Under the Microscope: Healing cancer while avoiding harm

Although immunotherapy has saved many lives, it can also come with serious side effects.

“As a clinician, the worst-case scenario is when I have a patient who not only doesn’t respond to a treatment but who also experiences severe toxicity because of it,” said V Scholar Aadel Chaudhuri, MD, Ph.D., from Washington University School of Medicine in St Louis. “Unfortunately, this can happen with immunotherapy because it can inadvertently cause the immune system to attack healthy tissues. Predicting who will experience this type of severe toxicity is very challenging.”

With funding from the V foundation and other sources, Chaudhuri has made significant progress toward generating a way to identify patients with the highest risk for severe toxicity from immunotherapy. He is also working to find ways to predict treatment response so that one day a simple blood test might provide clinicians the information necessary to select a treatment that will not only get rid of the cancer but also be the least harmful for a specific patient.

Predicting toxicity

To figure out who is most likely to experience toxicity from immunotherapies, Chaudhuri and his colleagues at Washington University, Yale University and Stanford University, used RNA sequencing and mass cytometry to analyze immune cells in blood samples from patients with melanoma. The samples were taken from blood circulating throughout the body during routine laboratory blood draws taken before patients started an immunotherapy known as immune checkpoint blockade.

As described in a recently published Nature Medicinepaper, the researchers found that patients who experienced severe toxicity had a higher abundance of certain immune cells – activated CD4 memory T cells – and also a greater diversity of receptors on the T-cells in their blood. Based on these characteristics, the researchers created a composite model for predicting who will develop severe or life-threatening toxicity.

“Although research has shown that patients who experience toxicity also have higher rates of response to immunotherapy, our research suggests that response and toxicity can be immunologically decoupled,” said Chaudhuri. “We think we’ve identified immune underpinnings that are specific to severe toxicity and aren’t significantly associated with treatment response.”

Going in a new direction

Chaudhuri points out that when he started studying immunogenomics and toxicity, he didn’t have a track record in this area. “This would have made it difficult to get NIH funding for this project,” he said. “The V Foundation took a leap of faith that allowed me to pivot my research to an important and interesting area that has enormous potential to improve cancer treatment.”

Chaudhuri and his collaborators are now working with the Melanoma Research Alliance to design a prospective study that will, if successful, translate their published research findings into a precision diagnostic blood test for predicting toxicity before treatment begins.

“We started this line of research with metastatic melanoma because immune checkpoint blockade is a front-line therapy in this disease,” said Chaudhuri. “However, we aim to translate our findings to predict immunotherapy toxicity in other cancer types too.”

Farther down the road, these new insights into the mechanisms responsible for immunotherapy toxicity could help inform the development of drugs that selectively block toxicities from these otherwise highly effective medicines.