A Novel Multimodality Immune Based Platform in Advanced Mycosis Fungoides

一种新型多模态免疫平台治疗晚期蕈样肉芽肿

• 批准号: 8678243
• 负责人: Catherine Sibyl Diefenbach
• 金额: $ 8.48万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8678243
• 关键词: Agonist; Allogenic; Behavior; Biology; Clinical; Clinical Trials; Correlative Study; Cutaneous; Data; Disease; Disease Progression; Epigenetic Process; FDA approved; Functional disorder; Histone Deacetylase Inhibitor; Immune; Immune System Diseases; Immune system; Immunity; Immunologics; Immunosuppressive Agents; In Situ; In complete remission; Infection; Intervention; Lesion; Limited Stage; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mediating; Morbidity - disease rate; Mycosis Fungoides; Patients; Phase; Pilot Projects; Play; Poly ICLC; Property; Quality of life; Radiation; Randomized Clinical Trials; Refractory; Relapse; Research; Safety; Sepsis; Stable Disease; Staging; Stem cell transplant; Syndrome; T-Cell Lymphoma; TLR3 gene; Testing; Therapeutic; Toll-like receptors; Vaccination; advanced disease; base; clinical efficacy; design; effective therapy; immune activation; immune function; improved; innovation; mortality; multimodality; novel; pilot trial; public health relevance; response; social; therapy resistant; treatment strategy; tumor

DESCRIPTION (provided by applicant): Cutaneous T cell lymphomas (CTCL) are largely incurable and in advanced stage, profoundly debilitating. Mycosis Fungoides (MF), one of the most common subtypes of CTCL, may be effectively treated in early stage, but there is no curative therapy for advanced MF except for allogeneic stem cell transplantation (SCT) for which few patients are eligible. Response to therapy is usually partial and transient; patients frequently succumb to sepsis and other infections as a consequence of immune dysfunction and loss of barrier protection. Effective and innovative treatment strategies for MF, derived from an understanding of lymphoma biology are an ongoing unmet need. Dysregulation of the innate immune system is seen at all stages of MF, and underlies both disease morbidity and lymphomagenesis. Immune stimulatory therapies, have demonstrated anti-tumor effects, primarily in early stage and limited disease. The FDA approved first line of therapy for patients with advanced MF is epigenetic therapy, using histone deacetylase inhibitors (HDACI). The response rate to these agents is modest, (overall response rate of 30% and complete response rate < 10%). This may be a result of the suppression of cellular immune function induced by HDACI despite their anti-tumor properties, exacerbating the immunologic deficiency that creates a permissive niche for this lymphoma. Effective treatment platforms for advanced MF are needed that combine anti-tumor therapy with immune stimulation; however, to date this strategy has not been tested. Our group at NYU has previously demonstrated that focal lesion radiation can induce immune stimulation and out of field tumor shrinkage (an 'abscopal' response). We propose to treat advanced MF patients receiving epigenetic therapy with in situ vaccination, consisting of focal lesion radiation with or without a toll-like receptor (TLR) agonist, an additioal immune stimulant. We hypothesize that this intervention will be well-tolerated, and will induce systemic immune activation and clinical response. The specific aims of the proposed research are: 1) Evaluate in a phase 1 pilot study the safety and clinical activity of the addition of in siu vaccination with focal lesion radiation and a TLR3 agonist to epigenetic therapy with romidepsin, in patients with advanced MF, and 2) Determine whether this treatment platform augments tumor specific immunity, and induces a) an immune signature consistent with tumor rejection in the microenvironment, and b) evidence of systemic immune activation. If these hypotheses are validated, this will support a larger scale clinical trial. This research is innovative because itis the first study to propose augmenting the anti-tumor effects of epigenetic therapy with immune stimulation in MF, an immune mediated lymphoma. It is significant because this therapeutic approach may be applied to the treatment of other lymphomas and/or immune mediated malignancies. If validated, this strategy may significantly impact the morbidity and mortality of MF patients.

描述（由申请人提供）：皮肤 T 细胞淋巴瘤 (CTCL) 基本上无法治愈，并且处于晚期阶段，会严重使人衰弱。蕈样肉芽肿（MF）是CTCL最常见的亚型之一，早期可以得到有效治疗，但晚期MF除了异基因干细胞移植（SCT）外​​尚无根治性治疗方法，而异基因干细胞移植（SCT）适合的患者很少。对治疗的反应通常是部分且短暂的；由于免疫功能障碍和屏障保护丧失，患者经常死于败血症和其他感染。源自对淋巴瘤生物学的理解的有效和创新的 MF 治疗策略是一个持续未得到满足的需求。 先天免疫系统的失调在 MF 的所有阶段都可见，并且是疾病发病和淋巴瘤发生的基础。免疫刺激疗法已被证明具有抗肿瘤作用，主要是在早期和有限的疾病中。 FDA 批准的晚期 MF 患者的一线治疗是使用组蛋白脱乙酰酶抑制剂 (HDACI) 的表观遗传学治疗。这些药物的缓解率较低（总体缓解率为 30%，完全缓解率 < 10%）。这可能是由于 HDACI 诱导的细胞免疫功能受到抑制，尽管其具有抗肿瘤特性，从而加剧了免疫缺陷，从而为这种淋巴瘤创造了有利的环境。 晚期 MF 需要有效的治疗平台，将抗肿瘤治疗与免疫刺激相结合；然而，迄今为止，这一策略尚未经过测试。我们纽约大学的研究小组之前已经证明，局灶性病变放射可以诱导免疫刺激和场外肿瘤缩小（“远隔”反应）。我们建议通过原位疫苗接种来治疗接受表观遗传治疗的晚期 MF 患者，包括使用或不使用 Toll 样受体 (TLR) 激动剂（一种额外的免疫刺激剂）的局灶性病变放射治疗。我们假设这种干预措施具有良好的耐受性，并将诱导全身免疫激活和临床反应。拟议研究的具体目标是： 1) 在 1 期试点研究中评估晚期 MF 患者在罗米地辛表观遗传治疗中添加局灶性病灶放射和 TLR3 激动剂的原位疫苗接种的安全性和临床活性， 2) 确定该治疗平台是否增强肿瘤特异性免疫，并诱导 a) 与微环境中肿瘤排斥一致的免疫特征，以及 b) 全身免疫激活的证据。如果这些假设得到验证，这将支持更大规模的临床试验。 这项研究具有创新性，因为这是第一项提出通过免疫刺激增强表观遗传疗法对 MF（一种免疫介导的淋巴瘤）的抗肿瘤作用的研究。其意义重大，因为这种治疗方法可以应用于其他淋巴瘤和/或免疫介导的恶性肿瘤的治疗。如果得到验证，该策略可能会显着影响 MF 患者的发病率和死亡率。