Chemotherapy delivery with nanoparticles for targeted induction of immunogenic cell death

摘要 免疫检查点阻断（ICB）旨在重新激活针对肿瘤的细胞毒性T细胞活性。电流 ICB治疗具有显著的治疗效果，但只有约20%的患者长期无肿瘤 生存有限应答率的一个潜在原因是缺乏用于T细胞识别的显性新抗原。 是的。几种化疗药物已被确定为免疫原性细胞死亡的有效诱导剂 (ICD)并积极研究与ICB药物联合作为标签外适应症。然而，一个主要的挑战- 使用化疗作为ICD诱导剂的长期挑战是剂量限制性副作用，包括对肌肉的毒性， 免疫细胞，这将直接危及癌症免疫治疗。为了用ICD诱导的ICB增强ICB， 在化疗中，特异性和有效地影响肿瘤细胞的递送系统是必要的。与翁戈- 使用R01载体（R01EB017791），我们开发了具有良好循环稳定性的纳米颗粒（NP）系统 和高载药能力，从而将更多的化疗药物递送至肿瘤并实现更大的抗肿瘤作用。 相对于商业基准产品的肿瘤功效。我们还证明了局部电离 放射（IR）进一步增加NP向肿瘤的递送。在这次续期申请中，我们建议使用 和IR以增强它们在肿瘤中诱导ICD的潜力，从而使肿瘤对ICB治疗敏感。 - 是的我们的中心假设是纳米颗粒将药物集中在肿瘤中而不增加全身毒性 诱导ICD并帮助保留释放的损伤相关分子模式和肿瘤抗原， 产生持久的抗肿瘤免疫反应。我们将联合收割机NP与高载药能力和良好的 循环稳定性以及有助于NP体内性能的表面改性剂， 获得用于肿瘤递送和细胞内摄取和保留的最佳NP。ICD诱导NP的活性 将通过促进抗肿瘤免疫应答的能力（目标1）进行评价; 将结合局部电离辐射（目标2）进行评价。为了研究ICD-1在 将NP引入ICB治疗，它们将与靶向PD-L1的siRNA或抗PD-1/PD-L1抗体组合 并在已知对免疫疗法敏感（不敏感）的肿瘤动物模型中进行评价（目的3）。创新 这一战略的一个方面是，它探讨了未开发的效用的纳米粒子作为一种方式，增加潜力， 化疗诱导ICD和载体在癌症免疫治疗中的作用。随着成功完成 通过这个项目，我们期望开发出一种新的治疗方案，具有持久的抗癌效果和高 完全缓解率

ABSTRACT Immune checkpoint blockade (ICB) aims to reactivate cytotoxic T-cell activities against tumors. Current ICB therapy has had a dramatic therapeutic impact, but only about 20% of patients have long-term tumor-free survival. A potential reason for the limited response rate is the lack of dominant neoantigens for T-cell recogni- tion. Several chemotherapeutic drugs have been identified as effective inducers of immunogenic cell death (ICD) and actively investigated in combination with ICB agents as off-label indications. However, a main chal- lenge in using chemotherapy as an ICD inducer is the dose-limiting side effects, including the toxicity to im- mune cells that will directly compromise cancer immunotherapy. In order to enhance ICB with ICD-inducing chemotherapy, a delivery system that specifically and efficiently affect tumor cells is necessary. With the ongo- ing R01 support (R01EB017791) we have developed nanoparticle (NP) systems with good circulation stability and high drug loading capacity that deliver more chemotherapeutic drugs to tumors and achieve greater anti- tumor efficacy relative to commercial benchmark products. We have also demonstrated that localized ionizing radiation (IR) further increased NP delivery to tumors. In this renewal application, we propose to use the NPs and IR to enhance their potential to induce ICD in tumors thereby sensitizing the tumors to ICB ther- apy. Our central hypothesis is that NPs will concentrate the drug in tumors without increasing systemic toxicity to induce ICD and help retain the released damage-associated molecular patterns and tumor antigens to gen- erate durable anti-tumor immune responses. We will combine NPs with high drug loading capacity and good circulation stability as well as surface modifiers that have contributed to in vivo performance of NPs in order to obtain optimal NPs for tumor delivery and intracellular uptake and retention. The activity of ICD-inducing NPs will be evaluated via the ability to promote anti-tumor immune responses (Aim 1); and their anti-cancer effect will be evaluated in combination with local ionizing radiation (Aim 2). To investigate the contribution of ICD-in- ducing NPs to ICB therapy, they will be combined with siRNA targeting PD-L1 or anti-PD-1/PD-L1 antibodies and evaluated in animal models of tumors with known (in)sensitivity to immunotherapy (Aim 3). The innovative aspect of this strategy is that it explores the untapped utility of NPs as a way of increasing the potential of chemotherapy to induce ICD and the role of carriers in cancer immunotherapy. With successful completion of this project, we expect to have developed a new therapeutic regimen with durable anti-cancer effects and high complete remission rates.