A novel approach to the sticky business of Crohn's disease therapy

A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn's disease. Yacyshyn BR, Bowen-Yacyshyn MB, Jewell L, Tami JA, Bennett CF, Kisner DL, Shanahan WR Jr. Gastroenterology 1998; 114:1133-42. ISIS 2303 is an antisense phosphorothioate oligodeoxy-nucleotide that inhibits intercellular adhesion molecule 1 (ICAM-1) expression. ICAM-1 is an adhesion molecule present on the surface, primarily of leukocytes and endothelial cells. Its ligands are β2 integrins which have an integral role in leukocyte transmigration across endothelium and trafficking to tissue. ISIS 2302 serves to reduce cellular mRNA and ultimately expression of ICAM-1. Twenty patients with active corticosteroid-treated Crohn's disease were randomized to receive 13 intravenous infusions over 26 days of either ISIS 2302 or placebo in a double blinded study, and were followed-up over 6 months. Three subjects received doses of 0.5 mg/kg, three subjects received 1.0 mg/kg, nine subjects received 2.0 mg/kg, and five subjects received placebo. However, the randomization process was not clear in this study and the actual group assignments were confusing as reported in the study design methods. One placebo subject was in remission at enrollment. Ultimately, there were no significant differences between the ISIS 2302 group and the placebo group in terms of numbers achieving remission, mean Crohn's Disease Activity Index scores, mean Endoscopic Index of Severity scores, and mean Inflammatory Bowel Disease Questionnaire scores. Short-term remissions were seen in 4 of 15 ISIS 2302 patients compared with 4 of 5 placebo patients. However, an additional 5 of 15 ISIS 2302 patients achieved remission during the 26-day treatment period and remained in remission at 6 months, compared with no placebo patients achieving a long-term remission. Two patients with gastroduodenal disease treated with ISIS 2302 remained symptom free at 1 year after treatment, and two patients with enterocutaneous fistulas closed during treatment, although the duration of closure is not reported. Intestinal mucosal ICAM-1 expression was reduced more commonly in subjects receiving 2 mg/kg doses of ISIS 2302 than any of the other groups. Serum ICAM-1 levels and mean percentage expression of CD54 on circulating CD3+ cells were surprisingly unchanged by this treatment. The percentage of CD3+ cells expressing β7 and αd both increased in the ISIS 2302-treated group compared with placebo. ISIS 2302 administration was associated with nausea and vomiting in 5 of 15 subjects on only 6 of 65 intravenous infusions of drug in those 5 subjects. ISIS 2302 is known to prolong the aPTT. Comment: Leukocyte trafficking and adhesion to the gut is a critical aspect of the immunoinflammatory response. Interfering with this process holds great promise as a mode of immunomodulatory therapy for diseases like Crohn's disease. In fact, disrupting the trafficking and sticking of immune cells is as logical as preventing the release of or blocking the activity of proinflammatory cytokines, such as with monoclonal antibody to tumor necrosis factor-α (N Engl J Med 1997;337: 1029-35). Dr. Yacyshyn and colleagues should be lauded for introducing two novel concepts to the Crohn's disease therapeutic armamentarium. First, is the use of an antisense compound to interfere with translation of the message of an important protein. Second, is a direct approach to interfering with leukocyte adhesion and transmigration across endothelium. The problems with the study design or lack of significant benefits compared with a very small placebo control group should not be overshadowed at this point by the foray into new therapeutic territory. The 33% lasting remission rate compares favorably (albeit in small numbers of patients) with other immunomodulatory agents such as intravenous cyclosporine (19% at 6 months) (Scand J Gastroenterol 1991;26:689-95), methotrexate (39% at 16 weeks) (N Engl J Med 1995;332:292-7) and anti-tumor necrosis factor (TNF)-α (24% at 12 weeks) (N Engl J Med 1997;337:1029-35). The therapeutic efficacy will be formally tested in a larger multicenter study that is ongoing. However, the current gold