Immune modulation of radiation therapy with Flt3 ligand

项目摘要 这项建议是一个独特的合作之间的一个小，但全面的能力生物技术公司 和一个专门从事放射治疗的学术机构。立体定向放射外科（SRS）正在 常用于控制有限转移患者的肉眼可见肿瘤。SRS的成功 在控制肉眼可见的疾病方面，产生了将SRS与全身性药物相结合的热情， 例如细胞毒性化疗剂和生物靶向剂 转移性癌症目的是在全身化疗的同时， 以微小的癌细胞为目标在全身疗法中，免疫疗法具有潜力， 与RT整合以诱导肿瘤特异性免疫反应，从而使身体自身的免疫系统能够发挥作用。 免疫系统靶向放射后未消融的残留和转移性肿瘤细胞 单独治疗。由于放射治疗导致肿瘤相关抗原从肿瘤细胞中释放， 死亡的肿瘤细胞，增加专职抗原呈递细胞的数量和活性， 树突状细胞可增强有效肿瘤免疫的诱导。我们已经证明 Fms样酪氨酸激酶3配体（Flt3L）的施用显著增加了细胞凋亡的数量。 树突状细胞，并与放射治疗协同作用，以改善肺的临床前模型中的存活率 癌症和非小细胞肺癌患者的初步人体试验结果。 该提案旨在通过扩大临床经验来扩大这些令人兴奋的发现， 治疗走向商业化，以获得更多的患者。该提案还包括 在临床试验中引入靶向CD40的树突状细胞活化抗体， 已经显示出与Flt3L和放射疗法协同作用。为了支持临床研究， 将生产临床级Fltr3L和CD40激动剂抗体。

Project Summary 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 metastases. 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 and in preliminary results from a pilot human trial of patients with non-small cell lung cancer. This proposal aims to broaden these exciting findings by expanding the clinical experience to move the therapy towards commercialization for greater patient access. The proposal also includes introduction into the clinical trial of a dendritic cell activating antibody that targets CD40, a pathway that has been shown to synergize with Flt3L and radiation therapy. To support the clinical study, clinical grade Fltr3L and the CD40 agonist antibody will be manufactured.