Laboratory research is critical for developing new blood cancer treatments.
The blood cancers acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are extremely challenging to treat. While advances in immunotherapy have cured many patients with other blood cancers, they haven’t been successful for AML and MDS. Together, these diseases kill thousands of people in the United States every year.
Now laboratory research, published online April 23 in Cell, shows it may be possible to develop an immunotherapy-based approach for treating aggressive forms of AML and MDS. The study was a collaboration among two labs from Memorial Sloan Kettering Cancer Center (MSK) and scientists from Fred Hutch Cancer Center in Seattle.
“The five-year survival rate for the high-risk forms of these cancers is still less than 25%,” says the paper’s co-senior author, physician-scientist Omar Abdel-Wahab, MD, Chair of the Molecular Pharmacology Program in the Sloan Kettering Institute. “We are really motivated to find more effective treatments.”
Dr. Abdel-Wahab joined forces with MSK cellular therapist and early drug development specialist Christopher Klebanoff, MD, an expert in developing new cancer therapies that harness the power of the immune system. Dr. Klebanoff was another co-senior author of the paper, along with Robert Bradley, PhD, a computational biologist at Fred Hutch. Their work was conducted using human cells and mouse models.
How Do Splicing Errors Cause Blood Cancers?
RNA splicing is a key function in the manufacture of proteins inside cells. Dr. Abdel-Wahab’s lab has discovered that certain mutations found in nearly 70% of patients with MDS and nearly one-third of patients with AML cause splicing to go wrong. This in turn leads to the production of defective proteins that drive the formation and growth of cancer.
Dr. Klebanoff’s lab focuses on teaching immune cells called T cells to better recognize these kinds of defective proteins, which are also known as neoantigens. He is looking at ways to train a patient’s own T cells to seek out and destroy cancer cells that contain neoantigens, while sparing healthy cells.
“The mutations that cause splicing errors have been extremely difficult to drug with targeted therapies,” Dr. Klebanoff says. “We think targeting neoantigens that directly result from abnormal splicing with immunotherapy will be a more effective path forward.”
Finding the Best Targets for AML and MDS Immunotherapy
Using samples from MSK patients treated for AML and MDS, the scientists performed analysis to find neoantigens present across most patients’ cancer cells. Those defective proteins would be good targets for immunotherapy.
Dr. Omar Abdel-Wahab studies the role of RNA splicing errors in blood cancers.
The researchers narrowed in on proteins that are found only in cancer cells — not in normal cells. Seeking out only these neoantigens is important to make sure the immunotherapy spares healthy blood cells and reduces treatment side effects for patients.
In addition, the team focused on neoantigens that are fundamental to the cancer’s development, rather than those that arise later as the cancer continues to mutate. The reason: Targeting the neoantigens present from the cancer’s beginning would ensure that the immunotherapy would destroy all the cancer cells, not just a subset of cells. Wiping out all the cells decreases the likelihood that the cancer will come back.
TCR Therapy Shows Promise in Mouse Models of AML
Once the scientists identified the best targets, they looked at how they might be able to engineer a patient’s T cells to more effectively recognize the neoantigens. To do this, they used a technique called T cell receptor (TCR) gene therapy.
Dr. Christopher Klebanoff is developing new immunotherapy treatments for cancer.
In some ways, TCR is similar to chimeric antigen receptor (CAR) T therapy, which has proven successful in treating some types of leukemia, lymphoma, and multiple myeloma. With CAR T therapy, a patient’s T cells are engineered to recognize proteins displayed on the surface of cancer cells. The T cells then destroy the cancer.
But the neoantigens that result from the splicing errors pose a challenge: They are located inside cancer cells, rather than on the surface. This required a TCR approach, a technique that empowers T cells to peer inside other cells and identify if there are abnormal proteins. “It’s akin to giving T cells X-ray vision,” Dr. Klebanoff says.
In the lab, Dr. Abdel-Wahab and Dr. Klebanoff showed that when mice with AML were treated with the TCR therapy, they had a significant reduction in their tumors. The mice also lived much longer than those that did not get the treatment, and studies suggested their healthy cells were spared the effects of the treatment.
“More work is needed before our team can begin to study this treatment in patients, but this research represents an important first step toward that goal,” Dr. Klebanoff adds.
How Basic Research Drives Discoveries That Help Patients
Both Dr. Abdel-Wahab and Dr. Klebanoff have received federal funding. This includes support from the National Cancer Institute, part of the National Institutes of Health (NIH), which allowed them to make many of the discoveries key to this work.
“RNA splicing has been studied as an essential process in molecular biology for decades,” Dr. Abdel-Wahab says. “We’ve been able to take this fundamental work and harness it for something that is directly related to human disease.”
“NIH-sponsored research has enabled us to build the infrastructure in our lab and develop the robust tools that are so essential to our work,” Dr. Klebanoff adds. “We can then pair that foundational knowledge with support from philanthropy, which allows us to take on more ambitious projects and make even greater leaps in our discoveries.”