权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目摘要/摘要