Development of a tumor-activated IL12 prodrug to treat solid tumors

项目摘要/摘要： 尽管最近在癌症免疫治疗方面取得了进展，但由于以下原因，实体肿瘤在很大程度上仍然难以治疗 肿瘤微环境(TME)破坏免疫平衡。在TME内部，以下各项的组合 缺氧、酸性、抑制细胞和免疫检查点导致I型效应细胞分化不良， 防止形成强大的免疫反应。IL12是一种自然产生的细胞因子，可以直接 天然淋巴样细胞(ILCs)表面IL12Rβ1/IL12Rβ2复合体诱导I型细胞免疫 和T细胞。在临床前试验中，IL12在治疗实体瘤方面取得了显著的成功，但其临床应用 由于全身免疫过度激活，致命性毒性已经损害了发育。我已经开发出一种 新的基于IL12的前药(ProIL12)，在体内没有明显的毒性，但保持完全的抗肿瘤作用 功效。ProIL12的动力学和细胞机制仍需确定，但初步数据表明 T细胞起关键作用，干扰素γ是诱导的主要细胞因子。因此，我假设ProIL12循环 处于惰性前药状态，直到被肿瘤特异性酶激活，在这一点上，它直接通过 IL-12受体和干扰素γ的产生。为了验证我的假设，我将首先验证ProIL12的S药物 通过确定最佳给药计划、监测肿瘤特异性激活和测量毒性来描述。 然后，我将探索ILC和T细胞中哪些特定的细胞亚型是排斥肿瘤所必需的。最后， 我将独立评估干扰素γ在协调ProIL12反应中的下游作用。通过系统地 对ProIL12的物理和机械性能进行表征，我将不仅为进一步的临床做准备 这不仅可以为未来的步骤，如联合治疗或预后标记物提供信息。作为一个整体，我的 研究将生产一种可耐受的免疫治疗剂，能够逆转TME诱导的免疫紊乱 消除实体瘤。

Project Summary/Abstract: Despite recent advances in cancer immunotherapy, solid tumors remain largely refractory to treatment due to disruption of immune homeostasis by the tumor microenvironment (TME). Within the TME, a combination of hypoxia, acidity, suppressive cells, and immune checkpoints leads to poor differentiation of type I effector cells, preventing the development of a robust immune response. IL12 is a naturally produced cytokine that can directly induce type I, cell-mediated immunity through the IL12Rβ1/IL12Rβ2 complex on innate lymphoid cells (ILCs) and T cells. IL12 has been remarkably successful against solid tumors in preclinical trials, but its clinical development has been impaired by lethal toxicity due to systemic immune overactivation. I have developed a novel IL12-based prodrug (proIL12) that displays no noticeable toxicity in vivo but maintains full antitumor efficacy. The kinetics and cellular mechanism of proIL12 must still be ascertained, but preliminary data suggests T cells play a critical role and IFNγ is the main cytokine induced. Therefore, I hypothesize that proIL12 circulates in inert prodrug form until activated by tumor-specific enzymes, at which point it activates T cells directly through IL12 receptor and secondarily through IFNγ production. To test my hypothesis, I will first validate proIL12’s drug profile by determining an optimal dosing schedule, monitoring tumor-specific activation, and measuring toxicity. Then, I will explore which specific cell subtypes among ILCs and T cells are necessary to reject tumors. Finally, I will independently assess the downstream role of IFNγ in coordinating the proIL12 response. By systematically characterizing both physical and mechanistic properties of proIL12, I will not only prepare it for further clinical development but also inform future steps such as combination therapies or prognostic markers. As a whole, my study will produce a tolerable immunotherapeutic agent capable of reversing TME-induced immune disarray to eliminate solid tumors.