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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