Immune modulation of radiation therapy with Flt3 ligand

Flt3配体对放射治疗的免疫调节

• 批准号: 9129622
• 负责人: Chandan Guha
• 金额: $ 53.89万
• 依托单位: CELLDEX THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9129622
• 关键词: Antigen-Presenting Cells; Biotechnology; Blood; Cancer Model; Clinical; Clinical Research; Clinical Trials; Collaborations; Data; Dendritic Cells; Disease; Disseminated Malignant Neoplasm; Early treatment; Environment; FLT3 ligand; FLT3LG gene; GMP lots; Goals; Health; Hematopoietic Cell Growth Factors; Immune; Immune response; Immune system; Immunologic Monitoring; Immunotherapy; Individual; Institution; Interferon Type II; Irradiated tumor; Ligands; Lung; Lymphocyte; Lymphoid Tissue; Malignant neoplasm of lung; Measures; Microscopic; Modeling; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Patients; Phase; Pre-Clinical Model; Predisposition; Radiation; Radiation therapy; Radiosurgery; Regimen; Research; Residual Tumors; Safety; Small Business Innovation Research Grant; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxic effect; Translating; Tumor Antigens; Tumor Immunity; Vascular Endothelial Growth Factor Receptor-1; Vial device; Work; base; cancer cell; chemotherapy; cytotoxic; immunoregulation; improved; in vivo Model; killings; neoplastic cell; pre-clinical; programs; response; stability testing; success; targeted agent; tumor

 DESCRIPTION (provided by applicant): This proposal is a unique collaboration between a small, but full capability biotechnology company and an academic institution specialized in radiation therapy. Stereotactic radiosurgery (SRS) is being frequently used to control macroscopic tumor in patients with limited metastates. The success of SRS in controlling macroscopic disease has generated enthusiasm in combining SRS with systemic agents, such as, cytotoxic chemotherapeutics and biologically targeted agents for the treatment of early metastatic cancer. The goal is to treat macroscopic tumor with SRS while systemic chemotherapy targets microscopic cancer cells. Among systemic therapeutics, immunotherapy has the potential to be integrated with RT to induce a tumor-specific immune response that could enable the body's own immune system to target residual and metastatic tumor cells that are not ablated after radiation therapy alone. Since radiation therapy results in the release of tumor associated antigens from the dying tumor cells, increasing the number and activity of professional antigen presenting cells such as dendritic cells could increase the induction of effective tumor immunity. We have shown that administration of Fms-like tyrosine kinase 3 ligand (Flt3L) significantly increases in the number of dendritic cells, and synergizes with radiation therapy to improve survival in preclinical models of lung cancer. This proposal aims to translate these exciting findings to patients by optimizing the regimen through the use of models, manufacturing clinical grade Fltr3L and performing a pilot clinical study to explore the safety, feasibility and efficacy of combining lung stereotactic body radiation therapy and Fltr3L therapy in patients with non-small cell lung cancer.

 描述(由申请人提供)： 这项提议是一家规模较小但能力全面的生物技术公司与一家专门从事放射治疗的学术机构之间的独特合作。立体定向放射外科治疗(SRS)经常用于控制转移有限的患者的肉眼肿瘤。SRS在控制宏观疾病方面的成功激发了人们将SRS与全身药物相结合的热情，如用于治疗早期转移癌的细胞毒性化疗药物和生物靶向药物。其目标是用SRS治疗肉眼肿瘤，而全身化疗针对的是微观癌细胞。在全身疗法中，免疫疗法有可能与RT相结合来诱导肿瘤特异性免疫反应，使人体自身的免疫系统能够针对仅经放射治疗而未被消融的残留和转移的肿瘤细胞。由于放射治疗导致肿瘤相关抗原从死亡的肿瘤细胞中释放出来，增加树突状细胞等专业抗原提呈细胞的数量和活性可以增加有效的肿瘤免疫诱导。我们已经证明，在临床前模型中，给予FMS样酪氨酸激酶3配体(Flt3L)显著增加树突状细胞的数量，并与放射治疗协同作用以提高存活率。 患上了肺癌。这项建议旨在通过使用模型来优化方案，制造临床级别的Fltr3L，并进行试点临床研究，以探索联合肺立体定向的安全性、可行性和有效性，从而将这些令人兴奋的发现转化为患者 非小细胞肺癌患者的全身放射治疗和Fltr3L治疗