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）： 该建议是一家小型但全能的生物技术公司与专门从事放射治疗的学术机构之间的独特合作。立体定向放射外科手术（SRS）经常用于控制转移有限的患者的宏观肿瘤。 SR在控制宏观疾病方面的成功在将SR与全身性剂相结合的热情中，例如细胞毒性化学治疗剂和生物学靶向剂，用于治疗早期转移性癌症。目的是用SRS治疗宏观肿瘤，而全身化疗则针对微观癌细胞。在全身治疗中，免疫疗法有可能与RT整合，以诱导肿瘤特异性免疫响应，该免疫响应可以使人体自己的免疫系统靶向单独放射治疗后未消除的残留和转移性肿瘤细胞。由于放射疗法导致肿瘤与垂死的肿瘤细胞释放相关的抗原，因此增加了专业抗原呈递细胞（例如树突状细胞）的数量和活性可能会增加有效的肿瘤免疫学的诱导。我们已经表明，FMS样酪氨酸激酶3配体（FLT3L）的给药显着增加了树突状细胞的数量，并与放射疗法合成以提高临床前模型的存活率 肺癌。该提案旨在通过使用模型，制造临床级FLTR3L并进行试验临床研究来探索结合肺立体定向的安全性，可行性和效率，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身体放射治疗和FLTR3L治疗。