Therapeutic modulation of the phagocytosis axis as a novel glioblastoma immunotherapy
吞噬轴的治疗调节作为一种新型胶质母细胞瘤免疫疗法
基本信息
- 批准号:10000176
- 负责人:
- 金额:$ 34.63万
- 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:2018-03-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAdvanced Malignant NeoplasmAffectAlkylating AgentsAnti-CD47AntibodiesAntigen PresentationAntigen-Presenting CellsAntigensAntitumor ResponseCD47 geneCell membraneCellsClinicalClinical TrialsCombined Modality TherapyCross PresentationCytotoxic agentDNADNA DamageDatabasesDevelopmentDiseaseEatingEffectivenessEndoplasmic ReticulumExhibitsExposure toGlioblastomaHumanImmuneImmune systemImmunityImmunotherapyImplantInnate Immune SystemMGMT geneMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of brainMemoryMolecularMolecular ChaperonesMusPatientsPatternPhagocytesPhagocytosisPlasma CellsPrimary Brain NeoplasmsProcessPropertyProteinsResistanceRoleSignal TransductionSignaling MoleculeSolid NeoplasmT cell responseT-LymphocyteThe Cancer Genome AtlasTherapeuticTumor AntigensUp-RegulationXenograft ModelXenograft procedureanti-tumor immune responseantigen-specific T cellsantitumor effectbasebiological adaptation to stresscalreticulincancer cellcancer immunotherapychemotherapeutic agentchemotherapyclinical investigationconventional therapyeffective therapyendoplasmic reticulum stressexperienceimmunogenicimmunological statusmacrophagemolecular subtypesnoveloverexpressionpre-clinicalreconstitutionrecruitresponsestandard carestandard of caresuccesstemozolomidetumortumor growth
项目摘要
ABSTRACT:
Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. Currently,
there is no effective therapy available, and the disease is universally fatal with a median overall survival of less
than 15 months among patients who received standard treatments. Cancer immunotherapy holds great
promises for GBM treatment, and growing evidence suggests that boosting the body's immune system can
help eliminate highly aggressive and advanced tumors, including those resistant to conventional therapies.
However, despite recent successes of cancer immunotherapies in other solid tumors, its effectiveness against
GBM remains unclear. Furthermore, even for highly immunogenic tumors, only a small percentage of patients
are likely responders. Therefore, there is an urgent need for the development of immunotherapies that are
consistently effective for GBM patients. We have recently identified that the standard-of-care chemotherapeutic
agent for GBM, temozolomide (TMZ), can induce immunogenic changes within the tumor via a mechanism that
is distinctive and novel from their well-characterized DNA damaging effects. GBM cells exposed to TMZ
experience a significant elevation in endoplasmic reticulum (ER) stress response with the corresponding
translocation of ER chaperone protein, calreticulin (CRT) to the plasma membrane. CRT is a pro-phagocytic
molecule that signals the recruitment for professional antigen presenting cells (APCs) for phagocytic clearance.
However, TMZ-induced CRT translocation alone is insufficient to promote significant tumor clearance by APCs,
suggesting that additional evasive signals are used by GBM to avoid eradication by the innate immune system.
We subsequently showed that the anti-phagocytotic CD47 is overexpressed in GBM. Although the blockade
of CD47 has been investigated as a potential therapy for multiple human cancers, its anti-tumor effect has
been inconsistent. Therefore, based on these observations, we hypothesize that the simultaneous induction of
CRT by TMZ and the blockade of CD47 signaling are both required to produce consistent and potent anti-GBM
responses. Enhanced GBM phagocytosis and tumor-associated antigen cross-presentation by APCs
subsequently heighten anti-tumor T cell adaptive response. Our proposal will mechanistically determine how
TMZ with CD47 blockade primes the antigen-specific anti-GBM T cell responses, and evaluate the therapeutic
utility of the combined treatment against TMZ-sensitive and TMZ-resistant GBMs. The proposed study will
validate the clinical utility of the combined therapy in patient-derived GBM xenograft models implanted in mice
with reconstituted human immune system. If successful, our study will demonstrate that conventional cytotoxic
agents may possess immunogenic properties that can be harnessed to enhance GBM immunotherapy and
generate relevant preclinical rationale to support further clinical investigations of TMZ and anti-CD47
combination for the treatment of GBM, particularly these resistant to TMZ.
