Re-energizing a patient’s immune cells

Versiti Blood Research Institute Senior Investigator Subramaniam Malarkannan, PhD, studies NK cells with a goal of understanding their particular functions in different contexts. “We want to know this for multiple reasons. Inflammation is really important—it’s critical to mounting a useful immune response,” he said. He added that inflammation is perfectly normal within a certain range; however, beyond that range, it can become detrimental to a patient’s health.

One option for treating patients with tumors is to use chimeric antigen receptor T-cell (CAR-T) therapy to genetically modify a patient’s cells and increase their tumor-fighting function. However, an unfortunate side effect of CAR-T therapy is that it increases inflammation, which can cause more harm than good. But Dr. Malarkannan believes that it may be possible to control these cells to fight tumors but minimize their more detrimental side effects. “We can make the cell kill and also reduce inflammation,” he said.

If successful, this therapy could be used to treat patients with cancer and autoimmune diseases, as the inflammation that autoimmune patients experience is caused by the same cells that cause inflammation in cancer patients.

The role of genetics in disease progression

In addition to his work with NK cells, Dr. Malarkannan studies the genetics behind diseases. He recalled that, 18 months ago, a 4-month-old baby came to the hospital with infections throughout her body. Doctors found that, due to a genetic condition, the baby was lymphopenic, meaning she did not have an adequate number of white blood cells to ward off infection. This genetic mutation, which is known to researchers, occurs in 1 in 10,000 babies; symptoms can range in severity, but little is known why some patients experience mild vs. severe effects.

Thankfully, the baby received a lifesaving bone marrow transplant and is healthy today. But researchers wanted to take a closer look at this phenomenon. Dr. Malarkannan discovered that the baby received the genetic mutation from her mother, who also carried the mutation but did not show any symptoms of lymphopenia. “We were able to take blood samples from the mother, baby and the father and compare all three using advanced technologies,” Dr. Malarkannan said, including genome sequencing, RNA sequencing and single-cell RNA sequencing. “This explained at a genetic level why these two patients with the same mutation had such a difference in severity.” Through this analysis, Dr. Malarkannan and his colleagues also determined that the baby’s mother may be developing the same disease.

DNA and its role in human health

Dr. Malarkannan is also involved in an ongoing study that follows a patient with Fanconi anemia, a rare genetic disease that affects the bone marrow. He says that inside each cell is something called the DNA repair complex. When cells divide, their DNA is copied and during that process, mistakes can happen. The DNA repair complex acts as a sort of proofreader, identifying and fixing errant mutations. But if the DNA repair complex doesn’t catch everything, patients can continue to develop harmful mutations that can cause cancer and other diseases. Currently, a bone marrow transplant is the best treatment option for these patients.

In the case of the patient with Fanconi anemia, a bone marrow transplant was recommended; however, the patient refused it. “On one hand, that’s not very good as far as treatments go. But on the other, we don’t know of any other patients like this that we can continue to monitor over a number of years,” Dr. Malarkannan said. By taking regular blood samples from this patient, researchers may be able to identify secondary genetic mutations that may predict future health issues.

The value of Versiti

According to Dr. Malarkannan, Versiti Blood Research Institute is the perfect place to conduct this groundbreaking research. “The BRI is a unique place because of its culture,” he said. “We are a small, tight-knit group that works closely together.”

He goes on to credit the Versiti Blood Research Institute Foundation for the ability to expand his research and follow it down other avenues or unexpected tracks—something that isn’t always possible within the bounds of grants from external sources. “We wouldn’t be able to do it without the Foundation,” he said. “Philanthropic gifts make it possible to accelerate our research and save lives at a faster pace.”

About the expert: Subramaniam Malarkannan, PhD, is a senior investigator and Gardetto Chair for Molecular Immunology and Immunotherapy at Versiti Blood Research Institute. He also serves as a professor in the Departments of Medicine – Hematology and Oncology, Microbiology and Immunology, Pediatrics, and Clinical and Translational Science Institute at the Medical College of Wisconsin.