权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
Betty Kim
金额：
$ 34.63万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
https://reporter.nih.gov/project-details/10376292
关键词：
Adult Advanced Malignant Neoplasm Affect Alkylating Agents Anti-CD47 Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Antitumor Response CD47 gene Cell membrane Cells Clinical Clinical Trials Combined Modality Therapy Cross Presentation Cytotoxic agent DNA DNA Damage Databases Development Disease Eating Effectiveness Endoplasmic Reticulum Exhibits Exposure to Glioblastoma Human Immune Immune system Immunity Immunotherapy Implant Innate Immune System MGMT gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Memory Molecular Molecular Chaperones Mus Patients Pattern Phagocytes Phagocytosis Plasma Cells Primary Brain Neoplasms Process Property Proteins Resistance Role Signal Transduction Signaling Molecule Solid Neoplasm T cell response T-Lymphocyte The Cancer Genome Atlas Therapeutic Tumor Antigens Up-Regulation Xenograft Model Xenograft procedure anti-tumor immune response antigen-specific T cells antitumor effect base biological adaptation to stress calreticulin cancer cell cancer immunotherapy chemotherapeutic agent chemotherapy clinical investigation conventional therapy effective therapy endoplasmic reticulum stress experience immunogenic immunological status macrophage molecular subtypes novel overexpression pre-clinical reconstitution recruit response standard care standard of care success temozolomide tumor tumor 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.

文摘:

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：
Nature nanotechnology
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：
Clinical cancer research : an official journal of the American Association for Cancer Research
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。