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

皮肤 T 细胞淋巴瘤：剖析检查点抑制疗法敏感性和耐药性的范例

基本信息

批准号：
9894772
负责人：
Christiane Querfeld
金额：
$ 56.84万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894772
关键词：
Address Affect Antitumor Response Biological CD28 gene CD8-Positive T-Lymphocytes CTLA4 gene Cells Chronic Clinical Combined Modality Therapy Complex Correlative Study Critical Pathways Cutaneous T-cell lymphoma Data Dendritic Cells Disease Down-Regulation Environment Etiology Expression Profiling Fostering Future Gene Expression Genetic Genetic Transcription Goals Growth Hematopoietic Neoplasms Image Imaging technology Immune Immune checkpoint inhibitor Immune response Immunologic Markers Immunologics Immunomodulators Immunotherapy In Situ In Vitro Individual Inflammation Inflammatory Knowledge Lead Link Lymphoma Lymphoma cell Malignant - descriptor Malignant Neoplasms Mature T-Lymphocyte Measures MicroRNAs Microscopy Modeling Molecular Molecular Profiling Morbidity - disease rate Multiple Myeloma Mus Mycosis Fungoides Myelogenous Non-Malignant Outcome PD-1 blockade PD-1/PD-L1 PD-L1 blockade PDL1 inhibitors PDL1 pathway Pathogenesis Pathway interactions Patients Pattern Phase Phase I/II Clinical Trial Phenotype Phosphorylation Population Predisposition Proliferating Proteins Public Health Publishing Randomized Regimen Reporting Research Personnel Resistance Resolution Role STAT3 gene Safety Sampling Serum Sezary Syndrome Signal Pathway Signal Transduction Site Skin T-Cell Lymphoma T-Cell Receptor T-Lymphocyte Techniques Therapeutic Toxic effect Treatment Efficacy Work anti-PD-L1 base checkpoint inhibition clinically relevant cytokine design early experience exhaustion experience experimental study immune checkpoint improved outcome insight lenalidomide mRNA Expression macrophage memory CD4 T lymphocyte monocyte novel therapeutics outcome forecast patient response phase I trial phase II trial phenotypic biomarker pre-clinical preclinical study predicting response profiles in patients programmed cell death ligand 1 programmed cell death protein 1 receptor receptor expression response therapy resistant tumor tumor microenvironment

项目摘要

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.

皮肤T细胞淋巴瘤（CTCL）代表起源于皮肤的血液癌。不幸的是，这个毁容性恶性肿瘤仍然是无法治愈的。该疾病的病因尚待阐明。这淋巴瘤在包括一系列非恶性免疫细胞的环境中生长。而不是破坏了癌症，非恶性细胞似乎促进了其生长。有令人信服的证据表明对癌症的免疫反应被抑制分子削弱。但是，具体信号创建宽松的微环境是未知的。怀疑调节的microRNA的表达基因表达及其靶标被称为免疫检查点分子，例如PD1和PD-L1，有助于创建 CTCL的允许环境。总体而言，检查点表达模式的变化已在其他恶性肿瘤，与微环境的改变有关，但它们的角色尚未在CTCL中进行了广泛的研究。关于使用检查点抑制剂在此治疗的情况下，知之甚少疾病，但研究人员对PD1/PD-L1相互作用的封锁的早期经历表明令人鼓舞结果。此外，研究人员还具有Lenalidomide（一种免疫调节药物）的临床经验这也可能影响淋巴瘤与其微环境的相互作用。基于初步研究，一项I/II期临床试验，研究了Durvalumab的安全性和功效，Durvalumab是PD-的抑制剂正在进行L1/PD1肿瘤相互作用，或者正在进行Lenalidomide，并具有高度有希望和安全的结果迄今为止。这两种药物在多发性骨髓瘤试验中也表现出了有利的安全性。在AIM 2中将使用CTCL中免疫表型的定量表征将使用晚期显微镜技术（多光谱成像，高分辨率显微镜）以及血清和皮肤前炎性细胞因子将与反应相关。在AIM 3中，临床前实验旨在识别决定关键免疫检查点调节剂表达的机制。预计基线免疫检查点和/或miRNA特征将与抗肿瘤反应有关 CTCL中异常免疫检查点表达的调节将具有治疗益处。这是预计PD1/PD-L1封锁将减少癌症的生长，并将与逆转相关宽松的微环境。引人入胜的初步数据为该项目提供了基本原理旨在了解哪些患者可能对治疗做出反应的重要决定因素，以便将来可以为那些最有可能从这种治疗中受益的人选择免疫疗法。在此外，从临床前研究中获得的机械见解将确定潜在的新目标和途径为了增强这种计划的治疗方法的功效。 CTCL是研究微环境，允许对发病率最小的患者肿瘤进行多部位和连续采样，从而代表了剖析敏感性和对检查点抑制疗法的抗性的范式。