Targeted Nanomedicines with Synergistic Chemotherapeutics to Enhance Immunotherapy of Metastatic Colorectal Cancer
靶向纳米药物与协同化疗增强转移性结直肠癌的免疫治疗
基本信息
- 批准号:10208813
- 负责人:
- 金额:$ 36.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAntibodiesAntigensAntitumor ResponseAzoxymethaneBiodistributionBiological MarkersCAR T cell therapyCD8-Positive T-LymphocytesCTLA4 geneCancer EtiologyCancer VaccinesCecumCell DeathCellsCessation of lifeChemicalsCleaved cellClinical TrialsCollaborationsColon CarcinomaColorectal CancerDNADNA Sequence AlterationDependenceDepositionDiagnosisDisseminated Malignant NeoplasmDistantDistant MetastasisDrug KineticsEpidermal Growth Factor ReceptorFDA approvedHumanImmuneImmune systemImmunotherapyImplantIn VitroInfiltrationInflammatory ResponseInjectionsMC38Microsatellite InstabilityMicrosatellite RepeatsMismatch RepairModelingMusNeoplasm MetastasisOperative Surgical ProceduresOrganPD-1 blockadePUVA PhotochemotherapyPatientsPermeabilityPhage DisplayPolymersProgression-Free SurvivalsProteinsRadiationRodentSignal TransductionSolidStable DiseaseSurvival RateTherapeuticTimeTreatment EfficacyTumor AntigensTumor-infiltrating immune cellsanti-PD-L1anti-PD-L1 antibodiesanti-PD1 antibodiesanti-canceranti-tumor immune responseantibody immunotherapybasebeta cateninbiomaterial compatibilitycancer cellcancer typeclinical translationcolon cancer patientscytotoxiceffective therapyexhaustionimmune activationimmune checkpointimmune checkpoint blockadeimmunogenicimmunogenic cell deathimprovedin vivometastatic colorectalmigrationmouse modelnanocarriernanomedicinenanoparticlenanoscalenanotherapeuticnovelnovel strategiesnovel therapeuticsoverexpressionoxaliplatinparticlepreclinical studyresponsetumortumor growth
项目摘要
Project Summary
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US.
Over half of CRC patients have regional or distant metastasis at the time of diagnosis, and
those with metastases to other organs have a 5-year survival rate of only ~12%. Checkpoint
blockade immunotherapy stimulates the host immune system to generate an antitumor immune
response, and has showed impressive results treating patients with mismatch repair (MMR)
deficient CRC. However, up to 95% of patients with metastatic CRC (mCRC) have MMR-
proficient, microsatellite-stable disease, who do not benefit from current immunotherapy. We
propose to develop nanoscale coordination polymer-based targeted nanomedicines containing
oxaliplatin and dihydroartemesinin (DHA), two immunogenic chemotherapeutics, for treating
mCRC. EGFR-targeted nanomedicines can exert direct cytotoxic effects on CRC cells, and
simultaneously induce and potentiate an antitumor immune effect. We propose the following
Specific Aims in order to develop a novel combined chemotherapeutic nanomedicine and
checkpoint blockade immunotherapy for the effective treatment of mCRC.
Aim 1: Evaluate the mechanisms of OxPt/DHA nanoparticle anticancer efficacy on CRC cells.
Aim 2: Actively target OxPt/DHA nanoparticles to CRC with an anti-EGFR Fab.
Aim 3: Evaluate the anticancer efficacy of OxPt/DHA and EGFR-OxPt/DHA nanoparticles in
orthotopic mouse models of CRC.
Aim 4: Elucidate the immune mechanisms of antitumor response in mice treated with OxPt/DHA
or EGFR-OxPt/DHA nanoparticles in combination with PD-L1 antibody.
Through these aims, we seek to establish a new paradigm for the treatment of mCRC by
increasing the response rate and therapeutic efficacy of immunotherapy for mCRC. Given that
checkpoint blockade immunotherapies have been approved by FDA to treat multiple types of
cancers, our strategy of utilizing chemotherapeutic nanomedicine as an immune system booster
to potentiate checkpoint blockade can have broad impact on treating other metastatic cancers.
