatal infections, although randomized control trials that compare different strategies are
    also needed to confirm these findings. The researchers have launched
    two such randomized phase II clinical trials for adult and pediatric
    leukemia patients.

    This research was supported by the National Institutes of Health (NIH;
    CA18029, CA15704, HL121568-01A1, CA 136551), the NIH Rapid Access to Intervention Development (project 298), the Damon Runyon Cancer Research Foundation, the Richard Lumsden Foundation (CI-57-11), the National
    Cancer Institute (K23CA154532), the Leukemia & Lymphoma Society and the Burroughs Wellcome Fund.

    Other authors on the study were Alison Sehgal, M.D., of Pitt and UPMC;
    Stuart Seropian, M.D., of Yale School of Medicine and Yale Cancer Center; Melinda A.

    Biernacki, M.D., Elizabeth F. Krakow, M.D., Ann Dahlberg, M.D., Paul
    J. Martin, M.D., Paul A. Carpenter, M.B.B.S., Mary E. Flowers, M.D.,
    Theodore A. Gooley, Ph.D., Keith Loeb, M.D., Ph.D., Stanley R. Riddell,
    M.D., and Brent L. Wood, M.D., Ph.D., of Fred Hutch and University of Washington; Heather Persinger, M.A., Barbara Hilzinger, B.Sc., Jenna
    Voutsinas, M.P.H., and Shelly Heimfeld, Ph.D., of Fred Hutch.

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


    ========================================================================== Journal Reference:
    1. Marie Bleakley, Alison Sehgal, Stuart Seropian, Melinda
    A. Biernacki,
    Elizabeth F. Krakow, Ann Dahlberg, Heather Persinger, Barbara
    Hilzinger, Paul J. Martin, Paul A. Carpenter, Mary E. Flowers, Jenna
    Voutsinas, Theodore A. Gooley, Keith Loeb, Brent L. Wood, Shelly
    Heimfeld, Stanley R. Riddell, Warren D. Shlomchik. Naive T-Cell
    Depletion to Prevent Chronic Graft-Versus-Host Disease. Journal
    of Clinical Oncology, 2022; DOI: 10.1200/JCO.21.01755 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/01/220110184837.htm
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