Immune modulation of radiation therapy with Flt3 ligand

 描述（由申请人提供）： 该提案是一家小型但能力齐全的生物技术公司和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（SRS）常用于控制有限转移患者的肉眼可见肿瘤。SRS在控制宏观疾病方面的成功已经产生了将SRS与全身性药物（例如细胞毒性化疗剂和生物靶向药物）组合用于治疗早期转移性癌症的热情。目标是用SRS治疗宏观肿瘤，而全身化疗靶向微观癌细胞。在全身治疗中，免疫治疗有可能与RT结合以诱导肿瘤特异性免疫应答，这可以使身体自身的免疫系统靶向在单独的放射治疗后未消融的残留和转移性肿瘤细胞。由于放射治疗导致肿瘤相关抗原从垂死的肿瘤细胞中释放，因此增加专职抗原呈递细胞如树突状细胞的数量和活性可以增加有效肿瘤免疫的诱导。我们已经证明，在临床前模型中，Fms样酪氨酸激酶3配体（Flt3L）的施用显著增加树突状细胞的数量，并且与放射疗法协同作用以改善存活率 肺癌的症状该提案旨在通过使用模型优化方案，制造临床级Fltr3L，并进行初步临床研究，以探索肺立体定向结合的安全性，可行性和有效性，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。

 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.