A Phospholipid-Derived Nanotherapeutic Platform for Improved Colorectal Cancer Immunochemotherapy

项目摘要/摘要 虽然免疫检查点抑制剂(ICIS)已经改变了癌症治疗范式的格局，但 应答率仅限于一小部分癌症患者(~20%)。对于结直肠癌(CRC)，第二个 美国癌症相关死亡的主要原因，只有错配修复缺陷或微卫星患者(~4%) 不稳定-高肿瘤可对ICIS产生反应，使绝大多数CRC患者仅限于没有临床 利益。越来越多的证据表明，化疗对整体抗肿瘤作用有显著贡献。 通过将肿瘤从“免疫冷”切换到“免疫热”，与ICIS联合应用的疗效。然而，由于 由于溶解性和药代动力学差，肿瘤蓄积有限，以及对健康的非特异性毒性 在组织中，化疗药物在提高ICIS疗效方面的效用受到了相当大的阻碍。至 提供更安全和更有效的化疗免疫反应，以配合ICIS，我们的长期- 学期目标是通过偶联作用开发一种创新的多功能脂质体纳米治疗平台 脂质体骨架磷脂的抗癌剂。我们已经开发出一种磷脂衍生的 喜树碱(CPT)脂质体(喜树碱)纳米平台，显著延长血液循环 与游离CPT相比，该药可缩短治疗时间，提高肿瘤摄取率和治疗效果，并将全身毒性降至最低。 此外，喜树碱增强了PD-L1/PD-1抑制剂的抗结直肠癌效果，导致部分 根除免疫能力强的小鼠的肿瘤。为了提高这种综合疗法的疗效，我们使用了 喜树联合交付一种针对另一个独立免疫检查点的抑制剂，吲哚胺2，3- 双加氧酶(IDO1)，显著增强抗结直肠癌的疗效和免疫力。为了进一步加强 并探索该纳米平台在增强PD-L1/PD-1阻断治疗方面的潜力 这项建议我们将： 目的1：改进喜树系统，增强治疗效果。 目的2：测定改良共给药系统的肿瘤给药效率和药代动力学 在小鼠结直肠癌模型中。 目的3：确定改进的共传递系统在阻断或不阻断PD-L1/PD-1的情况下的抗肿瘤作用 在小鼠结直肠癌模型中。三七总皂甙体内抗肿瘤作用及免疫应答的机制 联合治疗也将被阐明。这项提案的成功完成将产生一个创新和 用于改进和安全的结直肠癌免疫化疗的多功能纳米治疗平台。此外，在给定 IDO1在不同的癌细胞中表达，这种纳米平台对其他抗癌药物具有广泛的适用性 在药物方面，我们的组合纳米治疗系统有可能彻底改变癌症治疗模式。

Project Summary/Abstract While immune checkpoint inhibitors (ICIs) have transformed the landscape of cancer treatment paradigm, the response rate is limited to a small subset of cancer patients (~20%). For colorectal cancer (CRC), the second leading cause of cancer-related deaths in US, only patients (~4%) with mismatch-repair-deficient or microsatellite instability-high tumors can respond to ICIs, leaving the vast majority of CRC patients with limited to no clinical benefit. Chemotherapy has been increasingly manifested to contribute significantly to the overall antitumor efficacy when combined with ICIs via switching the tumors from “immune-cold” to ‘immune-hot’. However, owing to the poor solubility and pharmacokinetics, limited tumor accumulation, and non-specific toxicities to healthy tissues, the utility of chemotherapeutics in enhancing the efficacy of ICIs has been considerably hindered. To render a safer and more efficacious chemotherapy-enabled immune response to cooperate with ICIs, our long- term goal is to develop an innovative and multifunctional liposomal nanotherapeutic platform via conjugating anticancer agents to the backbone phospholipid of liposome. We have developed a phospholipid-derived camptothecin (CPT) liposome (Camptothesome) nanoplatform, which significantly prolonged blood circulation time, enhanced tumor uptake and therapeutic efficacy and minimized systemic toxicities compared to free CPT. Moreover, Camptothesome potentiated the anti-CRC efficacy of PD-L1/PD-1 inhibitors, resulting in partial eradication of tumors in immunocompetent mice. To improve the efficacy of this combined therapy, we used Camptothesome to co-deliver an inhibitor targeting another independent immune checkpoint, Indoleamine 2,3- dioxygenase (IDO1), which markedly enhanced anti-CRC efficacy and immunity. To further strengthen the delivery efficiency and explore the potential of this nanoplatform in enhancing PD-L1/PD-1 blockade therapy, in this proposal we will: Aim 1: Improve the Camptothesome system for enhanced therapeutic delivery. Aim 2: Determine the tumor delivery efficiency and pharmacokinetics of the improved co-delivery system in murine CRC models. Aim 3: Define antitumor effects of the improved co-delivery system with or without PD-L1/PD-1 blockade in murine CRC models. The mechanistic action for the in vivo antitumor efficacy and immune responses of the combined therapy will also be elucidated. Successful completion of this proposal will result in an innovative and multifunctional nanotherapeutic platform for improved and safe CRC immunochemotherapy. Moreover, given that IDO1 is expressed in diverse cancer cells, and the broad applicability of this nanoplatform to other anticancer drugs, our combination nanotherapeutic system has the potential to revolutionize cancer treatment paradigms.