Grant: Project Grant

The proposed Project Scheme has two major complementary aims. One is designed to leverage what is the most promising development in cancer therapy since the discovery of chemotherapy: the impact of new drugs which harness the body's immune system ability to fight cancer. The other is to develop improved mouse cancer models to better predict the clinical impact of immune therapy drugs when used in combination with other selected therapies to treat early or late stage distant metastatic disease. These other therapies are antiangiogenic drugs which target a tumor's blood supply, or chemotherapy given in a less toxic, continuous low dose ('metronomic') manner. The overall rationale is twofold. First, while the clinical impact of new immune therapies is remarkable, only a minor subset of patients (eg. 10-15%) derive dramatic benefits. So strategies are needed to improve these figures, e.g. to combine immunotherapy drugs creating 'cocktails' with different anti-cancer drugs - especially those where there is a sound underlying rationale. Second, initial assessment of new therapies is almost always done in mice - usually by treating localized 'primary' tumors - an approach historically poor in predicting what later happens in patients with distant metastatic disease. Dr. Kerbel's lab instead has focused on the development of postsurgical models of metastatic disease of different cancers to model "adjuvant" antiangiogenic drug or chemotherapy treatment of either early stage or advanced metastatic disease. His results have helped contribute to the initiation of phase II and III clinical trials, a number of which have now shown positive results. However, the models - which have been distributed to numerous investigators around the world - involve growth of human tumors in immune suppressed mice. This does not allow testing of immune therapy. So the next step is to develop a similar resource using immune competent mice for studying promising combination based immunotherapies.