For leukemias, lymphomas and other difficult-to-treat blood cancers, stem cell transplantation is the gold standard of care. The procedure involves replacing a patient’s own hematopoietic stem cells with a donor’s stem cells and in doing so, 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. This is because a patient’s stem cells must first be destroyed by intensive chemotherapy and sometimes full body irradiation before a donor’s stem cells are infused. This so-called conditioning regimen makes room for incoming donor stem cells, helps eliminate remaining cancer cells in the body, and depletes the patient’s immune system so that it cannot attack the donor stem cells. However, the toxicities and suppression of the immune system caused by conditioning regimens put patients at high risk for infections, organ damage and other potentially fatal side effects.
Now, studying mice, researchers at the 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 hematopoietic stem cells in the bone marrow with immunomodulatory drugs to prevent the immune system from rejecting new donor stem cells. With the new technique, mice have successfully undergone transplants of unrelated mouse stem cells without evidence of dangerously low blood cell counts characteristic of the traditional procedure. Data also suggests that such stem cell transplants may be effective against leukemia.
The study, available online in the Journal of Clinical Investigation, opens the door to a safer stem cell transplant, meaning more patients with various types of blood cancers could receive this potentially curative therapy, and it could be considered a treatment for other diseases, such as sickle cell anemia or other genetic disorders, which are less life threatening.
“Being able to do a stem cell transplant without having to administer radiation or chemotherapy would be a transformation,” said senior author and medical oncologist John F. DiPersio, MD, PhD, Virginia E. & Sam J. Golman and head of the oncology division of the Washington University School of Medicine. “This could eliminate dangerously low blood cell counts, bleeding complications, organ damage and infections. This has particular implications for performing bone marrow transplant or gene therapy for patients with disease. non-cancerous such as sickle cell anemia, where toxicities from chemotherapy- or It is important to avoid the conditioning associated with radiation. We still have some work to do before we are ready to translate these findings to people, but we are encouraged by the results of this study. “
As an alternative to high-dose chemotherapy and whole-body radiation therapy, DiPersio, who also heads the Center for Gene & Cellular Immunotherapy, and his colleagues have exploited drugs that are toxic to cells and paired these drugs with antibodies targeting specific surface proteins that are expressed primarily on stem cells in the bone marrow. It is only when these antibody-drug conjugates (ADCs) bind to these specific proteins that they are then internalized by the stem cells, resulting in the release of the payload of the drug inside the cell and , ultimately, cell death. Using ricin-derived saporin as the drug’s payload, the researchers generated two different ADCs to target two specific proteins found on the surface of blood stem cells, minimizing the risk of them damaging other types of cells. .
To prevent the recipient’s immune system from then rejecting the donor cells, the researchers treated the mice with immunosuppressive compounds called Janus kinase inhibitors (JAKs). In this study, the researchers mainly 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’s stem cells.
“By combining the antibody-drug conjugates with JAK inhibitors, we have successfully transplanted between two completely independent mouse strains,” said lead author Stephen P. Persaud, MD, PhD, instructor in pathology and immunology. “A successful transplant across such a strict immunological barrier holds promise for potentially exploiting this technique for patients with leukemia.”
The researchers also found that the new technique balanced the donor’s 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 tissue, a dangerous condition called graft versus host disease. The mice in this study did not develop graft-versus-host disease because immunosuppressive drugs prevented it, another unique and significant benefit of this approach, according to the researchers.
“When you give JAK inhibitors early on, they are shown to prevent graft versus host disease from developing later,” said DiPersio, who is deputy director of the Siteman Cancer Center at Barnes-Jewish. Hospital and Washington University School of Medicine. . “Additionally, unlike a regular transplant using radiation therapy and chemotherapy as transplant conditioning, none of the mice developed a reduction in their blood count, which is the main life-threatening complication of traditional stem cell transplants. Chemotherapy and radiation therapy destroy all the old cells. With the new strategy, the old cells were slowly replaced by donor cells, so we never saw a drop in the number of blood cells in these mice. could see that all the blood cells were from the new donor cells. “
After a while, the researchers found that they could gradually reduce the JAK inhibitors and, once the donor stem cells completely replaced the original cells, completely stop the immune suppression.
“We have shown that we can use this relatively simple regimen which is low in toxicity to transplant donor stem cells across immunological barriers into mice,” said Persaud. “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 probably test it in other animal models of leukemia before we start planning a clinical trial. to investigate the strategy in patients.
In collaboration with the Office of Technology Management at the University of Washington, DiPersio and Persaud filed a patent application for the combination of antibody-drug conjugates with JAK inhibitors for conditioning transplants.