Chemotherapy delivery with nanoparticles for targeted induction of immunogenic cell death

摘要 免疫检查点阻断(ICB)的目的是重新激活细胞毒性T细胞活性以对抗肿瘤。当前 ICB疗法产生了巨大的治疗效果，但只有大约20%的患者长期无瘤。 生死存亡。应答率有限的一个潜在原因是缺乏T细胞识别的主要新抗原。 提顿。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，一个主要的挑战是- 使用化疗作为ICD诱导剂的挑战是剂量限制的副作用，包括对注射的毒性。 将直接影响癌症免疫治疗的MUNE细胞。为了用ICD诱导增强ICB 化疗是一种特异而有效地影响肿瘤细胞的递送系统，这是必要的。有了OGO- ING 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 和高载药量，将更多的化疗药物输送到肿瘤，实现更大的抗肿瘤效果 相对于商业基准产品的肿瘤疗效。我们还证明了局域电离 放射治疗(IR)进一步增加了NP向肿瘤的递送。在此续期申请中，我们建议使用NP 和IR可增强其在肿瘤中诱导ICD的潜能，从而使肿瘤对ICB治疗敏感。 APY。我们的中心假设是，纳米粒将在肿瘤中浓缩药物，而不会增加全身毒性。 诱导ICD并帮助保留释放的损伤相关分子模式和肿瘤抗原以生成- 激发持久的抗肿瘤免疫反应。我们将结合具有高载药量和良好性能的纳米粒 循环稳定性以及有助于NPs体内性能的表面修饰剂，以便 获得肿瘤递送以及细胞内摄取和滞留的最佳NPs。ICD诱导的NPs的活性 将通过促进抗肿瘤免疫反应的能力进行评估(目标1)；以及它们的抗癌效果 将结合局部电离辐射进行评估(目标2)。调查ICD-in-in的贡献 将NPs引入ICB治疗，它们将与针对PD-L1或抗PD-1/PD-L1抗体的siRNA结合 并在已知对免疫疗法敏感的肿瘤动物模型中进行评估(目标3)。创新的 这一战略的一个方面是，它探索了NP的未开发效用，将其作为一种增加 化疗诱导ICD及携带者在肿瘤免疫治疗中的作用。随着成功完成 这个项目，我们希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.