Enhancing the efficacy of immunotherapy in DLBCL using rational combination approaches

使用合理的组合方法提高DLBCL免疫治疗的疗效

• 批准号: 10247897
• 负责人: Cheryl A London
• 金额: $ 69.96万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247897
• 关键词: Adverse event; Animal Model; B-Cell Activation; Biological; Biological Assay; Biological Markers; Biopsy; Cancer Patient; Canis familiaris; Categories; Clinical; Clinical Trials; Combination immunotherapy; Common Hematopoietic Neoplasm; Cytotoxic Chemotherapy; Data; Data Set; Disease; Disease remission; Dog Diseases; Doxorubicin; Drug Targeting; Enrollment; Future; Goals; Human; Immune; Immune checkpoint inhibitor; Immunotherapeutic agent; Immunotherapy; Lymphoma; Modeling; Molecular Genetics; Morbidity - disease rate; Mus; Mutation; Outcome; PTEN gene; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Progression-Free Survivals; Protocols documentation; Quality of life; Regimen; Regulatory T-Lymphocyte; Relapse; Sampling; TNF receptor-associated factor 3; Testing; Therapeutic; Time; Toxic effect; Tumor-infiltrating immune cells; advanced disease; anti-CD20; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; base; chemotherapy; design; disorder control; experience; genomic data; genomic profiles; high risk; human model; immunodeficient mouse model; improved; improved outcome; inhibitor/antagonist; large cell Diffuse non-Hodgkin' s lymphoma; molecular phenotype; novel; novel therapeutics; pilot trial; potential biomarker; predictive marker; prospective; prospective test; response; rituximab; side effect; small molecule; small molecule inhibitor; standard of care; success; targeted treatment; therapy resistant; tositumomab; transcriptome sequencing; treatment strategy; trial comparing; trial design; tumor

Project Summary/Abstract While small molecule inhibitors have made an impact in human diffuse large B-cell lymphoma (DLBCL), immunotherapy, specifically using anti-CD20 based approaches, has had the most profound effect on treatment strategies and long-term outcomes. Despite this progress, up to 40% of patients will ultimately succumb to their disease. Furthermore, even when treatment is successful, cytotoxic chemotherapy carries a high risk of long- term morbidities that impact quality of life. The recent success of targeted therapies and immune checkpoint inhibitors in the setting of lymphoma demonstrates the potential for additional progress in long-term disease control of DLBCL, with less toxicity. The molecular and genetic phenotype of canine DLBCL has been studied and it often resembles the activated B cell (ABC) category typically associated with aggressive DLBCL in people. Moreover, there is now substantial data that specific genetic changes and pathway aberrations are conserved across dogs and people with DLBCL supporting the notion that the canine disease can be used as a relevant spontaneous large animal model of the human counterpart. Toward this end, the purpose of this proposal is to use dogs with spontaneous naïve DLBCL to rapidly evaluate rational small molecule/immunotherapy combination approaches, with the ultimate goal of identifying the most effective combination to move forward in human patients with DLBCL. Specifically, we hypothesize that optimal combinations of anti-CD20, anti- PD1, XPO1 inhibition, NAMPT/PAK4 and PI3Kdelta inhibition will have better outcomes than doxorubicin based chemotherapy, resulting in a “chemo-free” blueprint for future human trials. Using an adaptive mini-pilot trial approach, those combinations deemed antagonistic and/or associated with unacceptable adverse events can be rapidly removed from consideration, while those with clear therapeutic promise can be most effectively studied in the front-line setting and enhanced. We will accomplish this by first determining the optimal chemo-free regimen with small molecule/ anti-CD20 combinations, then identifying the optimal chemo-free regimen with small molecule/anti-PD1 combinations and finally, by evaluating a frontline chemo-free novel combination regimen in canine DLBCL to demonstrate superiority to standard R-CHOP-based chemotherapy. Additionally, we will interrogate correlative biomarkers based on RNA sequencing of tumor samples obtained from dogs enrolled into the prospective trials and develop signatures that can be used to predict not only response to therapy, but more importantly long-term progression-free survival. Together, the data generated from this proposal will create a framework for effectively leveraging information gained from integrated immunotherapeutic trials in canine patients with DLBCL to develop chemo-free strategies that ultimately improve human outcomes.

项目总结/文摘