Grant: Project Grant

Immunotherapy is currently an effective and viable treatment for several cancers and this approach complements the existing standard treatment modalities of surgery, radiation and chemotherapy. The recent successes of immunotherapy agents (known as immune checkpoint inhibitors or ICIs) for metastatic and refractory, advanced-staged cancers have ushered in a new treatment era for melanoma, lung, renal and bladder cancer, to name a few. It is expected that the maximal benefit of cancer immunotherapy will only be derived from combination approaches that allow for additive or synergistic effects to mount a full-blown immune attack against the cancer, and that block the development of resistance to immunotherapy. Our results to date, and the aims outlined in this proposal, will provide information for a novel and effective combination immunotherapy for cancers that combines an ICI with a drug, known as a Smac mimetic compound (SMC), which targets the inhibitors-of-apoptosis (IAP) proteins. The IAPs were identified by our group over 20 years ago and are now known to be important cancer causing genes. Our progress over the last four years, in experimentally validating the effectiveness of this combination approach, has laid the foundation for the initiation of appropriate clinical trials. In fact, we have recently begun a clinical trial in November of 2017 under the direction of our clinical colleague, Dr. Glenwood Goss at the Ottawa Hospital, in which he will be combining an ICI with a SMC to treat lung cancer patients. This CIHR proposal seeks to further understand the mechanisms of SMC/ICI combination synergy in eradicating various cancers using animal models. Our proof-of-principle studies will improve our understanding of cancer and ultimately see the translation of these combinations into the clinic to treat cancer.