March 11, 2020
Acute myeloid leukemia’s minimal residual disease targeted by Moon Shot
BY Clayton Boldt, Ph.D.
In patients with leukemia, complete remission after treatment is currently defined by the absence of cancer cells in a bone marrow biopsy viewed under the microscope. However, it’s well-established that if no further treatment is given, some patients will relapse due to undetectable cancer cells remaining in the body. This small number of remaining cells is known as minimal residual disease (MRD).
Ghayas Issa, M.D., assistant professor of Leukemia, co-leads a flagship project of the Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) Moon Shot®. Their team focuses on finding new targets to more effectively treat minimal residual disease in patients with acute myeloid leukemia. He spoke with Cancer Frontline about their work.
How does having minimal residual disease impact treatment options for patients?
It has significant implications for how we treat patients after standard therapy. We now have better assays to detect these cells, including next generation sequencing and flow cytometry, and we try to determine for each patient if they have minimal residual disease. Those that don’t tend to have better outcomes, while those that are MRD-positive have increased risk of relapse.
Leukemia is quite a heterogeneous disease, so MRD status may mean different things in different patients. However, we can use this information to determine the best next course of therapy, based on when the minimal residual disease was discovered.
If a patient is identified as MRD-positive early in the course of treatment, we may give more treatment – either increasing doses or additional medications. If a patient is MRD-positive after all chemotherapy has been completed, this may be an indication that we should consider a stem cell transplant for a patient who might not otherwise have been a candidate.
Overall, MRD status tells us that we need to act before the leukemia progresses.
What are the goals of your minimal residual disease flagship project?
The overall goal of our flagship effort is to try to find targets that are specific to MRD, so that we can develop therapeutic approaches to prevent disease relapse. So instead of waiting for patients to relapse, what if we can find things that we can add to treatment that eliminate minimal residual disease in our patients, which is associated with cure?
In simple terms: can we take care of all leukemia cells, including the ones that are sensitive to initial treatment and those that are resistant? Is there anything specific about them for which we can develop targeted therapies?
What are some of the projects working toward that goal?
We’re doing multiple types of investigations to understand what makes those cells resistant or what allows them to evade our current treatments. We rely heavily on single-cell sequencing technology to analyze gene expression and gene mutations in the residual leukemia cells. Are expression patterns or mutations present in all cells, or only some of the cells? How do these factors cooperate to cause MRD?
Ultimately, we’re trying to use the abnormally expressed or mutant gene products as targets for new therapies. We’re looking for those found on the surface of leukemia cells so that we could target them with antibodies or immunotherapy to kill residual cells.
We also have patient-derived xenograft (PDX) models of minimal residual disease where we can potentially test promising new therapies in the future to see if they are effective.
We’re currently in the discovery phase of these efforts, but we have learned that these residual leukemia cells seem to be down-regulating genes that are important for the immune system. These cells probably escape the control of chemotherapy and our immune system because they have found a way to make themselves invisible to the immune system. This could be important in the future, because it could be used as a signature to predict response or may provide some candidates for us to target.
As we identify worthwhile therapeutic candidates, we will work closely with the ORBIT platform to develop antibody-based therapies that we hope will be effective in treating MRD and advance them to clinical trials.
How has the Moon Shots Program enabled this work in a way that might not have been possible before?
This is a high-risk project that would otherwise be difficult to get funded. The Moon Shots Program® has invested in bold ideas, like this, that could have a high return for all leukemia patients – especially those with high-risk disease. So, this is important funding to help lead us toward big discoveries that could launch other projects and eventually lead to new treatments.
The program also has established a valuable structure for this work. I’m one member on a team that involves multiple departments, labs and platforms. Through the Moon Shots Program, we’re able to collaborate with so many across the institution and utilize the platforms that aren’t available anywhere else. We’re encouraged to leverage these opportunities, and we certainly are.
Refer a patient to MD Anderson online or by calling 1-877-632-6789.
TopicsAcute Myeloid Leukemia Stem Cell Transplantation Cellular Therapy Moon Shots Program Myelodysplastic Syndrome
Those that are MRD-positive have increased risk of relapse.
Ghayas Issa, M.D.
Physician & Researcher