Improving Leukemia Treatment for the Aging

New Pathways to Hope Unlocked by the Synergy of Interleukin-37 and CAR T-cell Therapy

Fighting fire: Reducing inflammation in aging leukemia patients

Curtis Henry, PhD

Curtis Henry, PhD

Merging his immunology background with his studies on blood cancers, Curtis Henry, PhD, associate professor in pediatrics, is finding ways to improve the effectiveness of leukemia treatments amongst aging populations. This work is being performed in collaboration with Sunil S. Raikar, MD, assistant professor in the pediatrics institute, and Sarwish Rafiq, PhD, assistant professor in hematology, whose groups have expertise in the design of immunotherapy treatments for adult and pediatric patients with blood cancers.

Enhancing CAR T-cell therapy with Interleukin-37

Sarwish Rafiq, PhD

Sarwish Rafiq, PhD

What Henry and his lab have discovered is that combining interleukin-37 (IL-37) with CAR T-cell therapy reduces inflammation and significantly improves the therapeutic efficacy of aged CAR T-cells. IL-37 is an anti-inflammatory cytokine that is produced to reduce chronic inflammation, which can be pathological if left unresolved. Unfortunately, IL-37 production in humans declines with age.

“What we essentially determined is that chronic inflammation, which manifests with aging and other cancer associated co-morbidities, promotes leukemia development,” noted Henry. “We feel like our invention could help improve CAR T-cell treatment when T-cells are engineered to produce IL-37 which will mitigate the immunosuppressive effects of chronic inflammation in the TME.”

Understanding leukemia

Sunil Raikar, MD

Sunil Raikar, MD

Leukemia is a cancer of the blood cells. It is essentially the uncontrollable growth of immature blood cells. The cancer is driven by the acquisition of oncogenic mutations and changes in the tissue composition, which results in the proliferation of immature blood cells, which are unable to fulfill their roles as functional immune cells.

“Having leukemia reduces a person’s ability to fight infections and reduces the ability of blood to clot, which can lead to serve blood loss or strokes,” said Henry.

Addressing the aging comorbidity of leukemia

A common treatment for leukemia is chemotherapy, which is used to get the leukemia into remission. If a patient does not respond to initial chemotherapy or other standards-of-care treatments, they may receive chimeric antigen receptor (CAR) T-cell treatment. This treatment involves isolating a patient's white blood cells, and engineering T-cells to express receptors specific for antigens expressed on cancer cells. However, due to aging-associated compromised immunity and chronic inflammation, evidence is emerging that CAR T-cell therapy may be less effective, and potentially more toxic, in aged patients.

“As soon as an individual is over the age of 65, the likelihood that a person develops any form of cancer increases substantially,” noted Henry.

“A lot of these blood cancers, and most cancers in general, are aging-associated cancers. What happens with age in a person's body is that a lot of things change. Some things we can physically see, like graying hair and the onset of wrinkles, are tell-tale signs that a person is aging. However, we also physiologically age and one of the major systems that gets hit with a sledgehammer is your immune system. My team and colleagues have been trying to identify aging-associated factors that lead to immunological decline and target these factors or turn back the hands of time to restore youthful immunity to older individuals.”

Patient in Chemo Treatment

Patient in Treatment

Inflammaging is an aging-associated manifestation which combines the words “inflammation” and “aging.” Henry and his lab hypothesized that if you could reduce inflammaging, it would decrease the probability of developing blood cancers by increasing the quality of normal blood cells as we age.

“In several published studies, we were able to show that if you reintroduce IL-37 in the equation to aged populations, you are able to make more functional immature and more blood cells,” said Henry. “So, you can imagine a scenario where you're trying to put out a fire that increases with age, with the fire being chronic inflammation. In our hands the anti-inflammatory properties of IL-37 operates like water, enabling our team to reduce the intensity of that fire (chronic inflammation) which burns more intensely with age.”

Raj Guddneppanavar, Assistant Director, Licensing at Emory OTT, praised Henry’s findings: “It is very encouraging to see Dr. Henry’s work with aging populations. With so many comorbidities associated with aging, this work is very important for patients with declined immunity.”

The next steps

In the future, Henry hopes that this research will be applied clinically in settings of deregulated inflammation such as those associated with aging, obesity, or other pathologies associated with chronic inflammation. The goal with IL-37 treatment strategies will be to reduce excessive inflammation to a normal range mimicking those typically found in young, healthy individuals. If this goal can be achieved in patients with chronic inflammation, Henry and his team predict that the efficacy and safety of various therapies, especially immune-based, will improve. Given that immune-altering co-morbidities typically present at higher rates in underserved communities (e.g., obesity), work generated from these studies could be particularly important in promoting health equity for all patients.

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