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 bodyandapos;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.Project Narrative Radiation Therapy, in addition to the direct killing of tumor cells, causes release of tumor antigens, and can modify the tumor environment to increase the susceptibility of tumor cells for immune attack. The hematopoietic growth factor Flt3 ligand greatly increases the number of dendritic cells in blood and tissues, which are critical for the initiation of the anti-tumor immune response, and this process can be further enhanced by activation of the dendritic cells by a CD40 agonist antibody. When combined, we expect these approaches to have greater overall anti-tumor activity relative to the individual treatments and may provide a safe and effective option for the treatment of patients with lung cancer and other tumors.