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）在很大程度上是无法治愈的，处于晚期，严重衰弱。蕈样真菌病（Mycosis Fungoides， MF）是CTCL最常见的亚型之一，在早期可以得到有效的治疗，但对于晚期MF，除了同种异体干细胞移植（allogeneic stem cell transplantation， SCT）之外，没有治愈性的治疗方法，但很少有患者符合条件。对治疗的反应通常是部分的和短暂的；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。有效和创新的MF治疗策略，源于对淋巴瘤生物学的理解，是一个持续的未满足的需求。先天性免疫系统失调可见于MF的所有阶段，是疾病发病率和淋巴瘤发生的基础。免疫刺激疗法已经证明了抗肿瘤的作用，主要是在早期和有限的疾病。FDA批准晚期MF患者的一线治疗是表观遗传治疗，使用组蛋白去乙酰化酶抑制剂（HDACI）。这些药物的有效率一般（总有效率为30%，完全有效率< 10%）。这可能是由于尽管HDACI具有抗肿瘤特性，但却抑制了细胞免疫功能，加剧了免疫缺陷，从而为这种淋巴瘤创造了一个允许的生态位。晚期MF需要抗肿瘤与免疫刺激相结合的有效治疗平台；然而，到目前为止，这一策略还没有经过测试。我们在纽约大学的小组先前已经证明局灶性病变辐射可以诱导免疫刺激和野外肿瘤缩小（一种“抽离”反应）。我们建议通过原位疫苗接种治疗晚期MF患者，包括局灶性病变放疗，有或没有toll样受体（TLR）激动剂，一种额外的免疫兴奋剂。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。该研究的具体目的是：1)在1期先导研究中评估在罗米地新表观遗传治疗中加入局灶性病变辐射和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肿瘤特异性免疫，并诱导a)微环境中与肿瘤排斥反应一致的免疫特征，b)系统性免疫激活的证据。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，因为它是第一个提出通过免疫刺激来增强表观遗传治疗对MF（一种免疫介导的淋巴瘤）抗肿瘤作用的研究。这是重要的，因为这种治疗方法可能适用于治疗其他淋巴瘤和/或免疫介导的恶性肿瘤。如果得到验证，该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.