New technique may lead to safer stem cell transplants
Method, in mice, can eliminate need for chemotherapy, radiation, in
treating blood cancers, other diseases

Date:
November 11, 2021
Source:
Washington University School of Medicine
Summary:
Studying mice, researchers have developed a method of stem
cell transplantation that does not require radiation or
chemotherapy. Instead, the strategy takes an immunotherapeutic
approach, combining the targeted elimination of blood-forming stem
cells in the bone marrow with immune- modulating drugs to prevent
the immune system from rejecting the new donor stem cells.



FULL STORY ==========================================================================
For hard-to-treat leukemias, lymphomas and other blood cancers, stem cell transplantation is the gold standard of care. The procedure involves
replacing a patient's own blood-forming stem cells with a donor's stem
cells and, in the process, eradicating cancer cells in the blood, lymph
nodes and bone marrow.


==========================================================================
But many patients with such deadly blood cancers are too fragile to
undergo stem cell transplants. That's because a patient's stem cells
first must be destroyed by intensive chemotherapy and sometimes total
body radiation before a donor's stem cells are infused. This so-called conditioning regimen makes space for incoming donor stem cells, helps to
remove cancer cells remaining in the body, and depletes the patient's
immune system so it can't attack the donor's stem cells. However,
toxicities and suppression of the immune system caused by conditioning
regimens puts patients at high risk of infections, organ damage and
other life-threatening side effects.

Now, studying mice, researchers at Washington University School of
Medicine in St. Louis have developed a method of stem cell transplantation
that does not require radiation or chemotherapy. Instead, the strategy
takes an immunotherapeutic approach, combining the targeted elimination of blood-forming stem cells in the bone marrow with immune-modulating drugs
to prevent the immune system from rejecting the new donor stem cells. With
the new technique, mice underwent successful stem cell transplants from unrelated mice without evidence of dangerously low blood cell counts
that are a hallmark of the traditional procedure. The data also suggested
that such stem cell transplants can be effective against leukemia.

The study, available online in the Journal of Clinical Investigation,
opens the door to safer stem cell transplantation, meaning more patients
with various types of blood cancers could receive this potentially
curative therapy, and it could be considered as a treatment for other
diseases, such as sickle cell anemia or other genetic disorders, that
are less life-threatening.

"To be able to do a stem cell transplant without having to give
radiation or chemotherapy would be transformative," said senior author
and medical oncologist John F. DiPersio, MD, PhD, the Virginia E. & Sam
J. Golman Professor of Medicine and chief of the Division of Oncology
at Washington University School of Medicine. "It could eliminate the dangerously low blood cell counts, bleeding complications, organ damage,
and infections. It has particular implications for conducting bone marrow transplantation or gene therapy for patients with noncancerous diseases
such as sickle cell anemia, where the toxicities of chemotherapy- or radiation-associated conditioning are important to avoid. We have more
work to do before we're ready to translate these findings to people,
but we're encouraged by the results of this study." As an alternative
to high-dose chemotherapy and whole-body radiation, DiPersio, who also
directs the Center for Gene & Cellular Immunotherapy, and his colleagues harnessed drugs that are toxic to cells, and attached these drugs to
antibodies that target specific surface proteins that are expressed
primarily on bone marrow stem cells. Only when these antibody-drug
conjugates (ADCs) bind to those specific proteins are they then
internalized by the stem cells, which leads to release of the drug
payload inside the cell and, ultimately, cell death. Using the ricin
derivative saporin as the drug payload, the researchers generated two
different ADCs to target two specific proteins found on the surface of
blood stem cells, which minimizes the potential for them to cause damage
to other cell types.



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To prevent the recipient's immune system from then rejecting the donor
cells, the researchers treated the mice with immunosuppressive compounds
called Janus kinase (JAK) inhibitors. In this study, the investigators primarily used baricitinib, which is approved by the Food and Drug Administration to treat rheumatoid arthritis. They found that baricitinib prevented the recipient's immune cells, including T cells and natural
killer cells, from attacking the donor stem cells.

"By combining the antibody-drug conjugates with JAK inhibitors, we were
able to achieve a successful transplant between two completely unrelated strains of mice," said first author Stephen P. Persaud, MD, PhD, an
instructor in pathology & immunology. "A successful transplant across
such a stringent immunological barrier is promising for eventually
being able to harness this technique for patients with leukemia."
The researchers also found that the new technique struck a balance
between the donor immune cells attacking leukemia cells -- called the graft-versus-leukemia effect -- in a common mouse model of leukemia and
not attacking the recipient's healthy tissues, a dangerous condition
called graft-versus-host disease. The mice in this study did not develop graft-versus-host disease because the immune suppressing drugs prevented
it, another unique and significant advantage of this approach, according
to the researchers.

"When you give JAK inhibitors from the beginning, there is evidence
that they prevent graft-versus-host disease from developing later,"
said DiPersio, who serves as deputy director of Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. "In addition, unlike a regular transplant using radiation and chemotherapy
as transplant conditioning, none of the mice developed any reduction in
their blood counts, which is the major life-threatening complication of traditional stem cell transplants.

Chemotherapy and radiation destroy all the old cells at once. With the
new strategy, the old cells were slowly replaced by donor cells, and so
we never saw any drop in the blood cell counts in these mice. The blood
cell counts looked normal the whole way, and in the end, we could see
that all the blood cells originated from the new donor cells." After a
period of time, the researchers found that they could gradually reduce
the JAK inhibitors and, once the donor stem cells totally replaced the
original cells, stop the immune suppression altogether.

"We've shown that we can use this relatively simple regimen that is
minimally toxic to transplant donor stem cells across immunologic
barriers in mice," Persaud said. "We need more research to see if the
same strategy will be applicable to humans. We are working to optimize
the technique in mice, and then we will likely test it in other animal
models of leukemia before we would begin planning a clinical trial
to investigate the strategy in patients." Working with Washington
University's Office of Technology Management, DiPersio and Persaud
have filed a patent application for the combination of antibody- drug conjugates with JAK inhibitors for transplant conditioning.

========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Julia
Evangelou Strait. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Stephen P. Persaud, Julie K. Ritchey, Sena Kim, Sora Lim, Peter G.

Ruminski, Matthew L. Cooper, Michael P. Rettig, Jaebok Choi, John F.

DiPersio. Antibody-drug conjugates plus Janus kinase inhibitors
enable MHC-mismatched allogeneic hematopoietic stem cell
transplantation.

Journal of Clinical Investigation, 2021; DOI: 10.1172/JCI145501 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211111154254.htm

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