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）在很大程度上是不可治愈的，处于晚期，严重衰弱。蕈样肉芽肿（Mycosis Fungoides，MF）是CTCL最常见的亚型之一，早期可得到有效治疗，但晚期MF除异基因造血干细胞移植（allogeneic stem cell transplantation，SCT）外，尚无根治性治疗方法，适合患者较少。对治疗的反应通常是部分和短暂的;患者经常死于败血症和其他感染，这是免疫功能障碍和屏障保护丧失的结果。有效和创新的治疗策略MF，从淋巴瘤生物学的理解是一个持续的未满足的需求。 先天免疫系统的失调在MF的所有阶段都可以看到，并且是疾病发病率和淋巴瘤发生的基础。免疫刺激疗法已显示出抗肿瘤作用，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）的表观遗传治疗。对这些药物的反应率适中（总反应率为30%，完全反应率< 10%）。这可能是HDACI诱导的细胞免疫功能抑制的结果，尽管它们具有抗肿瘤特性，加剧了免疫缺陷，为这种淋巴瘤创造了一个允许的小生境。 需要将抗肿瘤治疗与免疫刺激相结合的晚期MF的有效治疗平台;然而，迄今为止，这种策略尚未经过测试。我们在纽约大学的研究小组以前已经证明，局灶性病变辐射可以诱导免疫刺激和场外肿瘤缩小（一种“远场”反应）。我们建议用原位疫苗接种治疗接受表观遗传治疗的晚期MF患者，包括局灶性病变放射治疗，加或不加Toll样受体（TLR）激动剂，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1期初步研究中评估在晚期MF患者中，将具有局灶性病变放射和TLR 3激动剂的原位疫苗接种添加到具有罗米地辛的表观遗传疗法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）与微环境中的肿瘤排斥一致的免疫特征，和B）系统性免疫激活的证据。如果这些假设得到验证，这将支持更大规模的临床试验。 这项研究是创新性的，因为它是第一个提出在MF（一种免疫介导的淋巴瘤）中用免疫刺激增强表观遗传治疗的抗肿瘤作用的研究。这是有意义的，因为这种治疗方法可以应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，这种策略可能会显着影响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.