Pacritinib in rel/refr T-cell lymphomas

项目摘要 T细胞淋巴瘤(TCL)是一个未得到满足的医疗需求领域的患者，特别是那些复发或 难治性疾病，很少用现有的治疗方法治愈。我们和其他人已经证明了抗原-- 共刺激信号和细胞因子依赖信号协同促进恶性T细胞的生长和存活 并使其对常规化疗产生抵抗力。这些信号级联通过以下方式传播 相关激酶的高重复功能获得性突变以及由 肿瘤微环境成分(TME)，包括淋巴瘤相关巨噬细胞(LAM)。早些时候 研究酪氨酸激酶抑制剂(TKI)选择性相关靶点的阶段临床试验 已经完成(或正在进行)，但对这些制剂观察到的大多数反应是部分的，很少持久。这个 与TCL和协作性(和部分冗余)相关的遗传和分子异质性 信号通路之间的相互作用可能解释了与许多靶向药物相关的次优活性。 TME的成分，特别是LAM，创造了一个利基市场，直接促进TCL的增长和生存， 通过为TCL相关抗原、共刺激和细胞因子受体提供外源配体，以及 间接通过抑制宿主抗肿瘤免疫。因此，另一种选择，可能是互补的， 治疗方法是以LAM为靶点。耗尽肿瘤相关巨噬细胞的努力在很大程度上 致力于克隆刺激因子-1受体(CSF-1R)拮抗剂，因为目前的教条表明，这是 组织内滞留巨噬细胞生存所需的主要动态平衡细胞因子。然而，我们自己的 初步数据对这一概念提出了挑战，至少在TCL背景下是这样。例如，Pexidartinib是一种选择性， FDA批准的CSF-1R TKI，TCL相关巨噬细胞对其大部分耐药。当林扮演一个 在TCL发病机制中的核心作用，我们的长期目标之一是开发新的、靶向的治疗方法，以损害 它们的扩张、生存和功能分化。考虑到这一目标，我们进行了一次不偏不倚的 通过与近200种靶向药物的吞吐量筛选，发现TCL相关的巨噬细胞，而 对多种选择性CSF-1R拮抗剂耐药，对帕利替尼高度敏感。帕利替尼是一种安全的 耐受的口服Janus家族激酶(JAK)抑制剂，已在多个I、II和III期进行研究 研究(主要是骨髓增生性肿瘤)。除了抑制多个JAK(JAK2、TYK2、JAK3)外， 我们已经证明帕利替尼在临床可达到的浓度下抑制CSF-1R和Src家族的激酶， 这两个目标在TCL中都是高度相关的目标。因此，我们的首要前提是，抑制 在TCL中具有细胞自主和非细胞自主角色的多个高度相关的激酶 发病机制是一种有吸引力但在很大程度上未被探索的治疗策略，值得进一步研究。 我们在这项申请中的总体目标是检查帕利替尼的疗效并询问相关的 研究人员发起的多中心II期临床试验中的预测性和药效学生物标记物。

PROJECT ABSTRACT The T-cell lymphomas (TCL) are an area of unmet medical need as patients, particularly those with relapsed or refractory disease, are rarely cured with existing therapies. We, and others, have shown that antigen-, costimulation-, and cytokine-dependent signaling cooperatively promote the growth and survival of malignant T cells and confers their resistance to conventional chemotherapy. These signaling cascades are propagated by highly recurrent gain-of-function mutations in relevant kinases and by exogenous ligands provided by constituents of the tumor microenvironment (TME), including lymphoma-associated macrophages (LAM). Early phase clinical trials investigating tyrosine-kinase inhibitors (TKI) selective for relevant targets have been completed (or are ongoing), but most responses observed with these agents are partial and rarely durable. The genetic and molecular heterogeneity associated with the TCL and the cooperativity (and partial redundancies) among signaling pathways may explain the suboptimal activity associated with many targeted agents. Constituents of the TME, particularly LAM, create a niche that promotes TCL growth and survival both directly, by providing exogenous ligands for TCL-associated antigen, costimulatory, and cytokine receptors, and indirectly by suppressing host anti-tumor immunity. Therefore, an alternative, and potentially complementary, therapeutic approach is to target LAM. Efforts to deplete tumor-associated macrophages have been largely devoted to colony-stimulating factor-1 receptor (CSF-1R) antagonists, as current dogma suggests that this is the dominant homeostatic cytokine required for the survival of tissue resident macrophages. However, our own preliminary data challenges this conception, at least in a TCL context. Pexidartinib, for example, is a selective, and FDA-approved, CSF-1R TKI, to which TCL-associated macrophages are largely resistant. As LAM play a central role in TCL pathogenesis, one of our long-term goals is to develop novel, targeted therapies that impair their expansion, survival, and functional polarization. With that goal in mind, we performed an unbiased, high- throughput screen with almost 200 targeted agents, and discovered that TCL-associated macrophages, while resistant to multiple selective CSF-1R antagonists, were highly sensitive to pacritinib. Pacritinib is a safe, well tolerated, oral Janus family kinase (JAK) inhibitor that has been investigated in multiple phase I, II, and III studies (largely in myeloproliferative neoplasms). In addition to inhibiting multiple JAKs (JAK2, TYK2, JAK3), we have shown that pacritinib inhibits CSF-1R and Src family kinases at clinically achievable concentrations, both of which are highly relevant targets in TCL. Therefore, our overarching premise, is that inhibition of multiple, highly relevant kinases with both cell-autonomous and non-cell-autonomous roles in TCL pathogenesis is an attractive, but largely unexplored, therapeutic strategy that warrants further investigation. Our overall objectives in this application are to examine the efficacy of pacritinib and interrogate relevant predictive and pharmacodynamics biomarkers in an investigator-initiated, multicenter, phase II clinical trial.