Development of IDO PET agents for immunotherapy

摘要 几种PD-1/PD-L1途径抑制剂最近被FDA批准用于各种实体瘤 恶性肿瘤。而每10名皮肤黑色素瘤患者中有3-4名患者会出现萎缩和 也许是持久的反应，任何其他癌症患者中，只有不到2/10会有任何临床益处。 这是一个需要解决的极其重要的问题，因为检查站免疫疗法费用高昂， 终身治疗，有潜在的副作用和相当大的医疗保健经济负担 来。为了解决检查点免疫疗法应答率低的问题，它与其他疗法相结合 治疗方法也正在被广泛评估，以提高总体应答率。其中， PD-1抑制剂与吲哚胺2，3-双加氧酶(IDO1)抑制剂的结合引起了人们对 由于IDO1在免疫治疗中发挥着特殊的作用。IDO1是一种其基因表达是 受干扰素-正向调节，这是一种仅由免疫细胞产生的免疫细胞因子 亚群(自然杀伤细胞、自然杀伤T细胞、CD4和CD8T细胞、先天淋巴样细胞)。因此，只有 携带肿瘤浸润性免疫细胞(即所谓的“炎症”)的肿瘤预计会产生IDO1。 其次，IDO1分解免疫细胞激活所需的必需氨基酸色氨酸。 IDO1的表达和活性升高不仅会导致色氨酸的枯竭，还会导致色氨酸的积累 犬尿氨酸代谢产物也会阻断T细胞活化，诱导T细胞凋亡，并促进 将幼稚T细胞分化为CD4+调节性T细胞，进一步抑制CD8+效应性T细胞。临床 IDO1途径的重要性反映在世卫组织特异性IDO1抑制剂的临床开发上 与PD-1抑制剂相结合，在各种实体肿瘤中显示出显著更高的抗肿瘤活性 在早期的临床研究中与单独使用任何一种药物进行比较。这一快速的进步和动态的本质 免疫系统迫切需要在体内重复监测IDO的活性。在这项建议中，我们的目标是 基于IDO1底物和核素的新型18F-IDO1PET显像剂的合成与评价 IDO1抑制剂。与11C-AMT相比，我们的试剂不仅合成容易，半衰期更长，而且 提高了靶向特异性(例如，通过阻断Trp环5位的氢化反应)。我们期待着 这项拨款提案的结果将使我们能够在体内非侵入性和重复地监测IDO1的活动， 这将为在未来使用PD-1的多中心临床试验中测试这些探针提供基础 单用抑制剂评估是否有肿瘤浸润性免疫细胞；或与IDO1联合应用 跨越各种癌症的抑制剂，以监测治疗期间IDO1的表达情况，并选择最佳 基于每个患者的个人资料的时间点和有效剂量(个性化用药)。

Abstract 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 naïve 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).