项目摘要
结直肠癌(CRC)是美国与癌症相关死亡的第二大原因。
超过一半的CRC患者在诊断时患有区域或远处转移,并且
那些转移到其他器官的人的生存率仅为12%。检查点
封锁免疫疗法刺激宿主免疫系统以产生抗肿瘤免疫
反应,并显示出令人印象深刻的结果治疗不匹配修复患者(MMR)
不足的CRC。但是,多达95%的转移性CRC患者(MCRC)患有MMR-
熟练,微卫星稳定的疾病,他们没有从当前的免疫疗法中受益。我们
提议开发纳米级协调聚合物基于靶向的纳米药物,其中含有
奥沙利铂和二氢烷辛(DHA),两种免疫原性化学疗法,用于治疗
MCRC。 EGFR靶向的纳米医学可以对CRC细胞发挥直接的细胞毒性作用,而
同时诱导并增强抗肿瘤免疫作用。我们提出以下内容
具体目的是为了开发一种新型的化学治疗纳米医学和
检查点封锁免疫疗法,用于有效治疗MCRC。
目标1:评估CRC细胞上OX/DHA纳米颗粒抗癌疗效的机制。
AIM 2:用抗EGFR Fab主动将OX/DHA纳米颗粒靶向CRC。
AIM 3:评估OX/DHA和EGFR-OXPT/DHA纳米颗粒的抗癌疗效
CRC的原位小鼠模型。
AIM 4:阐明用OXPT/DHA处理的小鼠中抗肿瘤反应的免疫机制
或EGFR-OXPT/DHA纳米颗粒与PD-L1抗体结合使用。
通过这些目标,我们试图建立一个新的范式来治疗MCRC
提高免疫疗法对MCRC的反应率和治疗功效。鉴于
FDA已批准检查点封锁免疫疗法以治疗多种类型的
癌症,我们利用化学治疗性纳米医学作为免疫系统增强的策略
增强检查点的封锁可能会对治疗其他转移性癌症产生广泛的影响。
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)
专利数量(0)
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{{ truncateString('Wenbin Lin', 18)}}的其他基金
Tumor-Targeted Multimodality Nanoscale Coordination Polymers for Chemo-Immunotherapy of Metastatic Colorectal Cancer
用于转移性结直肠癌化疗免疫治疗的肿瘤靶向多模态纳米配位聚合物
- 批准号:
10639649 - 财政年份:2023
- 资助金额:
$ 36.98万 - 项目类别:
Nanoscale Coordination Polymers of Cyclic-di-nucleotides and Peptide Antigens for Effective Therapy of Metastatic Colorectal Cancer
环二核苷酸和肽抗原的纳米级配位聚合物可有效治疗转移性结直肠癌
- 批准号:
10731680 - 财政年份:2023
- 资助金额:
$ 36.98万 - 项目类别:
Nanoscale Metal-Organic Frameworks Enable Radiotherapy-Radiodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Generate Tumor Vaccines and Potentiate Immunotherapy of Head and Neck Cancers
纳米级金属有机框架实现放射治疗-放射动力学治疗并提供 CpG 寡脱氧核苷酸以生成肿瘤疫苗并增强头颈癌的免疫治疗
- 批准号:
10450090 - 财政年份:2020
- 资助金额:
$ 36.98万 - 项目类别:
Nanoscale Metal-Organic Frameworks Enable Radiotherapy-Radiodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Generate Tumor Vaccines and Potentiate Immunotherapy of Head and Neck Cancers
纳米级金属有机框架实现放射治疗-放射动力学治疗并提供 CpG 寡脱氧核苷酸以生成肿瘤疫苗并增强头颈癌的免疫治疗
- 批准号:
10684142 - 财政年份:2020
- 资助金额:
$ 36.98万 - 项目类别:
Nanoscale Metal-Organic Frameworks Enable Radiotherapy-Radiodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Generate Tumor Vaccines and Potentiate Immunotherapy of Head and Neck Cancers
纳米级金属有机框架实现放射治疗-放射动力学治疗并提供 CpG 寡脱氧核苷酸以生成肿瘤疫苗并增强头颈癌的免疫治疗
- 批准号:
10203892 - 财政年份:2020
- 资助金额:
$ 36.98万 - 项目类别:
Nanoscale Metal-Organic Frameworks Enable Radiotherapy-Radiodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Generate Tumor Vaccines and Potentiate Immunotherapy of Head and Neck Cancers
纳米级金属有机框架实现放射治疗-放射动力学治疗并提供 CpG 寡脱氧核苷酸以生成肿瘤疫苗并增强头颈癌的免疫治疗
- 批准号:
10060188 - 财政年份:2020
- 资助金额:
$ 36.98万 - 项目类别:
Nanoscale Coordination Polymers Co-deliver Chemotherapeutics and siRNAs for Efficacious Treatment of Resistant Ovarian Cancer
纳米级配位聚合物共同提供化疗药物和 siRNA,有效治疗耐药性卵巢癌
- 批准号:
10329991 - 财政年份:2018
- 资助金额:
$ 36.98万 - 项目类别:
Targeted Nanomedicines with Synergistic Chemotherapeutics to Enhance Immunotherapy of Metastatic Colorectal Cancer
靶向纳米药物与协同化疗增强转移性结直肠癌的免疫治疗
- 批准号:
10436331 - 财政年份:2018
- 资助金额:
$ 36.98万 - 项目类别:
Nanoscale Metal-organic Frameworks for Light Triggered and X-ray Induced Photodynamic Therapy of Head and Neck Cancers
用于光触发和 X 射线诱导光动力治疗头颈癌的纳米级金属有机框架
- 批准号:
9150514 - 财政年份:2015
- 资助金额:
$ 36.98万 - 项目类别:
Nanoscale Metal-organic Frameworks for Light Triggered and X-ray Induced Photodynamic Therapy of Head and Neck Cancers
用于光触发和 X 射线诱导光动力治疗头颈癌的纳米级金属有机框架
- 批准号:
8959832 - 财政年份:2015
- 资助金额:
$ 36.98万 - 项目类别:
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