A Novel Multimodality Immune Based Platform in Advanced Mycosis Fungoides

描述(由申请人提供)：皮肤T细胞淋巴瘤(CTCL)基本上是不治之症，处于晚期，严重虚弱。真菌病(MF)是CTCL最常见的亚型之一，早期可有效治疗，但对于晚期MF，目前尚无根治方法，仅有少数患者符合条件接受异基因干细胞移植。对治疗的反应通常是部分和短暂的；由于免疫功能障碍和屏障保护的丧失，患者经常死于败血症和其他感染。基于对淋巴瘤生物学的了解，对MF的有效和创新的治疗策略是一个持续未得到满足的需求。先天性免疫系统的失调见于MF的所有阶段，是疾病发病率和淋巴肿大的基础。免疫刺激疗法已经显示出抗肿瘤的效果，主要是在早期和有限的疾病中。FDA批准的晚期MF患者的一线治疗是表观遗传疗法，使用组蛋白脱乙酰酶抑制剂(HDACi)。对这些代理商的应答率不高(总体应答率为30%，完全应答率为10%)。这可能是由于HDACi诱导的细胞免疫功能受到抑制，尽管它们具有抗肿瘤的特性，加剧了免疫缺陷，从而为这种淋巴瘤创造了一个允许的利基。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，到目前为止，这一策略还没有得到测试。我们在纽约大学的团队之前已经证明，局灶性病变放射可以诱导免疫刺激和野外肿瘤缩小(一种“非局部性”反应)。我们建议对接受表观遗传治疗的晚期MF患者进行原位免疫接种，包括局部皮损照射，并使用或不使用Toll样受体(TLR)激动剂，这是一种额外的免疫刺激剂。我们假设，这种干预将是耐受性良好的，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)在第一阶段初步研究中，评估晚期MF患者在使用romidessin进行表观遗传治疗的基础上，加入局部病变放射和TLR3激动剂的SIU疫苗的安全性和临床活性，以及2)确定该治疗平台是否增强了肿瘤特异性免疫，并诱导a)与微环境中的肿瘤排斥反应一致的免疫特征，以及b)全身免疫激活的证据。如果这些假设得到证实，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在免疫介导的淋巴瘤MF中通过免疫刺激增强表观遗传治疗抗肿瘤效果的研究。这是有意义的，因为这种治疗方法可以应用于其他淋巴瘤和/或免疫介导性恶性肿瘤的治疗。如果得到验证，这一策略可能会显著影响MF患者的发病率和死亡率。

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.