SBIR-STTR Award

Radiation therapy (RT), specifically stereotactic radiosurgery (SRS), is frequently used in cancer treatment of localized disease. Emerging evidence provides a rationale for combining SRS with immunotherapy for treatment of incurable metastatic solid tumors. In addition to the direct killing of tumor cells, RT can cause the release of tumor antigens and molecules that promote an anti-tumor immune response. Further, RT can modify the tumor environment to increase the susceptibility of tumor cells for immune attack. We propose to combine RT with two powerful immune modulators, Fms-like tyrosine kinase ligand (Flt3L) and an antibody that activates CD27. Flt3L is a potent hematopoietic growth factor that mobilizes stem cells and greatly increases the number of dendritic cells in blood and tissues. The dendritic cells are critical for the initiation of the anti-tumor immune response. CD27 is key pathway for generating T cell immunity and memory. We will use an antibody that activates CD27 together with Flt3L to investigate the benefits of these immune modulators when combined with RT in mouse models to provide the basis for future clinical studies. By addressing the lack of immune based cancer therapies, our product offers the potential of considerable impact in reducing the toll of cancer.

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.

Public Health Relevance Statement:


Public Health Relevance:
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.

NIH Spending Category:
Cancer; Clinical Research; Lung; Lung Cancer

Project Terms:
Antigen-Presenting Cells; base; Biotechnology; Blood; cancer cell; Cancer Model; chemotherapy; Clinical; Clinical Research; Clinical Trials; Collaborations; cytotoxic; Data; Dendritic Cells; Disease; Disseminated Malignant Neoplasm; Early treatment; Environment; FLT3 ligand; GMP lots; Goals; Hematopoietic Cell Growth Factors; Immune; Immune response; Immune system; Immunologic Monitoring; immunoregulation; Immunotherapy; improved; in vivo Model; Individual; Institution; Interferon Type II; Irradiated tumor; Killings; Ligands; Lung; Lymphocyte; Lymphoid Tissue; Malignant neoplasm of lung; Measures; Microscopic; Modeling; Mus; Neoplasm Metastasis; neoplastic cell; Non-Small-Cell Lung Carcinoma; Patients; Phase; pre-clinical; Pre-Clinical Model; Predisposition; programs; public health relevance; Radiation; Radiation therapy; Radiosurgery; Regimen; Relative (related person); Research; Residual Tumors; response; Safety; Small Business Innovation Research Grant; stability testing; success; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxic effect; Translating; tumor; Tumor Antigens; Tumor Immunity; Vascular Endothelial Growth Factor Receptor-1; Vial device; Work