Immune modulation of radiation therapy with Flt3 ligand

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.