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.
Querfeld:Trillium: Consultancy, Other: Investigator, Research Funding; Soligenix: Other: Investigator; Celgene: Other: Investigator, Research Funding; Medivir: Consultancy; Elorac: Other: Investigator, Research Funding; miRagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Bioniz: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Kyowa: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Eisai: Other: Investigator; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; City of Hope Cancer Center and Beckman Research Institute: Employment. William:Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Guidepoint Global: Consultancy; Defined Health: Consultancy. Brammer:Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Sokol:EUSA: Consultancy. Tagaya:Bioniz: Research Funding; Bioniz: Membership on an entity's Board of Directors or advisory committees. Frohna:Bioniz: Employment. Azimi:Bioniz: Employment. Zain:Seattle Genetics: Honoraria, Speakers Bureau; spectrum: Honoraria.
Asterisk with author names denotes non-ASH members.