抽象的:
胶质母细胞瘤(GBM)是成年人中最常见和侵略性的原发性恶性脑肿瘤。现在,
没有有效的疗法可用,这种疾病普遍致命,总体生存率较少
接受标准治疗的患者中的15个月。癌症免疫疗法很棒
GBM治疗的承诺以及越来越多的证据表明,增强身体的免疫系统可以
有助于消除高度侵略性和晚期肿瘤,包括对常规疗法的耐药性肿瘤。
但是,尽管最近在其他实体瘤中取得了癌症免疫疗法的成功,但其有效性
GBM仍然不清楚。此外,即使对于高度免疫原性肿瘤,只有一小部分患者
可能是响应者。因此,迫切需要开发免疫疗法
始终对GBM患者有效。我们最近确定了护理标准化学治疗性
GBM,替莫唑胺(TMZ)的药物可以通过一种机制诱导肿瘤内的免疫原性变化
与其特征良好的DNA破坏效应相关的独特和新颖。暴露于TMZ的GBM细胞
经历内质网(ER)应力反应的显着升高
ER伴侣蛋白,钙网蛋白(CRT)转移到质膜。 CRT是一种促细胞
标志着专业抗原呈递细胞募集的分子(APC)用于吞噬清除率。
但是,仅TMZ诱导的CRT易位不足以促进APC的大量肿瘤清除,
这表明GBM使用了其他回避信号,以避免先天免疫系统消除。
随后,我们表明抗毒性CD47在GBM中过表达。虽然是封锁
已研究CD47作为多种人类癌症的潜在疗法,其抗肿瘤作用具有
不一致。因此,基于这些观察,我们假设同时诱导
TMZ的CRT和CD47信号的封锁都需要产生一致且有效的抗GBM
回答。 APCS增强了GBM吞噬作用和与肿瘤相关的抗原交叉呈现
随后增强了抗肿瘤T细胞自适应反应。我们的建议将机械化确定如何
TMZ用CD47封锁素数抗原特异性抗GBM T细胞反应,并评估治疗性
对TMZ敏感和抗TMZ耐药的GBM的联合处理的实用性。拟议的研究将
验证植入小鼠的患者衍生的GBM异种移植模型中联合治疗的临床实用性
与重构的人类免疫系统。如果成功,我们的研究将证明常规的细胞毒性
药物可能具有可以利用的免疫原性,以增强GBM免疫疗法和
产生相关的临床前原理,以支持TMZ和Anti-CD47的进一步临床研究
治疗GBM的组合,尤其是这些对TMZ的抗药性。
项目成果
期刊论文数量(0)
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Betty Kim其他文献
Betty Kim的其他文献
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{{ truncateString('Betty Kim', 18)}}的其他基金
Microfluidics Array Based Sorting, Isolation, and RNA Analysis in Single Extracellular V csicles
基于微流体阵列的单个细胞外 V 颗粒的分选、分离和 RNA 分析
- 批准号:
10015368 - 财政年份:2019
- 资助金额:
$ 34.63万 - 项目类别:
Microfluidics Array Based Sorting, Isolation, and RNA Analysis in Single Extracellular V csicles
基于微流体阵列的单个细胞外 V 颗粒的分选、分离和 RNA 分析
- 批准号:
10487539 - 财政年份:2019
- 资助金额:
$ 34.63万 - 项目类别:
Microfluidics Array Based Sorting, Isolation, and RNA Analysis in Single Extracellular V csicles
基于微流体阵列的单个细胞外 V 颗粒的分选、分离和 RNA 分析
- 批准号:
9811934 - 财政年份:2019
- 资助金额:
$ 34.63万 - 项目类别:
Microfluidics Array Based Sorting, Isolation, and RNA Analysis in Single Extracellular V csicles
基于微流体阵列的单个细胞外 V 颗粒的分选、分离和 RNA 分析
- 批准号:
10327852 - 财政年份:2019
- 资助金额:
$ 34.63万 - 项目类别:
Therapeutic modulation of the phagocytosis axis as a novel glioblastoma immunotherapy
吞噬轴的治疗调节作为一种新型胶质母细胞瘤免疫疗法
- 批准号:
10376292 - 财政年份:2018
- 资助金额:
$ 34.63万 - 项目类别:
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