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Role of Heat Shock Protein 70 as a Mediator and Therapeutic Target in T-cell Lymphomas

热休克蛋白 70 作为 T 细胞淋巴瘤介质和治疗靶点的作用

基本信息

批准号：
10669221
负责人：
Javeed Iqbal
金额：
$ 47.42万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-20 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669221
关键词：
Address Adoptive Cell Transfers African African ancestry Amanitins Antibodies Antibody-drug conjugates Area Asian B-Cell Lymphomas B-Cell NonHodgkins Lymphoma B-Lymphocytes Binding Biological Assay Blood CAR T cell therapy Cancerous Cell Line Cell model Cell surface Cells Cellular biology Classification Clinic Clinical Codon Nucleotides Country Cutaneous Cutaneous T-cell lymphoma Data Deacetylase Development Diagnosis Disease Dose Doxorubicin Drug Approval Effectiveness Exclusion Gene Expression Gene Expression Profiling Genetic Genomic approach Genomics Goals Growth Heat-Shock Proteins 70 Hematologic Neoplasms Heterogeneity Human Immunophenotyping In Vitro Incidence Industry Interferons Janus kinase Ki-1 Large-Cell Lymphoma Link Lymphoma Malignant Neoplasms Mediator Medical Membrane Messenger RNA Modeling Molecular Molecular Profiling Monoclonal Antibodies Morphology Mus Mycosis Fungoides Non-Hodgkin&apos s Lymphoma Normal Cell Normal tissue morphology Nuclear Oncogenes Oncogenic Outcome Pathway interactions Patient-Focused Outcomes Patients Pattern Peripheral Pharmaceutical Preparations Physiological Population Prognosis Protein Overexpression Proteome Proteomics Regimen Relapse Research Role STAT protein Sampling Schedule Sezary Syndrome Signal Transduction Skin Subgroup System T cell therapy T-Cell Lymphoma T-Cell and NK-Cell Neoplasm T-Lymphocyte TNFRSF8 gene Testing Therapeutic Therapeutic Monoclonal Antibodies Thymus Gland United States Variant Vorinostat Work Xenograft procedure anaplastic lymphoma kinase beta-Chemokines biomarker driven cancer cell chemokine receptor chimeric antigen receptor chimeric antigen receptor T cells cytotoxicity differential expression efficacy evaluation efficacy validation experimental study improved improved outcome in vitro Model in vitro activity in vivo in vivo Model inhibitor kinase inhibitor lymph nodes neoplastic new therapeutic target non-Hodgkin&apos s lymphoma patients novel novel therapeutics patient derived xenograft model peripheral blood rational design statistics synergism therapeutic target transgene expression translational approach tumor vector

项目摘要

PROJECT SUMMARY / ABSTRACT Non-Hodgkin lymphoma (NHL) is the most frequent hematologic malignancy, and is divided into B-cell and T- cell lymphoma subtypes. B-cell NHL patient outcomes have improved dramatically with the development of new targeted therapies, but similar progress has not been made against peripheral T-cell (PTCL) and cutaneous T-cell (CTCL) lymphomas. Indeed, patients who relapse after initial PTCL therapy have a less than 1 year median survival, and patients with the CTCL subtype mycosis fungoides that is advanced, or that has Sézary syndrome with skin, blood, and lymph node disease, have a median survival of one year from diagnosis. Thus, the identification of novel targets and drugs with activity against PTCL and CTCL will be critical for this area of unmet medical need to help cure these diseases, which have not been a major focus for industry-sponsored research due to their heterogeneity and lower incidence. To address this challenge, we investigated the cell surface proteome of PTCL and CTCL cell lines and found Heat shock protein 70 (HSP70) to be highly expressed. Then, we developed monoclonal antibodies to human HSP70 and found that one, designated clone 239-87, recognized HSP70 on PTCL and CTCL cells but not on normal T-cells. To convert 239-87 into a drug, we linked it to monomethyl auristatin E (MMAE) to generate an antibody-drug conjugate (ADC), which we found inhibited PTCL and CTCL cell line growth as well as and, in some cases, better than brentuximab vedotin (BV), another ADC already approved for T-cell NHL. Also, 239-87-MMAE showed synergy when combined with other therapies already used against PTCL and CTCL, including the deacetylase inhibitor vorinostat and the ADC BV. Next, we used the 239-87 single chain variable fragment sequence to create chimeric antigen receptor (CAR) guided T-cells, and these were activated in the presence of T-cell NHL cell lines. Finally, in a cell line-based xenograft, the 239-87-MMAE ADC cured mice with an aggressive PTCL variant. Our preliminary data support the central hypothesis that targeting cell surface HSP70 using an ADC or CAR T-cell therapy approach will be both novel and effective against PTCL and CTCL, and could ultimately improve patient outcomes. In order to test this hypothesis, we propose three aims: (1) To investigate the differential expression of HSP70 in PTCL and CTCL models, including in primary patient samples, and to perform studies to identify pathways in these cancer cells that regulate HSP70 expression; (2) To identify the best ADC and CAR T-cell construct based on our 239-87 antibody, and explore which combinations will show greatest synergy; and (3) To use in vivo models, including patient-derived xenografts, to determine effective strategies against these lymphomas that will work best in the clinic. Taken together, successful completion of these studies will increase our understanding of the role of HSP70 in PTCL and CTCL biology, provide the rationale to take these approaches to the clinic for patients with PTCL and CTCL who are looking for novel therapies and, ultimately, improve their outcomes.

