Grant: Project Grant

The most significant recent advance in oncology is the remarkable success of new drugs which harness the immune system to treat advanced metastatic disease of a number of different cancers. Foremost among these drugs are "immune checkpoint inhibitor" (ICI) antibodies. However, a dose of reality has set in to temper some of the initial euphoria about these drugs. First, they are enormously expensive, placing a likely unsustainable strain on health care system budgets. Second, only minor subsets of patient (an average of ~15%) benefit from receiving ICIs. Third, they can be very toxic causing a number of immune related adverse events (irAEs). Finally, tumors which initially respond to ICI therapy usually acquire resistance and relapse. A strategy being studied to improve the efficacy of ICIs is by combination with other types of drug. But this approach can exacerbate the problems of both overall toxicity and cost. This proposal is designed to evaluate a strategy to deal with both problems, and using it to combat ICI drug resistance, namely, evaluating the impact of using lower and hence less toxic doses of certain inexpensive off-patent oral chemotherapy drugs, but given in a close regular fashion - known as "metronomic" chemotherapy (MC) - which Dr. Kerbel's lab has helped pioneer; it has shown positive results in some recent phase III clinical trials, especially when used as maintenance therapies after initial induction chemotherapy. There is evidence that certain chemotherapy drugs given as MC can actually stimulate rather than suppress tumor immunity, the latter of which can occur when given at conventional 'maximum tolerated doses'. Finally, the research will involve use of a number of new mouse models that mimic the clinical treatment of metastatic disease, and new tumor models that are either minimally sensitive, or intrinsically resistant to an ICI, or which have acquired resistance after showing major durable tumor regressions.