Pacritinib in rel/refr T-cell lymphomas

项目摘要 T细胞淋巴瘤（TCL）是一个未满足医疗需求的领域，因为患者，特别是那些复发或复发的患者， 难治性疾病，很少用现有疗法治愈。我们和其他人已经证明， 共刺激和依赖于精氨酸的信号协同促进恶性T细胞的生长和存活。 并赋予它们对常规化疗的抵抗力。这些信号级联通过 相关激酶中的高度复发性功能获得性突变，以及由 肿瘤微环境（TME）的组成部分，包括淋巴瘤相关巨噬细胞（LAM）。早期 研究酪氨酸激酶抑制剂（TKI）对相关靶点的选择性的临床试验阶段已经 已完成（或正在进行），但观察到的这些药物的大多数反应是部分的，很少持久。的 与TCL相关的遗传和分子异质性以及协同性（和部分冗余） 在信号通路中，可以解释与许多靶向药物相关的次优活性。 TME的组成部分，特别是LAM，创造了一个利基市场，直接促进TCL的增长和生存， 通过提供针对TCL相关抗原、共刺激和细胞因子受体的外源配体，和 间接抑制宿主的抗肿瘤免疫。因此，另一种可能的补充方案， 治疗方法是靶向LAM。消耗肿瘤相关巨噬细胞的努力在很大程度上是 致力于集落刺激因子-1受体（CSF-1 R）拮抗剂，因为目前的教条表明，这是 组织驻留巨噬细胞存活所需的占主导地位的稳态细胞因子。然而，我们自己的 初步数据挑战了这一概念，至少在TCL的背景下。例如，Pexidartinib是一种选择性的， 和FDA批准的CSF-1 R TKI，TCL相关巨噬细胞对其具有很大的抗性。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治疗， 它们的扩张、生存和功能极化。为了实现这一目标，我们进行了一次无偏见的，高- 通量筛选了近200种靶向药物，发现TCL相关巨噬细胞， 对多种选择性CSF-1 R拮抗剂耐药，对pacritinib高度敏感。Pacritinib是一种安全的， 一种耐受的口服Janus家族激酶（JAK）抑制剂，已在多个I、II和III期研究中进行了研究 研究（主要是骨髓增生性肿瘤）。除了抑制多种JAK（JAK 2、TYK 2、JAK 3）之外， 我们已经表明，在临床可达到的浓度下， 这两者都是TCL高度相关的目标。因此，我们的首要前提是， 在TCL中具有细胞自主和非细胞自主作用的多种高度相关的激酶 发病机制是一个有吸引力的，但在很大程度上未探索，治疗策略，值得进一步研究。 本申请的总体目标是检查pacritinib的疗效，并询问相关的 预测和药效学生物标志物在一个兴奋剂启动的，多中心，II期临床试验。

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.