Several PD-1/PD-L1 pathway inhibitors were recently FDA approved for various solid tumor malignancies. While for every 10 patients with cutaneous melanoma 3-4 patients will have shrinkage and perhaps durable response, less than 2 out of 10 patients with any other cancer will have any clinical benefit. This is an extremely important problem to be solved because the checkpoint immunotherapies are expensive, lifelong treatments with potential side effect and considerable economic burden in health care in the years to come. In order to solve the low response rate of checkpoint immunotherapy, its combination with other treatment methods are also being widely evaluated to improve the overall response rate. Among them, the combination of PD-1 inhibitor with Indoleamine2,3-dioxygenase (IDO1) inhibition draws special interest in the field due to the special role of IDO1 played in immunotherapy. IDO1 is an enzyme whose gene expression is positively regulated by interferon-gamma (IFN?), an immune cytokine that is only produced by immune cell subsets (natural killer, natural killer T cells, CD4 and CD8 T cells, innate lymphoid cells). Therefore, only tumors bearing tumor-infiltrating immune cells (the so called ?inflamed?) are expected to produce IDO1. Second, IDO1 breaks down the essential amino acid tryptophan that is required for immune cell activation. Elevated IDO1 expression and activity will not only cause tryptophan depletion, but the resulting accumulation of kynurenine metabolites will also block T cell activation, induce T cell apoptosis, and promote the differentiation of nave T cells into CD4+ regulatory T cells that further inhibit CD8+ effector T cells. Clinical importance of the IDO1 pathway is reflected upon the clinical development of specific IDO1 inhibitors who in combination with PD-1 inhibitors have shown significantly higher antitumor activity across various solid tumors in early clinical studies compared with either agent alone. This fast advancement and dynamic nature of immune system prompt the urgent need to monitor IDO activity repetitively in vivo. In this proposal, we aim to synthesize and evaluate novel 18F labeled agents for IDO1 PET imaging based on both IDO1 substrate and IDO1 inhibitors. Compared with 11C-AMT, our agents not only allow easy synthesis and longer half-life, but also has improved target specificity (for example by blocking hydroxynation at 5 position of Trp ring). We anticipate that results from this grant proposal will allow us to monitor IDO1 activity non-invasively and repetitively in vivo, which will provide the foundation for testing these probes in future multicenter clinical trials using PD-1 inhibitors alone to evaluated whether there is tumor-infiltrating immune cells; or in combination with IDO1 inhibitors across various cancers to monitor IDO1 expression profile during the treatment and select the best time point and effect dosage based on each patient?s profile (personalized medicine).
This proposal describes a unique collaboration between basic scientists and physician at the University of North Carolina-Chapel Hill, wherein discoveries made at ?bench? have a clear future pathway for clinical translation. The proposed research aims to develop IDO-1 PET agents that could help us select patients that would likely response to the novel checkpoint immunotherapy and guide corresponding treatment plan (to use PD-1 alone or in combination with IDO inhibitors). The success of our approach will not only fill the gap between patient screening/selection and personalized treatment, but also reduce the economic burden in health care. .
