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

项目概要/摘要： 尽管癌症免疫疗法最近取得了进展，但由于肿瘤免疫抑制，实体瘤在很大程度上仍然难以治疗。 肿瘤微环境（TME）破坏免疫稳态。在TME内， 缺氧、酸性、抑制性细胞和免疫检查点导致I型效应细胞分化不良， 阻止了强大免疫反应的发展。IL 12是一种天然产生的细胞因子， 通过先天淋巴细胞（ILC）上的IL 12 R β1/IL 12 R β2复合物诱导I型细胞介导的免疫 和T细胞。IL 12在临床前试验中已经非常成功地对抗实体瘤，但其临床应用还不多见。 由于系统性免疫过度激活而导致的致命毒性损害了发育。我开发了一个 一种新的基于IL-12的前药（proIL-12），其在体内没有明显的毒性，但保持完全的抗肿瘤活性， 功效proIL 12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，IFNγ是诱导的主要细胞因子。因此，我假设proIL 12在体内循环 以惰性前药形式存在，直到被肿瘤特异性酶激活，此时它直接通过 IL-12受体介导，IFN-γ介导。为了验证我的假设，我将首先验证proIL 12的药物 通过确定最佳给药方案、监测肿瘤特异性活化和测量毒性来确定肿瘤特征。 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IFNγ在协调proIL 12应答中的下游作用。通过系统地 为了表征proIL 12的物理和机械特性，我不仅将其用于进一步的临床应用， 这些信息不仅可以帮助开发，而且可以为未来的步骤提供信息，例如联合治疗或预后标记物。作为一个整体，我 研究将产生一种能够逆转TME诱导的免疫紊乱的可耐受的免疫抑制剂， 消除实体肿瘤。

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.