Alan K. Matsumoto

T cell receptor peptide vaccination in rheumatoid arthritis : A placebo-controlled trial using a combination of Vβ3, Vβ14, and Vβ17 peptides

OBJECTIVE Restricted T cell receptor (TCR) gene usage has been demonstrated in animal models of autoimmune disease and has resulted in the successful use of TCR peptide therapy in animal studies. This clinical trial was undertaken to determine the safety and efficacy of a combination of Vbeta3, Vbeta14, and Vbeta17 TCR peptides in Freunds incomplete adjuvant (IFA) in patients with rheumatoid arthritis (RA). METHODS A double-blind, placebo-controlled, multicenter, phase II clinical trial was undertaken using IR501 therapeutic vaccine, which consists of a combination of 3 peptides derived from TCRs (Vbeta3, Vbeta14, and Vbeta17) in IFA. A total of 99 patients with active RA received either 90 microg (n = 31) or 300 microg (n = 35) of IR501 or IFA alone (n = 33) as a control. The study medication and placebo were administered as a single intramuscular injection (1 ml) at weeks 0, 4, 8, and 20. RESULTS Treatment with IR501 was safe and well tolerated. None of the patients discontinued the trial because of treatment-related adverse events. Efficacy was measured according to the American College of Rheumatology 20% improvement criteria. Using these criteria, patients in both IR501 dosage groups showed improvement in disease activity. In the most conservative analysis used to evaluate efficacy, an intent-to-treat analysis including all patients who enrolled, the 90-microg dosage group showed a statistically significant improvement compared with control patients at the 20-week time point after the third injection. Trends toward improvement were shown in both the 90-microg and the 300-microg dosage groups at week 24 after the fourth injection. CONCLUSION IR501 therapeutic vaccine therapy was safe and well tolerated, immunogenic, and demonstrated clinical improvement in RA patients. Additional clinical trials are planned to confirm and extend these observations.

Results of a Phase II Rheumatoid Arthritis Clinical Trial Using T-Cell Receptor Peptides

Restricted T-cell receptor gene use has been found in animal models of autoimmune disease. This observation has resulted in the successful use of T-cell receptor peptide therapy in animal studies. Initial phase I studies in patients with rheumatoid arthritis (RA) indicated that this therapy was safe and well tolerated. A double-blind, placebo-controlled, multicenter phase II rheumatoid arthritis clinical trial was undertaken using IR501 therapeutic vaccine, which consists of a combination of three peptides derived from T-cell receptors (Vβ3, Vβ14, Vβ17) in incomplete Freund’s adjuvant (IFA). These T-cell receptors were previously reported to be restricted in RA patients. A total of 99 patients received either 90μg (31 patients) or 300μg (35 patients) of IR501 therapeutic vaccine or IFA alone (33 patients) as a control. IR501 therapeutic vaccine was administered as a 1.0-ml intramuscular injection at weeks 0, 4, 8, and 20. Patients were followed for 32 weeks. The results of the trial indicated that the treatment was safe, with none of the patients discontinuing the trial because of treatment-related adverse events. No significant adverse events attributable to the study drug were observed. Patients in both dose groups treated with IR501 therapeutic vaccine showed improvement in disease condition. Most importantly, the 90-μg dose group showed a statistically significant improvement when compared to control patients after the third and fourth injections. More than 50% of the treated patients showed improvement compared to 19% of controls, as measured in accordance with the American College of Rheumatology definition for clinical response (ACR 20 criteria).

Anti-Tumor Necrosis Factor Agents

The development of inhibitors of tumor necrosis factor (TNF) evolved from a targeted bench-to-bedside approach in which lessons learned from basic pathophysiological research were tested in patients with debilitating chronic inflammatory diseases, particularly rheumatoid arthritis (RA) and inflammatory bowel disease. Insofar as all prior treatments for (RA) evolved primarily from serendipitous observations, the TNF inhibitors represent the first “rationally based” treatment, as well as the first Food and Drug Administration (FDA)-approved recombinant proteins (“biologies”) for the treatment of RA. This chapter will focus on RA as a paradigm for examining the role of TNF in the pathogenesis and propagation of chronic inflammation, and for evaluating anti-TNF therapy as a strategy for the treatment of chronic inflammatory disease.