Inge Verbrugge
The Netherlands Cancer Institute, The Netherlands
Title: Radio-immunotherapy of cancer: Therapeutic efficacy, underlying mechanisms and potential applications
Biography
Biography: Inge Verbrugge
Abstract
Radiotherapy is one of the most successful cancer therapies but may benefit from coincident or subsequent immunotherapy. We designed novel combinations of radiotherapy with immunomodulatory monoclonal antibodies (mAbs) that were evaluated in pre-clinical mouse breast cancer models. We demonstrate that in combination with both single-dose and fractionated radiotherapy, mAbs designed to enhance T-cell function [anti-(α)-CD137] and relieve immunosuppression through blocking T-cell inhibitory signaling [α-programmed death (PD)-1] induce tumor regression in up to 100% of mice. Radio-immunotherapy induced immunological memory in cured mice and CD8+ T-cells were critical for its therapeutic efficacy. Radiotherapy up regulates MHC class I (MHCI) expression on tumor cells, which may further support immune-mediated killing. We show that this involves mTOR activation by ionizing radiation by a still unresolved mechanism. Yet, mTOR is important as mTOR inhibition almost completely abrogated the therapeutic effect of radio-immunotherapy. We conclude that radio-immunotherapy effectively cures mice that bear established mammary tumors and that therapy response is critically dependent on the activity of cytotoxic T-lymphocytes as well as on mTOR signaling. We predict that other tumor types to which T-cells are present in the peripheral repertoire and in which radiotherapy is used as a primary course of treatment, will also respond to radio-immunotherapy.