Bnz-1, a Selective γ-Chain Cytokine Inhibitor Has Clinical Activity in Patients with Cutaneous T Cell Lymphoma By Selectively Blocking IL-2, IL-15 and IL-9 Signaling: Results of a Multicenter, Open-Label Phase 1 Trial

Background: Cutaneous T cell lymphoma is incurable with current therapies and there is an urgent need for more effective therapies. BNZ-1 is a pegylated peptide antagonist that binds to the common γc signaling receptor for the cytokines IL-2, IL-9 and IL-15. These cytokines, particularly IL-2 and IL-15, have been implicated in the pathogenesis of CTCL through activation of JAK/Stat signaling pathways, Therefore, we hypothesized that inhibition of the IL-2 and IL-15 signaling pathways in CTCL will induce antitumor activity in patients with CTCL.

Methods: A multicenter, open-label Phase 1 study is ongoing to characterize the safety and tolerability of BNZ-1 (NCT03239392). Patients with a diagnosis of mycosis fungoides (MF) of any stage or Sézary syndrome (SS) are eligible for this trial. Pts are enrolled in sequential dose cohorts of 0.5 mg/kg, 1mg/kg, 2 mg/kg, and 4 mg/kg to receive intravenous dose of BNZ-1 to characterize safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity. Infusions are administered weekly for four doses to evaluate for safety. Thereafter, patients are enrolled on an extension phase for 3 months of weekly dosing of BNZ-1. If patient attain a response, they are eligible for a long-term extension arm, as approved by the FDA. Blood samples are collected to assess the impact of BNZ-1 on the anti-tumor response.

Results: pts with MF/SS (11 M/5F, median age 61 years, range 32-89) have been enrolled. Clinical stages include IB (n=6), IIA (n=1), IIB (n=6), IVA1 (n=2), IVB (n=1). Patients were previously treated with a median of 2 ( 1-5) topical therapies and 3 (1-11) systemic therapies. Single and sequential doses of weekly 1 mg, 2 mg, or 4 mg BNZ-1 infusions have been well tolerated. The most frequently reported adverse events were pruritus (n=9), fatigue (n=5) and dry skin (n=3). All treatment-related AEs were Grade 1 or 2 in severity. No SAEs or dose limiting toxicity have been observed to date. Notably reductions in mSWATs and CAILs was noted even in patients with advanced stage disease and/or with features of large cell transformation and folliculotropic subtype. Flow cytometry of peripheral blood at baseline and during treatment indicated activation of anti-lymphoma immune responses associated with the downregulatio of PD1. Concommittantly, excess expression of cytotoxic granules (perforin & Granzyme B) has been downregulated, suggesting the silencing of inflammatory T-cell responses.

Conclusions: These preliminary Phase 1 results suggest that pegylated BNZ-1 is well-tolerated and inhibition of IL-2 and IL-15 leads to clinical improvement in patients with CTCL. Evidence for the rejuvenation of anti-lymphoma immunity and a decreasing inflammatory responses was seen in cases showing clinical response consistent with our hypothesis. An expansion cohort in CTCL is currently underway to validate these promising early results.