A phase 1 study of interleukin-15 in combination with mogamulizumab in relapsed and refractory T-cell malignancies

Blood Neoplasia Pub Date : 2025-02-01 DOI:10.1016/j.bneo.2024.100054

Max J. Gordon ∗ , Sigrid Dubois ∗ , Milos D. Miljkovic , Samuel Ng , Bonita Bryant , Rahul Lakhotia , Christopher Melani , Stefania Pittaluga , Kevin Conlon , Thomas Waldmann , Louis M. Staudt , Wyndham H. Wilson , Mark Roschewski

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Abstract

Recombinant human interleukin-15 (rhIL-15) is an immunotherapeutic agent that enhances natural killer (NK) cells to augment the antibody-dependent cellular cytotoxicity (ADCC) of monoclonal antibodies. Mogamulizumab is a CC chemokine receptor 4–directed monoclonal antibody that exerts cytotoxicity through ADCC and depletes regulatory T cells within the tumor microenvironment. We conducted a phase 1 clinical trial of rhIL-15 in combination with mogamulizumab. Patients with relapsed or refractory adult T-cell leukemia/lymphoma (ATLL), mycosis fungoides (MF), and Sezary syndrome (SS) received a fixed dose mogamulizumab, combined with escalating doses of rhIL-15 to identify the maximum tolerated dose (MTD). Six patients were enrolled, 4 with ATLL and 2 with MF/SS. The most common adverse events were rash, infection, and fever (67% of all). Two patients (33%) had grade 4 acute kidney injury, and in 25% of cycles, grade 3 or higher anemia was present. The MTD was dose level 1. One patient with ATLL had a partial response despite receiving only 4 cycles because of grade 4 myositis. Circulating NK cells were increased in all patients during the first cycle and a rapid reduction in tumor cells within the peripheral circulation was noted. Ex vivo assessment demonstrated increased NK cell activation and increased cell lysis in the presence of monoclonal antibodies after only 5 days. Our small study suggests that rhIL-15, in combination with mogamulizumab, leads to effector NK cell activation and regulatory T-cell depletion but has an unfavorable safety profile. Future development of combinations of immunotherapy that target the microenvironment in relapsed or refractory T-cell lymphomas remains rational. This trial was registered at www.ClinicalTrials.gov as #NCT04185220.

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白介素-15联合莫加珠单抗治疗复发和难治性t细胞恶性肿瘤的一期研究

摘要：组合人白细胞介素-15 （rhIL-15）是一种免疫治疗剂，可增强自然杀伤细胞（NK），增强单克隆抗体的抗体依赖性细胞毒性（ADCC）。Mogamulizumab是一种CC趋化因子受体4定向单克隆抗体，通过ADCC发挥细胞毒性并消耗肿瘤微环境中的调节性T细胞。我们进行了rhIL-15联合mogamulizumab的一期临床试验。复发或难治性成人t细胞白血病/淋巴瘤（ATLL），蕈样真菌病（MF）和Sezary综合征（SS）的患者接受固定剂量的mogamulizumab，联合递增剂量的rhel -15以确定最大耐受剂量（MTD）。6例患者入组，4例为ATLL， 2例为MF/SS。最常见的不良事件是皮疹、感染和发烧（占所有不良事件的67%）。2例患者（33%）有4级急性肾损伤，在25%的周期中，存在3级或更高级别的贫血。MTD为剂量水平1。由于4级肌炎，1例ATLL患者仅接受了4个疗程，但仍有部分缓解。在第一个周期中，所有患者的循环NK细胞增加，外周循环中肿瘤细胞迅速减少。体外评估显示，在单克隆抗体存在的情况下，仅5天后NK细胞活化增加，细胞裂解增加。我们的小型研究表明，rhIL-15联合mogamulizumab可导致NK细胞激活效应和调节性t细胞耗竭，但安全性不佳。针对复发或难治性t细胞淋巴瘤的微环境免疫治疗组合的未来发展仍然是合理的。该试验在www.ClinicalTrials.gov上注册为#NCT04185220。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Blood Neoplasia

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