2015 ACR/ARHP Annual Meeting: Role of Tumor Necrosis Factor Cytokines in Autoimmune Diseases Examined

For example, he highlighted data showing that blocking TL1A in mice models of colitis showed a remarkable benefit in preventing pathology and demonstrated a significant effect on acute TL1A. Similar data were obtained from a mice model that showed the efficacy on preventing erosions in blocking TL1A in mice with collagen-induced arthritis.

From human studies, evidence shows that TL1A is elevated in the serum specifically in patients with rheumatoid arthritis and declines in response to TNF blocking therapy. “This suggests that [TL1A] may be a biomarker for TNF in RA,” said Dr. Siegel.

Overall, Dr. Siegel emphasized that TL1A, along with other members of the TNF cytokine family, may become therapeutic targets for rheumatic disease “in addition to TNF, RANK-ligand and BlyS, which are currently targeted by FDA-approved therapeutics.”

Cytokine OX40L & Receptor OX40

Michael Croft, PhD, professor and head, Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, Calif., spoke on the importance of another cytokine of the TNF superfamily—OX40L and its receptor OX40. He said that OX40 signals enhance and sustain division and survival of T cells, and drive T cell clonal expansion and T cell memory (both CD4+ and CD8+ T cells). Thus, targeting OX40 to reduce pathologic T cell activity is also of interest in ongoing studies.

From human studies, evidence shows that TL1A is elevated in the serum specifically in patients with rheumatoid arthritis & declines in response to TNF blocking therapy. ‘This suggests that [TL1A] may be a biomarker for TNF in RA.’ —Dr. Siegel.

Evidence from mouse models has shown that blocking OX40 reduces the pathology, often to a great extent, of many diseases, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, asthma and diabetes.

Dr. Croft

Based on the efficacy in these studies, several phase I clinical trials are underway. To date, he said, one study has gone into phase II trial that looked at the effect of anti-OX40L in mild allergic asthma.² The study included 28 patients with mild, atopic asthma randomized to an anti-OX40L monoclonal antibody (MAb) or placebo. To assess late-phase asthmatic response, the primary endpoint of the study, patients were administered allergen inhalation challenges at 56 and 113 days following the first dose of the study drug. Early-phase asthmatic response was also assessed.

The study found no difference between the two groups in early- or late-phase asthmatic response. The failure of OX40L blockade to meet the trial endpoints was surprising, said Dr. Croft, given the large evidence on this benefit in mouse models.