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.
This proposal is based on the combination of two therapies, radiation therapy and the hematopoietic growth factor Flt3 ligand. 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. Flt3L greatly increases the number of dendritic cells in blood and tissues. The dendritic cells are critical for the initiation of theanti-tumor immune response. 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.
| Lázár-Molnár, Eszter; Scandiuzzi, Lisa; Basu, Indranil et al. (2017) Structure-guided development of a high-affinity human Programmed Cell Death-1: Implications for tumor immunotherapy. EBioMedicine 17:30-44 |