项目概要/摘要非霍奇金淋巴瘤（NHL）是最常见的血液恶性肿瘤，分为 B 细胞和 T 细胞细胞淋巴瘤亚型。随着 B 细胞 NHL 患者预后的发展，新的靶向疗法，但针对外周 T 细胞 (PTCL) 和皮肤 T 细胞 (CTCL) 淋巴瘤。事实上，初次 PTCL 治疗后复发的患者的死亡率低于中位生存期 1 年，且患有晚期或已患有 CTCL 亚型蕈样肉芽肿的患者患有皮肤、血液和淋巴结疾病的塞扎里综合征的中位生存期为一年诊断。因此，对 PTCL 和 CTCL 具有活性的新靶点和药物的鉴定将是对于这一未满足的医疗需求领域至关重要，以帮助治愈这些疾病，这些疾病并不是主要关注点由于其异质性和较低的发生率，行业赞助的研究。为了应对这一挑战，我们研究PTCL和CTCL细胞系的细胞表面蛋白质组，发现热休克蛋白70（HSP70）得到高度表达。然后，我们开发了针对人类 HSP70 的单克隆抗体，并发现，命名为克隆239-87，可识别PTCL和CTCL细胞上的HSP70，但不能识别正常T细胞上的HSP70。转换将 239-87 转化为药物，我们将其与单甲基 auristatin E (MMAE) 连接以生成抗体-药物缀合物 (ADC)，我们发现它可以抑制 PTCL 和 CTCL 细胞系的生长，并且在某些情况下比 brentuximab vedotin (BV) 是另一种已获批准用于 T 细胞 NHL 的 ADC。此外，239-87-MMAE 显示与已用于治疗 PTCL 和 CTCL 的其他疗法（包括脱乙酰酶）联合使用时产生协同作用抑制剂伏立诺他和 ADC BV。接下来，我们使用239-87单链可变片段序列创建嵌合抗原受体 (CAR) 引导的 T 细胞，这些细胞在 T 细胞 NHL 存在的情况下被激活细胞系。最后，在基于细胞系的异种移植中，239-87-MMAE ADC 治愈了患有侵袭性 PTCL 的小鼠变体。我们的初步数据支持中心假设，即使用 ADC 或靶向细胞表面 HSP70 CAR T 细胞疗法对于 PTCL 和 CTCL 来说既新颖又有效，最终可能改善患者的治疗效果。为了验证这一假设，我们提出三个目标：（1）研究 HSP70 在 PTCL 和 CTCL 模型中的差异表达，包括在主要患者样本中，以及进行研究以确定这些癌细胞中调节 HSP70 表达的途径； (2) 至基于我们的 239-87 抗体确定最佳 ADC 和 CAR T 细胞构建体，并探索哪些组合将显示出最大的协同效应； (3) 使用体内模型，包括源自患者的模型异种移植，以确定针对这些淋巴瘤的有效策略，该策略在诊所。总而言之，成功完成这些研究将加深我们对 HSP70 在 PTCL 和 CTCL 生物学中的应用，为将这些方法应用于临床治疗患有以下疾病的患者提供了理论依据： PTCL 和 CTCL 正在寻找新的疗法并最终改善其结果。