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:10247897
- 负责人:
- 金额:$ 69.96万
- 依托单位:
- 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 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:Adverse eventAnimal ModelB-Cell ActivationBiologicalBiological AssayBiological MarkersBiopsyCancer PatientCanis familiarisCategoriesClinicalClinical TrialsCombination immunotherapyCommon Hematopoietic NeoplasmCytotoxic ChemotherapyDataData SetDiseaseDisease remissionDog DiseasesDoxorubicinDrug TargetingEnrollmentFutureGoalsHumanImmuneImmune checkpoint inhibitorImmunotherapeutic agentImmunotherapyLymphomaModelingMolecular GeneticsMorbidity - disease rateMusMutationOutcomePTEN genePathway interactionsPatientsPeripheral Blood Mononuclear CellPhenotypePlasmaProgression-Free SurvivalsProtocols documentationQuality of lifeRegimenRegulatory T-LymphocyteRelapseSamplingTNF receptor-associated factor 3TestingTherapeuticTimeToxic effectTumor-infiltrating immune cellsadvanced diseaseanti-CD20anti-PD-1anti-PD1 antibodiesanti-PD1 therapybasechemotherapydesigndisorder controlexperiencegenomic datagenomic profileshigh riskhuman modelimmunodeficient mouse modelimprovedimproved outcomeinhibitor/antagonistlarge cell Diffuse non-Hodgkin&aposs lymphomamolecular phenotypenovelnovel therapeuticspilot trialpotential biomarkerpredictive markerprospectiveprospective testresponserituximabside effectsmall moleculesmall molecule inhibitorstandard of caresuccesstargeted treatmenttherapy resistanttositumomabtranscriptome sequencingtreatment strategytrial comparingtrial designtumor
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.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Cheryl A London其他文献
Tissue factor-targeted immunotherapy of melanoma and triple negative breast cancer using a second generation ICON
- DOI:
10.1186/2051-1426-3-s2-p304 - 发表时间:
2015-11-04 - 期刊:
- 影响因子:10.600
- 作者:
Zhiwei Hu;Elizabeth McMichael;Amanda Campbell;Cheryl A London;William E Carson - 通讯作者:
William E Carson
Cheryl A London的其他文献
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{{ truncateString('Cheryl A London', 18)}}的其他基金
Optimizing integration of veterinary clinical research findings with human health systems to improve strategies for early detection and intervention
优化兽医临床研究结果与人类健康系统的整合,以改进早期检测和干预策略
- 批准号:
10764456 - 财政年份:2023
- 资助金额:
$ 69.96万 - 项目类别:
Resources and workforce development for the New England Regional Biosafety Laboratory
新英格兰地区生物安全实验室的资源和劳动力发展
- 批准号:
10793931 - 财政年份:2023
- 资助金额:
$ 69.96万 - 项目类别:
Generation of tumor specific immunity in canine osteosarcoma through dendritic cell hyperactivation
通过树突状细胞过度激活在犬骨肉瘤中产生肿瘤特异性免疫
- 批准号:
10688274 - 财政年份:2022
- 资助金额:
$ 69.96万 - 项目类别:
Cross-Disciplinary Research Training for Veterinary Students
兽医学生跨学科研究培训
- 批准号:
10666627 - 财政年份:2022
- 资助金额:
$ 69.96万 - 项目类别:
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:
10256800 - 财政年份:2017
- 资助金额:
$ 69.96万 - 项目类别:
c-Kit Mutations and Their Role in Tumor Biology
c-Kit 突变及其在肿瘤生物学中的作用
- 批准号:
6785866 - 财政年份:2002
- 资助金额:
$ 69.96万 - 项目类别:
c-Kit Mutations and Their Role in Tumor Biology
c-Kit 突变及其在肿瘤生物学中的作用
- 批准号:
7219356 - 财政年份:2002
- 资助金额:
$ 69.96万 - 项目类别:
c-Kit Mutations and Their Role in Tumor Biology
c-Kit 突变及其在肿瘤生物学中的作用
- 批准号:
6546067 - 财政年份:2002
- 资助金额:
$ 69.96万 - 项目类别:
c-Kit Mutations and Their Role in Tumor Biology
c-Kit 突变及其在肿瘤生物学中的作用
- 批准号:
6640368 - 财政年份:2002
- 资助金额:
$ 69.96万 - 项目类别:
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