Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma
Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma
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DOI：
10.1182/blood-2017-08-802470
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发表时间：
2018-02-22
期刊：
影响因子：
20.3
通讯作者：
Weinstock, David M.
中科院分区：
文献类型：
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作者：
Horwitz, Steven M.;Koch, Raphael;Weinstock, David M.
Duvelisib (IPI-145) 是一种口服磷脂酰肌醇 3-激酶 (PI3K)-delta/gamma 亚型抑制剂，目前正处于临床开发阶段。 PI3K-delta/gamma 抑制可直接抑制恶性 T 细胞生长，使 duvelisib 成为外周 (PTCL) 或皮肤 (CTCL) T 细胞淋巴瘤患者的有希望的候选药物。任一亚型的抑制也可能通过调节非恶性免疫细胞来促进临床反应。我们在 TCL 队列中研究了 duvelisib 在复发或难治性 PTCL (n = 16) 和 CTCL (n = 19) 患者中的 1 期开放标签研究以及 TCL 的体外和体内模型的双重效应。 PTCL 和 CTCL 患者的总体缓解率分别为 50.0% 和 31.6% (P = .32)。有 3 例完全缓解，全部为 PTCL 患者。在多种亚型中都观察到了活动。最常见的 3 级和 4 级不良事件是转氨酶升高（丙氨酸转氨酶 40%，天冬氨酸转氨酶 17%）、斑丘疹（17%）和中性粒细胞减少症（17%）。应答者和无应答者在 duvelisib 诱导的血清细胞因子谱中存在显着不同的变化。在体外，duvelisib 有效杀死了 4 个含有组成型磷酸 AKT (pAKT) 的 TCL 细胞系中的 3 个，而 7 个细胞系中缺乏 pAKT 的细胞只有 0 个 (P = .024)，并且超过了 PI3K-delta 特异性抑制剂 idelalisib 的细胞杀伤力。对移植了 PTCL 患者来源的异种移植物的小鼠施用 duvelisib 导致肿瘤相关巨噬细胞从免疫抑制性 M2 样表型转变为炎症性 M1 样表型。总之，duvelisib 在复发/难治性 TCL 中表现出有前景的临床活性和可接受的安全性，以及肿瘤细胞自主效应和免疫介导效应的临床前证据。
Duvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 3-kinase (PI3K)-delta/gamma isoforms currently in clinical development. PI3K-delta/gamma inhibition may directly inhibit malignant T-cell growth, making duvelisib a promising candidate for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma. Inhibition of either isoform may also contribute to clinical responses by modulating nonmalignant immune cells. We investigated these dual effects in a TCL cohort from a phase 1, open-label study of duvelisib in patients with relapsed or refractory PTCL (n = 16) and CTCL (n = 19), along with in vitro and in vivo models of TCL. The overall response rates in patients with PTCL and CTCL were 50.0% and 31.6%, respectively (P = .32). There were 3 complete responses, all among patients with PTCL. Activity was seen across a wide spectrum of subtypes. The most frequently observed grade 3 and 4 adverse events were transaminase increases (40% alanine aminotransferase, 17% aspartate aminotransferase), maculopapular rash (17%), and neutropenia (17%). Responders and nonresponders had markedly different changes in serum cytokine profiles induced by duvelisib. In vitro, duvelisib potently killed 3 of 4 TCL lines with constitutive phospho-AKT (pAKT) vs 0 of 7 lines lacking pAKT (P = .024) and exceeded cell killing by the PI3K-delta-specific inhibitor idelalisib. Administration of duvelisib to mice engrafted with a PTCL patient-derived xenograft resulted in a shift among tumor-associated macrophages from the immunosuppressive M2-like phenotype to the inflammatory M1-like phenotype. In summary, duvelisib demonstrated promising clinical activity and an acceptable safety profile in relapsed/refractory TCL, as well as preclinical evidence of both tumor cell-autonomous and immune-mediated effects.