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

基本信息

批准号：
10256800
负责人：
Cheryl A London
金额：
$ 69.65万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10256800
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 Genomics 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 high risk human model immunodeficient mouse model improved improved outcome inhibitor/antagonist large cell Diffuse non-Hodgkin&apos 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

项目摘要

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.

项目摘要/摘要虽然小分子抑制剂对人弥漫性大B细胞淋巴瘤（DLBCL）产生了影响，但免疫疗法，特别是使用基于抗CD20的方法的免疫疗法，对治疗具有最深远的影响策略和长期成果。尽管取得了这种进展，多达40％的患者最终会屈服于他们的疾病。此外，即使治疗成功，细胞毒性化学疗法也具有长期的高风险影响生活质量的术语。有针对性疗法和免疫切除点的最新成功在淋巴瘤的情况下抑制剂证明了长期疾病进展的潜力控制DLBCL，毒性较小。 DLBCL的分子和遗传表型已经研究了它通常类似于激活的B细胞（ABC）类别，通常与人中的侵略性DLBCL相关。此外，现在有大量数据表明特定的遗传变化和途径像差是保守的跨狗和DLBCL的人支持犬类疾病可以用作相关的观念人类对应物的赞助大型动物模型。为此，该提议的目的是使用具有赞助的幼稚DLBCL的狗快速评估有理小分子/免疫疗法结合方法的最终目标是确定最有效的组合以前进 DLBCL的人类患者。具体而言，我们假设抗CD20的最佳组合 PD1，XPO1抑制作用，NAMPT/PAK4和PI3KDELTA抑制作用将比阿霉素更好基于化学疗法，为未来的人类试验提供了“无化学”蓝图。使用自适应迷你驾驶试验方法，这些组合被认为是拮抗和/或与不可接受的对手有关的事件可以迅速从考虑因素中删除，而那些具有明确治疗诺言的人可以是最多的有效地研究前线设置并增强。我们将首先确定最佳与小分子/抗CD20组合的无化学方案，然后识别最佳化学疗法具有小分子/抗PD1组合的方案，最后，通过评估一条无化学化学的小说犬DLBCL中的组合方案表现出与标准基于R-CHOP化学疗法的优越性。此外，我们将根据获得的肿瘤样品的RNA测序询问相关生物标志物从参加前瞻性试验的狗，开发签名，不仅可以预测对治疗的反应，但更重要的是长期无进展生存。一起生成的数据从该提案中将创建一个框架，以有效利用从集成中获得的信息 DLBCL的犬类患者的免疫治疗试验，以开发无化学策略，最终改善人类的结果。