standard for novel biological therapy has been set by anti-TNF-α (N Engl J Med 1997; 337:1029-35) in that it was administered as a single intravenous infusion over 2 hours. The administration of 13 doses intravenously over 26 days represents a major health service and patient cost and inconvenience. Is ICAM-1 the appropriate adhesion molecule to target? ICAM-1 is the ligand for the β2 integrins LFA-1 and Mac-1, both expressed on leukocytes. LFA-1 is primarily involved in lymphocyte trafficking, and Mac-1 with neutrophils. LFA-1 is important in the costimulation of mucosal T cells, and Mac-1 may have a role in host defense since it can bind pathogens. The lymphocyte expression of ICAM-1 can be upregulated by interferon-γ, interleukin-1, and TNF-α (Nature 1990;346:425-34) and thus, is likely an integral step in the recruitment of other cells to the inflammatory site. Increased expression of LFA-1 and ICAM-1 in Crohn's disease tissue has been shown (Clin Immunol Immunopathol 1998;86: 147-59). Decreased mean percentage of peripheral blood lymphocyte expression of LFA-1 in Crohn's disease has also been reported, possibly suggesting egress of cells bearing this molecule out of the blood. (Dig Dis Sci 1997;42:2338-49). Furthermore, monoclonal antibodies to LFA-1, Mac-1, and ICAM-1 have all been shown to diminish disease activity in various animal models of inflammation (Arthritis Rheum 1992;35:541-549; J Immunol 1993;150:655-63). Other integrins, such as β7 may have an even larger role in lymphocyte trafficking to the gut, and monoclonal antibodies to this molecule are also currently being studied for use in Crohn's disease. The cellular adhesion molecule expression findings in this study require verification and further exploration as they may provide insight into the role of ICAM-1 in trafficking between the peripheral blood and the lamina propria, as well as in relation to other integrins. The increase in β7 and αd expression in ISIS 2302-treated patients relative to placebo was based mostly on an early drop in CD3+ cell expression of these molecules in placebo-treated patients. Is this a reflection that in patients with active Crohn's disease there is a tendency for cells bearing β7 or ad to egress from the blood into the tissue? Does the interference with ICAM-1 expression lead to upregulation of integrins such as β7 or αd that rely on other endothelial ligands? It is curious that CD3+ cell expression of CD54 (ICAM-1) was unchanged between the two groups. The investigators offer the explanation that expression of ICAM-1 is primarily reduced in the tissue after ISIS 2302, and perhaps cells expressing this ligand or cells that use it as a receptor are released from tissue and enter the circulation. That ISIS 2302 prolongs the aPTT apparently by inhibition of intrinsic tenase complex raises an interesting possible explanation regarding the therapeutic efficacy of ICAM-1. The production of other adhesion molecules such as selectins may be critical in the generation of thrombosis (G Shaw. Therapeutic potential of recombinant soluble PSGL-1. In: Molecular Mechanisms of Leukocyte Trafficking. Keystone Symposium, March, 1998). Blocking thrombosis may be of value, much like heparin, which may have some efficacy in treating ulcerative colitis (Am J Gastroenterol 1995;90:220-3). This also fits within the paradigm of the vascular activation/microthrombosis hypothesis of Crohn's disease (Can J Gastroenterol 1994;8: 70-4). Yacyshyn and colleagues have introduced us to a novel “antistick,” antithrombosis treatment for Crohn's disease. We have come to learn that some of our old favorite immunomodulatory therapies, such as corticosteroids and methotrexate may function to diminish cell adhesion (Proc Natl Acad Sci USA 1992;88:9991-5; Gastroenterology 1993;104:31-7), and so a more specific antisense, antiadhesion approach with ISIS 2302 makes sense in Crohn's disease. The challenge for these investigators will be to prove its efficacy in the large multicenter trial that is ongoing, to find a way to limit the frequency of systemic administration or ultimately to develop vehicles that allow for oral drug administration.

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