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:10376292
- 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 2024-03-31
- 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.
摘要:
胶质母细胞瘤(GBM)是成人中最常见和最具侵袭性的原发性恶性脑肿瘤。目前,
没有有效的治疗方法,这种疾病是普遍致命的,中位总生存期不到
在接受标准治疗的患者中超过15个月。癌症免疫疗法具有巨大的
GBM治疗的承诺,越来越多的证据表明,提高身体的免疫系统,
有助于消除高度侵袭性和晚期肿瘤,包括那些对传统疗法有抵抗力的肿瘤。
然而,尽管最近癌症免疫疗法在其他实体瘤中取得了成功,但其对肿瘤的有效性仍然存在局限性。
GBM仍不清楚。此外,即使对于高免疫原性肿瘤,也只有一小部分患者
可能是响应者。因此,迫切需要开发免疫疗法,
对GBM患者持续有效。我们最近发现标准治疗化疗药物
用于GBM的药物替莫唑胺(TMZ)可以通过一种机制诱导肿瘤内的免疫原性变化,
是独特的和新颖的,从他们的良好表征的DNA损伤作用。暴露于TMZ的GBM细胞
经历内质网(ER)应激反应的显著升高,
ER伴侣蛋白钙网蛋白(CRT)易位至质膜。CRT是促吞噬细胞
一种分子,其发出募集专职抗原呈递细胞(APC)用于吞噬清除的信号。
然而,TMZ诱导的CRT易位单独不足以促进APC的显著肿瘤清除,
这表明GBM使用额外的逃避信号来避免被先天免疫系统根除。
我们随后发现,抗吞噬CD47在GBM中过表达。虽然封锁
CD47作为多种人类癌症的潜在疗法已经被研究,其抗肿瘤作用已经被证实。
不一致。因此,基于这些观察,我们假设,
TMZ的CRT和CD47信号传导的阻断都是产生一致和有效的抗GBM所必需的
应答APCs增强GBM吞噬和肿瘤相关抗原交叉呈递
随后增强抗肿瘤T细胞适应性应答。我们的建议将机械地决定如何
TMZ与CD47阻断剂引发抗原特异性抗GBM T细胞应答,并评估治疗效果。
针对TMZ敏感性和TMZ抗性GBM的组合治疗的效用。拟定的研究将
在植入小鼠的患者来源的GBM异种移植物模型中验证联合治疗的临床效用
重建人体免疫系统如果成功,我们的研究将证明,
试剂可具有免疫原性,其可用于增强GBM免疫治疗,
生成相关临床前依据,以支持TMZ和抗CD47的进一步临床研究
用于治疗GBM,特别是那些对TMZ具有抗性的GBM的组合。
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Considerations for designing preclinical cancer immune nanomedicine studies.
- DOI:10.1038/s41565-020-00817-9
- 发表时间:2021-01
- 期刊:
- 影响因子:38.3
- 作者:Jiang W;Wang Y;Wargo JA;Lang FF;Kim BYS
- 通讯作者:Kim BYS
The Reciprocity between Radiotherapy and Cancer Immunotherapy.
放射治疗和癌症免疫治疗之间的相互作用。
- DOI:10.1158/1078-0432.ccr-18-2581
- 发表时间:2019-03-15
- 期刊:
- 影响因子:0
- 作者:Wang Y;Liu ZG;Yuan H;Deng W;Li J;Huang Y;Kim BYS;Story MD;Jiang W
- 通讯作者:Jiang W
Immunomodulating Nanomedicine for Cancer Therapy.
用于癌症治疗的免疫调节纳米药物。
- DOI:10.1021/acs.nanolett.8b02340
- 发表时间:2018-11-14
- 期刊:
- 影响因子:10.8
- 作者:Liu Z;Jiang W;Nam J;Moon JJ;Kim BYS
- 通讯作者:Kim BYS
Nanotechnology platforms for cancer immunotherapy.
- DOI:10.1002/wnan.1590
- 发表时间:2019-11
- 期刊:
- 影响因子:0
- 作者:Zhaogang Yang;Yifan Ma;Hai Zhao;Yuan Yuan-Yuan;Betty Y. S. Kim
- 通讯作者:Zhaogang Yang;Yifan Ma;Hai Zhao;Yuan Yuan-Yuan;Betty Y. S. Kim
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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:
10000176 - 财政年份:2018
- 资助金额:
$ 34.63万 - 项目类别: