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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.

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：
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。