Today’s best treatment options for blood cancer kill tumor cells with high doses of radiation and chemotherapy. These treatments are a double-edged sword, as they also kill the patient’s bone marrow — a critical part of the body’s immune system. Bone marrow is particularly important to blood cancer patients after these treatments, as it is the body’s natural defense to any residual tumor cells that can cause relapse. For around 15,000 blood cancer patients each year worldwide, a bone marrow transplant (BMT) is the best option. However, BMT often comes with its own complications. Although donor and patient are matched based on certain cell surface markers called human leukocyte antigens (HLAs), perfect matching of donor and patient is not feasible in most cases, resulting in between 35 and 50 percent of BMT recipients experiencing graft-versus-host disease (GVHD), a potentially life-threatening complication that occurs when donor immune cells interpret the patient’s own body as foreign and attack it.
Catch-22 situation:
Current therapeutic approaches to mitigate GVHD use drugs called immunosuppressants to suppress the patient’s new immune system. This can be a fatal catch-22 for the patients who are relying on the transplanted immune system to fight infection and tumor relapse. Clinicians are left striving to find a balance between attenuating GVHD and maintaining immune function against residual malignancy or infection. Scientists at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, a world leader in cancer research and treatment, and City of Hope National Medical Center in California, the world’s largest and most successful bone marrow and blood stem cell transplant center, are independently developing methods to improve survivability and quality of life for blood cancer patients who receive bone marrow transplantation.
Immune-cell modulation approach:
The approach under development at MSKCC involves the use of a drug developed in house to selectively modulate the donor immune cells. PreScouter spoke to Dr. Salma Buddaseth from the Department of Molecular Pharmacology and Radiation Oncology at MSKCC, who is one of the lead researchers on a project focused on the development of the drug.
According to Dr. Buddaseth, “the key to our treatment is that the immune system fights tumor cells and infection with a different weapon than it uses to attack the patient’s own cells, as in the case of GVHD. Unlike the commonly used immunosuppressants, our drug only inhibits the weapon that attacks the patient, leaving the immune system capable of defending the patient against tumors and infection. So far, our findings show this drug will not only protect the patient from side effects of bone marrow transplantation but also prevent tumor relapse and infection.”
Prior to this project, Dr. Buddaseth has worked in the field of transplantation, where she studied HLA matching between donor and patients and authored a publication that identified a new HLA marker in patients. Additionally, she studied and published work on FTY-720, a drug that has been studied for use in reducing GVHD in patients.
This drug candidate is based on genetic models published by MSKCC in 2009. It is now in preclinical development and is currently licensed to a New York City–based biotech startup that has received seed funding for further development and commercialization of the drug candidate.
Immune cell depletion approach:
In April 2017, a team of researchers led by City of Hope’s Dr. Defu Zeng published work that demonstrated in preclinical studies that the selective depletion of a class of immune cells from the donor cells immediately after infusion into the recipient can prevent the deleterious effects of GVHD while maintaining the donor immune cells’ ability to fight tumors and infection. The researchers found that the depletion of one class of immune cell (CD4+) essentially caused another type of immune cell (CD8+) to become exhausted in their quest to destroy normal tissue, but strengthened in their fight against cancer. This approach makes use of selective immune cell depletion and the difference in outcome of immune cell interaction in diverse tissue environments.
Dr. Zeng hopes to translate this novel regimen into clinical application at City of Hope and is accordingly planning clinical trials to test the approach.
Outlook:
While neither approach has reached the clinical stage yet, they both provide the promise of improving survival outcome and quality of life after bone marrow transplants — a curative therapeutic option for blood cancer patients. If either or both approaches translate into clinical applications, they will promote increased use of BMT to treat blood cancer, thus offering patients a treatment without the specter of GVHD and ultimately a greatly improved quality of life.
