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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：
10582566
负责人：
Christiane Querfeld
金额：
$ 55.24万
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 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10582566
关键词：
Address Affect Antitumor Response Biological CD28 gene CD8-Positive T-Lymphocytes CTLA4 gene Cells Chronic Clinical Clonal Expansion Combined Modality Therapy Complex Correlative Study Critical Pathways Cutaneous T-cell lymphoma Data Dendritic Cells Disease Down-Regulation Environment Etiology Experimental Designs Fostering Future Gene Expression Genetic Genetic Transcription Goals Growth Hematopoietic Neoplasms Imaging technology Immune Immune checkpoint inhibitor Immune response Immunologic Markers Immunologics Immunophenotyping Immunotherapy In Situ In Vitro Individual Infiltration Inflammation Inflammatory Knowledge Link Lymphoma Lymphoma cell Macrophage 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 inhibitors 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 Prognosis 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 Activation T-Cell Lymphoma T-Cell Receptor T-Lymphocyte Techniques Therapeutic Toxic effect Treatment Efficacy Work anti-PD-L1 cancer infiltrating T cells checkpoint inhibition clinically relevant cytokine early experience exhaustion experience immune checkpoint immune modulating agents immunoregulation improved outcome insight lenalidomide mRNA Expression memory CD4 T lymphocyte monocyte novel therapeutics patient response permissiveness 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 spectrograph superresolution microscopy therapeutically effective 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）是一种起源于皮肤的血癌。不幸的是,这