Leonard Calabrese, DO, on Advances in Immunology

At the 2019 IAS Meeting, Leonard Calabrese, DO, highlighted recent studies that depicted the recent advances in immunology and inflammatory medicine, as well as the importance of understanding cellular and molecular mechanisms of inflammatory disease and upcoming novel therapeutics.

Calabrese, who is a professor of medicine at Cleveland Clinic, first discussed advances in cardiovascular (CV) risk reduction. He highlighted the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) clinical trial, a large international multicenter trial that compared the interleukin-1 (IL-1) canakinumab to placebo for the prevention of adverse cardiac events.

“The hypothesis of the trial was that IL-1 is a driver of inflammation and if inflammation can be neutralized, then coronary artery disease can be reduced,” Calabrese said during his presentation. “The conclusion [of the study] was that interfering with the inflammatory pathway via IL-1 inhibition could reduce CV mortality.”

However, Calabrese acknowledged challenges within the study.

“The problem with the study was your taking people with no immune-mediated disease and putting them all on biologics,”, he said, which led to adverse events and infections. Still, the outcomes of the CANTOS trial led to greater discussion of finding other anti-inflammatories that would be easier and safer in reducing inflammation to reduce CV mortality.

Calabrese also highlighted findings from the Cardiovascular Inflammation Reduction Trail (CIRT), a randomized clinical trial that investigated whether low-dose methotrexate can reduce heart attacks, strokes, or mortality among individuals with type 2 diabetes or metabolic syndrome who had a previous heart attack or multiple coronary blockages.

Methotrexate is known to have a protective effect against CV risk among patients with rheumatoid arthritis (RA), Calabrese said. However, in the CIRT study, low dose methotrexate did not have a protective effect against cardiovascular events and did not reduce C-Reactive Protein (CRP) levels.

“This was a profound disappointment,” Calabrese said.

Aging, sarcoidosis >>

Another topic Calabrese discussed included the ongoing development of anti-aging therapeutics.

“Aging at the biologic level is really mediated, we believe, by dysfunction of discrete pathways within the umbrella of cell biology,” Calabrese said. “Certain pathways create the aging effect and certain pathways don’t.”

One of the critical pathways in aging is the mechanistic target of rapamycin (mTOR). According to Calabrese, the switch in mTOR Complex 1 (mTORC1) and mTOR Complex 2 pathways have been of great interest in aging biology for many years.

“As it turns out, if you can inhibit mTOR in the appropriate way, you see longevity, and this has been carried out in [various] murine experiments,” he said.

Most recently, a study by Mannick et al evaluated whether 6-week low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates among 264 elderly individuals. Overall, the findings showed that selective mTORC1 inhibition may improve immune function and reduce infection incidence among the elderly, with mild adverse events and possible persistent effects, according to Calabrese’s presentation.

Calabrese also discussed new research in changes in the microbiome. Recent studies have suggested the womb is not sterile, the vasculature is not sterile, many nosocomial infections actually originate in our gut microbiome, and giving probiotics after antimicrobials may cause delayed return of diversified microbiome.

The implications of microbiome in cancer immunotherapy is another area of interest, Calabrese said.

“Cancer immunotherapy, checkpoint inhibitor therapy, is now a pillar of the treatment of cancer. The Achilles heel of this is autoimmune disease,” he said.

Calabrese also spoke about the relationship between the microbiome and immune response. He highlighted a study by Tanoue et al that evaluated the impact of human fecal transplants on germ-free murine models. The researchers found 11 strains of bacteria that appeared to be optimum for reconstituting the CD8 cells in the mice.

“They then challenged this idea with listeria,” Calabrese said. “Indeed, if you had the 11 strains of bacteria, the mouse could protect itself,” which suggested the immune system’s ability to reconstitute. “This is a major step forward in understanding the positive and essential effects of the microbiome and needs to be taken forward,” Calabrese said.

The last topic Calabrese discussed was the current state of sarcoidosis. He highlighted a study by Damsky et al where a patient with cutaneous sarcoidosis was treated with tofacitinib, a janus kinase (JAK) inhibitor.

“At the end of the day, the scoring system of this patient dramatically fell on this drug,” Calabrese said. “It gives us some interesting data to build on.”

Calabrese ended his presentation by calling immunology a “field of surprises” with more in store for the future.

Reference:

Calabrese L. Advances in basic and clinical immunology. Presented at: Interdisciplinary Autoimmune Summit; April 5-7, 2019; Chicago, IL.