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.

项目概要/摘要虽然小分子抑制剂对人类弥漫性大 B 细胞淋巴瘤 (DLBCL) 产生了影响，免疫疗法，特别是使用基于抗 CD20 的方法，对治疗产生了最深远的影响尽管取得了这些进展，但仍有多达 40% 的患者最终会屈服于他们的策略和长期结果。此外，即使治疗成功，细胞毒性化疗也会带来长期的高风险。影响生活质量的足月疾病最近靶向治疗和免疫检查点的成功。淋巴瘤治疗中的抑制剂显示出在长期疾病方面取得进一步进展的潜力控制 DLBCL，毒性较小已经研究了犬 DLBCL 的分子和遗传表型。它通常类似于激活的 B 细胞 (ABC) 类别，通常与人类侵袭性 DLBCL 相关。此外，现在有大量数据表明特定的遗传变化和途径畸变是保守的对患有 DLBCL 的狗和人进行的研究支持了犬类疾病可以用作相关疾病的观点为此，本提案的目的是建立人类对应的自发大型动物模型。使用患有自发性幼稚 DLBCL 的狗来快速评估合理的小分子/免疫疗法组合方法，最终目标是确定最有效的组合以推动具体来说，我们勇敢地选择了抗CD20、抗-CD20的最佳组合。 PD1、XPO1 抑制、NAMPT/PAK4 和 PI3Kdelta 抑制将比阿霉素获得更好的结果基于化疗，为未来的人体试验提供“无化疗”蓝图。小型试点试验方法，那些被认为具有拮抗性和/或与不可接受的不良反应相关的组合事件可以迅速从考虑中删除，而那些具有明确治疗前景的事件可能是最重要的我们将通过首先确定最佳方案来实现这一目标。采用小分子/抗 CD20 组合的免化疗方案，然后确定最佳免化疗方案小分子/抗 PD1 组合的治疗方案，最后通过评估一线无化疗新药联合方案在犬 DLBCL 中证明优于标准 R-CHOP 化疗。此外，我们将根据获得的肿瘤样本的 RNA 测序来询问相关生物标志物来自参加前瞻性试验的狗并开发出不仅可以用于预测的特征对治疗的反应，但更重要的是长期无进展生存期。该提案将创建一个框架，以有效利用从综合信息中获得的信息对患有 DLBCL 的犬患者进行免疫治疗试验，以开发最终改善病情的无化疗策略人类成果。