IL-27 as a potential immunotherapeutic for cancer

基于阻断免疫检查点的癌症免疫疗法已经取得了显著的成功。 然而，超过50%的晚期癌症患者对这种免疫疗法不敏感。 虽然对癌症抵抗的因素还不完全清楚，但缺乏预先存在的T细胞 肿瘤微环境（TME）中的浸润被认为是抗PD-1的最重要因素 阻力此外，尽管不是绝对的，但肿瘤中PD-L1表达的缺乏被认为是肿瘤发生的原因。 另一个重要因素。最后，虽然在人类癌症中还没有很好的建立，但调节性T细胞的积累 TME中的TME细胞（TME）已经显示有助于小鼠模型中的抗PD-1抗性。treg是 已知其在癌症患者中扩增并在癌症病变中富集。在抗CTLA-4抗体治疗的癌症中 患者中，肿瘤病变中的Treg缺失与治疗反应相关。抗CTLA-4治疗还 抗PD-1治疗的反应率显著提高，但代价是3级和4级毒性增加。 因此，开发能够克服这些局限性的新策略对于增强 癌症免疫治疗的现状 IL-27的抗肿瘤活性已经被认识了10多年。然而，将IL-27开发成 尚未很好地获得治疗已确定癌症的治疗剂。重组腺相关病毒 载体（rAAV）是用于基因治疗的高度通用的基因递送剂。缺乏免疫原性， 毒性使得rAAV可以说是人类临床试验的基因治疗载体的选择。最近我们 产生了表达IL-27的rAAV（AAV-IL-27），其可以在受体小鼠中有效地产生IL-27，并使 根据新的观察。首先，AAV-IL-27显著抑制广谱肿瘤的生长， 老鼠的类型第二，AAV-IL-27治疗导致TcR的显著降低，而不引起TcR的升高。 自身免疫第三，我们已经发现AAV-IL-27疗法与PD-1抗体在抑制IL-27表达方面显示出强的协同作用。 肿瘤生长基于这些观察，我们假设AAV-IL-27治疗可以促进肿瘤的发生， 同时抑制自身免疫，并具有单独用于癌症治疗或增强 目前的免疫疗法。为了验证这一假设，我们将首先确定AAV-IL-27如何增强肿瘤特异性免疫应答。 TME中的T细胞反应。然后我们将研究AAV-IL-27介导的T细胞耗竭的机制， 并确定它如何增强肿瘤免疫力而不引起自身免疫。此外，我们将调查 AAV递送的IL-27和抗PD-1治疗的组合在癌症治疗中的潜力，确定了肿瘤治疗的有效性。 协同作用的潜在机制，并评估联合治疗中潜在的自身免疫副作用。 最后，我们将研究IL-27诱导的T细胞表型是否可以在体内人T细胞中复制。的 拟议的研究不仅将揭示IL-27抗肿瘤活性的新见解，而且还将导致新的 可以单独或与抗PD-1抗体协同作用用于癌症治疗的候选治疗药物。

Cancer immunotherapies based on blockade of immune checkpoints have achieved significant success. However, more than 50% of patients with advanced cancer are not sensitive to this type of immunotherapy. Although the factors that are responsible for cancer resistance are not fully understood, lack of pre-existing T cell infiltration in the tumor microenvironment (TME) is considered to be the most important factor for anti-PD-1 resistance. Additionally, although not absolute, lack of expression of PD-L1 in tumors has been considered to be another important factor. Finally, although not well-established in human cancer, accumulation of regulatory T cells (Tregs) in the TME has been shown to contribute to anti-PD-1 resistance in mouse models. Tregs are known to be expanded in cancer patients and enriched in cancer lesions. In anti-CTLA-4 antibody-treated cancer patients, Treg-depletion in tumor lesion correlated with therapeutic response. Anti-CTLA-4 treatment also significantly enhanced response rate to anti-PD-1 therapy, but with the price of increased grade 3 and 4 toxicity. Thus, developing novel strategies that can overcome these limitations is critical to enhance the efficacy of current cancer immunotherapies. The anti-tumor activity of IL-27 has been appreciated for more than 10 years. However, developing IL-27 into a therapeutic to treat established cancer has not been well achieved. Recombinant adeno-associated viral vectors (rAAV) are highly versatile gene delivery agents for gene therapy. The lack of immunogenicity and toxicity make rAAV arguably the gene therapy vector of choice for human clinical trials. Recently, we have produced IL-27-expressing rAAV (AAV-IL-27) that can efficiently produce IL-27 in recipient mice and made the following novel observations. First, AAV-IL-27 significantly inhibited the growth of a broad-spectrum of tumor types in mice. Second, AAV-IL-27 treatment resulted in dramatic reduction of Tregs without causing autoimmunity. Third, we have found that AAV-IL-27 therapy show strong synergy with PD-1 antibody in inhibiting tumor growth. Based on these observations, we hypothesize that AAV-IL-27 therapy can promote tumor immunity while inhibit autoimmunity, and has a potential to be used alone for cancer therapy or to enhance current immunotherapies. To test this hypothesis, we will first determine how AAV-IL-27 enhances tumor specific T cell responses in the TME. We will then investigate the mechanisms of AAV-IL-27-mediated depletion of Tregs and determine how it enhances tumor immunity without causing autoimmunity. Additionally, we will investigate the potential of the combination of AAV-delivered IL-27 and anti-PD-1 therapy in cancer therapy, determine the potential mechanisms of synergy and evaluate potential autoimmune side effects in the combination therapy. Finally, we will investigate if IL-27-induced T cell phenotypes can be reproduced in human T cells in vivo. The proposed studies will not only reveal new insights of the anti-tumor activity of IL-27, but also lead to a new candidate therapeutic that can work alone or synergistically with anti-PD-1 antibodies for cancer treatment.