IL-27 as a potential immunotherapeutic for cancer

IL-27 作为癌症的潜在免疫疗法

• 批准号: 10640105
• 负责人: Sujit Basu
• 金额: $ 34.97万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640105
• 关键词: Advanced Malignant Neoplasm; Adverse event; Affect; Antigens; Autoimmune; Autoimmune Diseases; Autoimmunity; CD34 gene; CXCR3 gene; Cancer Patient; Cells; Clinical Trials; Combined Modality Therapy; Data; FOXP3 gene; Gene Delivery; Gene Therapy Agent; Gene Transduction Agent; Goals; Growth; Hematopoietic stem cells; Human; Immunosuppressive Agents; Immunotherapy; Infiltration; Interferons; Interleukin-10; Interleukin-2; Lesion; Malignant Neoplasms; Mediating; Mus; PD-1 blockade; PPBP gene; Patients; Phenotype; Price; Production; RANTES; Recombinants; Regulation; Regulatory T-Lymphocyte; Rejuvenation; Resistance; Role; Signal Transduction; Specificity; Suppressor-Effector T-Lymphocytes; T cell infiltration; T cell response; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Tumor Antigens; Tumor Immunity; Tumor Promotion; Work; adeno-associated viral vector; anti-CTLA-4 therapy; anti-CTLA4; anti-CTLA4 antibodies; anti-PD-1; anti-PD-1/PD-L1; anti-PD-L1 antibodies; anti-PD1 antibodies; anti-PD1 therapy; antigen-specific T cells; cancer immunotherapeutics; cancer immunotherapy; cancer therapy; exhaust; immune checkpoint blockade; immunogenicity; improved; in vivo; insight; lymphoid neoplasm; melanoma; mouse model; novel; novel strategies; peripheral lymphoid organ; prevent; programmed cell death ligand 1; receptor; response; side effect; stem cell engraftment; stem cells; success; synergism; therapeutic candidate; treatment response; tumor; tumor growth; tumor microenvironment

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.

基于免疫检查点阻塞的癌症免疫疗法取得了显着成功。 但是，超过50％的晚期癌症患者对这种免疫疗法不敏感。 尽管尚未完全了解导致癌症抗性的因素，但缺乏预先存在的T细胞 肿瘤微环境（TME）的浸润被认为是抗PD-1的最重要因素 反抗。另外，尽管不是绝对的，但肿瘤中PD-L1缺乏表达被认为是 另一个重要因素。最后，尽管在人类癌症中没有建立的良好成就，但调节t的积累 TME中的细胞（Tregs）已显示出在小鼠模型中有助于抗PD-1抗性。 Treg是 已知可以在癌症患者中扩展并富含癌症病变。在抗CTLA-4抗体处理的癌症中 患者，肿瘤病变中的Treg止动与治疗反应有关。抗CTLA-4治疗 对抗PD-1治疗的反应率显着提高，但价格的增加了3级和4级毒性。 因此，制定可以克服这些限制的新型策略对于增强的疗效至关重要 当前的癌症免疫疗法。 IL-27的抗肿瘤活性已被赞赏已有10多年了。但是，将IL-27开发到 治疗已建立癌症的治疗方法尚未得到很好的成就。重组腺相关病毒 载体（RAAV）是用于基因治疗的高度用途基因递送剂。缺乏免疫原性和 毒性可以说是RAAV人类临床试验首选的基因治疗载体。最近，我们有 产生了表达IL-27的RAAV（AAV-IL-27），可以在接受者小鼠中有效产生IL-27 遵循新颖的观察。首先，AAV-IL-27显着抑制了肿瘤广谱的生长 小鼠类型。第二，AAV-IL-27处理导致Treg急剧减少而不会引起 自身免疫性。第三，我们发现AAV-IL-27疗法在抑制时与PD-1抗体表现出强烈的协同作用 肿瘤生长。基于这些观察结果，我们假设AAV-IL-27治疗可以促进肿瘤 免疫力虽然抑制自身免疫性，并且有可能单独用于癌症治疗或增强 当前的免疫疗法。为了检验该假设，我们将首先确定AAV-IL-27如何增强肿瘤特异性 TME中的T细胞反应。然后，我们将研究AAV-IL-27介导的Treg耗尽的机制 并确定它如何增强肿瘤免疫力而不会引起自身免疫性。此外，我们将调查 癌症治疗中AAV的IL-27和抗PD-1治疗的组合的潜力，确定 协同作用的潜在机制并评估联合疗法中潜在的自身免疫副作用。 最后，我们将研究是否可以在体内人类T细胞中再现IL-27诱导的T细胞表型。这 拟议的研究不仅会揭示IL-27抗肿瘤活性的新见解，还会导致新的见解 可以单独或与抗PD-1抗体进行癌症治疗的候选治疗方法。

项目成果

Is AAV-delivered IL-27 a potential immunotherapeutic for cancer?

• 发表时间: 2020-11
• 期刊: American journal of cancer research
• 影响因子: 5.3
• 作者: Jin-qing Liu;Jianmin Zhu;Aiyan Hu;A. Zhang;Chunbaixue Yang;Jianyu Yu;K. Ghoshal;S. Basu;X. Bai