Cutaneous T cell lymphoma: a paradigm for dissecting susceptibility and resistance to checkpoint inhibition therapy

皮肤T细胞淋巴瘤(CTCL)是一种起源于皮肤的血癌。不幸的是，这 毁容的恶性肿瘤仍然是无法治愈的。该病的病因尚待阐明。这个 淋巴瘤生长在包括一系列非恶性免疫细胞的环境中。而不是 通过摧毁癌细胞，非恶性细胞似乎促进了癌细胞的生长。令人信服的证据表明 对癌症的免疫反应被抑制分子钝化。然而，具体的信号表明 创造一个宽松的微环境是未知的。据推测，调控的microRNAs的表达 基因表达及其被称为免疫检查点分子的靶分子，如PD1和PD-L1，有助于创建 CTCL的宽松环境。总体而言，中报告了检查点表达式模式的更改 其他恶性肿瘤，并与微环境的改变有关，但它们的作用尚未 在CTCL有广泛的研究。关于检查点抑制剂在治疗这种疾病中的使用知之甚少。 疾病，但研究人员早期阻断PD1/PD-L1相互作用的经验显示令人鼓舞 结果。此外，研究人员还拥有免疫调节药物来那度胺的临床经验。 这也可能影响淋巴瘤与其微环境的相互作用。在初步调查的基础上 研究，一项I/II期临床试验，调查了杜伐单抗的安全性和有效性，杜伐单抗是一种PD- L1/PD1肿瘤相互作用，单独或与来那度胺，正在进行，结果非常有希望和安全 到目前为止。这两种药物在多发性骨髓瘤试验中也显示出良好的安全性。在目标2中， CTCL失调免疫表型谱的定量特征将用 先进的显微技术(多光谱成像、高分辨率显微镜)以及血清和皮肤蛋白 炎性细胞因子将与反应相关。在目标3中，临床前实验旨在确定 决定关键免疫检查点调节因子表达的机制。预计基线 免疫检查点和/或miRNA签名将与抗肿瘤反应联系在一起，并下调- 调节CTCL中异常免疫检查点的表达将有治疗上的好处。它是 预计PD1/PD-L1阻断将减缓肿瘤生长，并将与逆转 宽松的微环境。令人信服的初步数据为该项目提供了理论依据和相关 旨在了解哪些患者可能对治疗有反应的重要决定因素，以便 未来可以选择免疫疗法来治疗那些最有可能从这种治疗中受益的人。在……里面 此外，从临床前研究中获得的机械性见解将确定潜在的新靶点和途径。 以提高这一计划中的治疗方法的有效性。CTCL是一个独特的模型来研究 微环境，允许以最低的发病率对患者肿瘤进行多点和连续采样，因此 代表了一种分析检查点抑制疗法的敏感性和耐药性的范例。

Cutaneous T-cell lymphoma (CTCL) represents a blood cancer that originates in the skin. Unfortunately, this disfiguring malignancy continues to be incurable. The etiology of this disease remains to be elucidated. The lymphoma grows in an environment that includes a spectrum of non-malignant immune cells. Rather than destroying the cancer, the non-malignant cells appear to foster its growth. There is compelling evidence that the immunologic response against the cancer is blunted by inhibitory molecules. However, the specific signals that create a permissive microenvironment are unknown. It is suspected that the expression of microRNAs that regulate gene expression, and their targets known as immune checkpoint molecules such as PD1 and PD-L1, help create the permissive environment in CTCL. Overall, changes in checkpoint expression patterns have been reported in other malignancies and are associated with alterations in the microenvironment, yet their roles have not been extensively studied in CTCL. Very little is known about the use of checkpoint inhibitors in the treatment of this disease, but the investigators' early experience with blockade of the PD1/PD-L1 interaction showed encouraging outcomes. In addition, the investigators have clinical experience with lenalidomide, an immunomodulatory drug that may also affect the interaction of the lymphoma with its microenvironment. On the basis of the preliminary studies, a phase I/II clinical trial investigating the safety and efficacy of durvalumab, an inhibitor of the PD- L1/PD1 tumor interaction, alone or with lenalidomide, is being conducted, with highly promising and safe results to date. These two agents also showed a favorable safety profile in a multiple myeloma trial. In Aim 2, the quantitative characterization of the dysregulated immunophenotypic profile in CTCL will be determined using advanced microscopy techniques (multispectral imaging, high resolution microscopy), and serum and skin pro- inflammatory cytokines will be correlated with response. In Aim 3, preclinical experiments are designed to identify mechanisms that dictate expression of critical immune checkpoint regulators. It is expected that baseline immune checkpoint and/or miRNA signatures will be linked to anti-tumor response and that down- regulation of the aberrant immune checkpoint expression in CTCL will have therapeutic benefits. It is anticipated that PD1/PD-L1 blockade will decrease cancer growth and will correlate with reversal of the permissive microenvironment. The compelling preliminary data provide rationale for this project with correlative aims important determinants toward understanding which patients are likely to respond to therapy, so that this immunotherapy in the future can be selected for those individuals who most likely benefit from this treatment. In addition, mechanistic insights gained from the preclinical studies will identify potential new targets and pathways to enhance the efficacy of this planned therapeutic approach. CTCL is a unique model to study the microenvironment, allowing for multi-site and serial sampling of patients tumors with minimal morbidity, and thus represents a paradigm for dissecting susceptibility and resistance to checkpoint inhibition therapy.