Adjuvant therapy with agonistic antibodies to CD134 (OX40) increases local control following surgical or radiation therapy of cancer in mice

摘要

Tumor recurrence from residual local or micro-metastatic disease remains a problem in cancer therapy. In patients with soft-tissue sarcoma and patients with inoperable non-small cell lung cancer, local recurrence is common and significant mortality is caused by the subsequent emergence of metastatic disease. Thus, while the aim of the primary therapy is curative, the outcome may be improved by additional targeting of residual microscopic disease. We demonstrate in a murine model that surgical removal of a large primary sarcoma results in local recurrence in approximately 50% of animals. Depletion of CD8 T cells results in local recurrence in 100% of animals, indicating that these cells are involved in control of residual disease. We further demonstrate that systemic adjuvant administration of αOX40 at surgery eliminates local recurrences. In this model, αOX40 acts to directly enhance tumor antigen-specific CD8 T cell proliferation in the lymph node draining the surgical site, and results in increased tumor antigen-specific cytotoxicity in vivo. These results are also corroborated in a murine model of hypofractionated radiation therapy of lung cancer. Administration of αOX40 in combination with radiation significantly extended survival compared to either agent alone, and resulted in a significant proportion of long-term tumor free survivors. We conclude that αOX40 increases tumor antigen-specific CD8 T cell cytotoxic activity resulting in improved endogenous immune control of residual microscopic disease, and we propose that adjuvant αOX40 administration may be a valuable addition to surgical and radiation therapy for cancer.