A novel IL-2 biologic and tumor immunity

 描述（由申请人提供）：免疫治疗是转移性黑色素瘤患者的重要治疗选择，但缓解率仍然较低。多次输注高剂量IL-2治疗以直接增强免疫力代表了一种这样的选择，但它因高和严重的毒性以及同时发生的T细胞增殖而复杂化。较新的选择是抗CTLA 4（ipilimumab）和抗PD-1（nivolumab）治疗，阻断负性免疫调节以诱导抗肿瘤反应。这些疗法通过恢复预先存在的CTL来响应肿瘤而显示出希望，并且有助于重新唤起对癌症免疫疗法的兴趣和热情。这种方法有时伴随着副作用，如结肠炎，自身免疫性垂体炎和严重的皮肤皮肤反应。更重要的是，许多患者对这种疗法没有反应。对于一些癌症（包括黑色素瘤）的理想疗法可能是捕获IL-2的有益特征以增强CTL的免疫力和免疫记忆，以及阴性检查点抑制剂（如抗CTLA 4或抗PD 1）的免疫力和免疫记忆，以进一步驱动抗肿瘤免疫应答。然而，为了使这成为现实，必须重新使用IL-2以降低毒性并最大限度地减少对TcB的影响。我实验室的新发现可能会实现这一目标。简而言之，我们已经了解到，以激动剂IL-2/抗IL-2复合物的形式或与在我的实验室中开发的新型IL-2融合蛋白（IL-2FP）一起瞬时应用IL-2仅瞬时影响T细胞，同时高度增强T效应子（Teff）和持久的记忆应答。这种方法需要低得多的IL- 2水平，这将使与高剂量IL-2相关的非特异性毒性最小化。在IL-2治疗期间，特别是在肿瘤疫苗的情况下，施用抗CTLA 4或抗PD 1可以引导对肿瘤的稳健应答，导致应答率增加，并使脱靶自身反应性T细胞最小化。该提案的主要假设是，单独或与阴性检查点抑制剂、抗CTLA 4或抗PD 1联合短暂给予IL-2FP将大大增强内源性或疫苗诱导的抗肿瘤免疫反应。将使用弱免疫原性B16黑色素瘤模型在小鼠中测试该假设，因为已经定义了几种肿瘤抗原，这有助于相关肿瘤疫苗的生产和内源性肿瘤反应性T细胞的鉴定，并且因为对B16肿瘤抗原gp 100具有特异性的CD 8 + TCR转基因T细胞可用于促进机制研究。为了验证这一假设，我们提出了以下目标。1)评估IL-2FP直接或在肿瘤疫苗的情况下增强C57 BL/6小鼠对B16黑色素瘤的肿瘤免疫的程度。将测试阴性检查点抑制剂抗CTLA 4或抗PD 1对IL-2依赖性肿瘤应答的影响。2)评估IL-2FP单独或联合治疗导致肿瘤免疫的机制。这包括评估CD 8 + T细胞肿瘤内免疫应答增强的程度。

 DESCRIPTION (provided by applicant): Immunotherapy represents an important treatment option for patients with metastatic melanoma but response rates remain low. Multiple infusion high dose IL-2 therapy to directly boost immunity represents one such option, but it is complicated by high and severe toxicity and by concurrent expansion of Tregs. Newer options are anti-CTLA4 (ipilimumab) and anti-PD-1 (nivolumab) therapy that blocks negative immune regulation to induce an anti-tumor response. These therapies shows promise by reviving pre-existing CTLs to respond to the tumor and have helped to renew interest and enthusiasm for immunotherapy of cancer in general. This approach is sometimes accompanied by sides effects such a colitis, autoimmune hypophysitis, and severe cutaneous skin reactions. More importantly, many patients still do not respond to this therapy. An ideal therapy for some cancers, including melanoma, may be to capture the beneficial features of IL-2 to boost immunity and immune memory of CTL and those of negative checkpoint inhibitors, such as anti-CTLA4 or anti-PD1, to further drive anti-tumor immune responses. However, for this to become a reality, the use of IL-2 must be repurposed to reduce toxicity and minimize effects on Tregs. New findings from my laboratory may achieve this goal. In brief we have learned that transient application of IL-2, in the form of agonist IL-2/anti-IL-2 complexes or with a novel IL-2 fusion protein (IL-2FP) developed in my lab only transiently affects Tregs while highly boosting T effector (Teff) and long-lasting memory responses. This approach required much lower levels of IL- 2 that should minimize non-specific toxicity associated with high dose IL-2. Administering anti-CTLA4 or anti- PD1 during IL-2 therapy, particularly in the context of a tumor vaccine, may direct robust responses toward the tumor, leading to increased response rates, and minimize off target self-reactive T cells. The main hypothesis of this proposal is that endogenous or vaccine-induced anti-tumor immune responses will be greatly enhanced by transient administration of IL-2FP alone or in conjunction with the negative checkpoint inhibitors, anti-CTLA4 or anti-PD1. This hypothesis will be tested in mice using the weakly immunogenic B16 melanoma model because several tumor antigens have been defined, which facilitate production of relevant tumor vaccines and identification of endogenous tumor-reactive T cells, and because CD8+ TCR transgenic T cells, specific for B16 tumor antigen gp100, are available to facilitate mechanistic studies. To test this hypothesis we propose the follow aims. 1) To assess the extent that IL-2FP boosts tumor immunity toward the B16 melanoma in C57BL/6 mice directly or in the context of tumor vaccines. The effect of the negative checkpoint inhibitors, anti-CTLA4 or anti-PD1, will be tested on IL-2-dependent tumor responses. 2) To evaluate the mechanisms by which IL-2FP alone or in combination therapies leads to tumor immunity. This includes evaluating the extent CD8+ T cell intra-tumor immune responses are enhanced.