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Low doses of the recombinant T-cell growth factor interleukin 2 (IL-2, aldesleukin, Proleukin) were well tolerated among patients with moderate-to-severe ulcerative colitis in a , with only one patient being withdrawn because of a dose-limiting toxicity, a researcher reported.

There also were preliminary suggestions of efficacy, with 38.4% of the 26 patients enrolled achieving a clinical response and 15.4% being in clinical remission by week 8, according to Jessica R. Allegretti, MD, of Harvard University in Boston.

"Regulatory T cells promote intestinal health and protect against autoimmunity. In autoimmune diseases such as inflammatory bowel disease, patients can be deficient in regulatory T cells," she said at a presentation at the virtual Crohn's and Colitis Congress.

Regulatory T cells (Tregs) are more sensitive to IL-2 than conventional T cells (Tcons) because of high affinity receptors present only on the Tregs. Expansion of Tregs has shown promise for other immune-mediated diseases such as and in . Aldesleukin has been FDA approved for use in and metastatic .

To explore the possibility that low-dose IL-2 could be beneficial in ulcerative colitis, Allegretti's group enrolled 26 adult patients who had a confirmed diagnosis of ulcerative colitis, with total Mayo scores of 6 to 12 and a history of failing at least one conventional therapy. The vast majority of patients had failed more than two biologics prior to study entry.

In the first dose-escalation phase of the open-label study, patients received one of three doses by daily subcutaneous injection:

• Dose A: 0.3 x 10⁶ IU/m²/day
• Dose B: 1 x 10⁶ IU/m²/day
• Dose C: 1.5 x 10⁶ IU/m²/day

The primary objectives were safety and determination of the maximum tolerated dose, which was defined as the highest tolerated dose level at which fewer than two patients experienced a dose-limiting toxicity. Clinical and laboratory assessments were performed before treatment initiation and at weeks 1, 2, 4, 6, 8, and 12, and flexible sigmoidoscopy at baseline and week 8.

Four patients were given dose A, and at that dose, no dose-limiting toxicities were observed. Peripheral Treg expansion was noted in two of the four, and one patient achieved a clinical response.

Among the seven patients given dose B, one patient developed a rash that was considered a dose-limiting toxicity and withdrew from the study. At that dose, all patients experienced peripheral Treg expansion, two achieved clinical remission, and one had a clinical response, using standard criteria with Mayo scores for those degrees of response.

In the five patients given dose C, there were no dose-limiting toxicities, although low-grade side effects such as injection site reactions, fever, and malaise were common. Peripheral Treg expansion was seen in all patients, but no patients showed a clinical response. Further investigation of these patients determined that at this highest dose, there was not only Treg expansion but also Tcon activation, which may explain the lack of clinical response. Accordingly, the remainder of the study focused on dose B as the maximum effective dose.

An additional 10 patients were then enrolled at dose B, with none experiencing dose-limiting toxicities and peripheral Treg expansion being noted in all. Treg expansion in the colonic mucosa was not necessary for clinical response, Allegretti explained.

In this dose B group, clinical responses were seen in 53% of the 10 and clinical remission in 23.8%.

Additional safety findings included two patients withdrawing because of the common low-grade side effects, three because of worsening of the colitis, and one because of uveitis that was not considered to be drug-related. There were no serious adverse events.

"Low-dose subcutaneous IL-2 was well tolerated and associated with a biological response and peripheral Treg expansion in patients with moderate-to-severe ulcerative colitis. The maximum effective dose was found to be 1 x 10⁶ IU/m²/day," she concluded.

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