Platelets-Mediated Delivery of Checkpoint Inhibitors for Post-Surgical Cancer Immunotherapy

项目摘要 尽管手术技术不断改进，但手术切除后的癌症复发仍然是一个令人担忧的问题。 癌症治疗中的重大挑战。手术也被证实会诱发促癌 转移在这项提案中，利用血小板作为运载工具，该小组打算开发一种 用于局部释放免疫检查点抑制剂以实现手术后根除 残留的癌细胞在初步研究中，使用携带B16 F10黑色素瘤的C57 BL/6小鼠 模型，已经证明抗-PDL 1（aPDL 1）附着的血小板（命名为P-aPDL 1）可以 促进aPDL 1向残留微小肿瘤的手术床积聚。 重要的是，负载的aPDL 1可以有效地从活化的血小板中释放， 血小板衍生的微粒（PMP）在原位血小板活化。此外，血小板可以产生 局部发炎的肿瘤微环境，这可以增强T细胞和其他免疫细胞的活性。在这里， 该小组建议进一步证实、优化和扩展血小板作为输送平台的能力 用于基于检查点阻断的癌症免疫疗法。该小组将验证详细的治疗方法 并对其理化性质进行优化。P-aPDL 1用于 还将评估治疗循环肿瘤细胞（CTC）的方法。此外，该小组还将评估 的血小板，以实现aPDL 1和吉西他滨（GEM）的联合递送，这可以上调两者 PDL 1和PD 1分别作用于肿瘤细胞和肿瘤浸润免疫细胞。此外，Twam将 扩展该平台以共同递送不同的“细胞”-装载治疗剂的血小板和特异性嵌合抗原 受体（CAR）T细胞。将追求三个目标：在目标1中， 检查点抑制剂将得到验证和优化;在目标2中， 将评估使用血小板的aPDL 1和GEM;在目标3中，创新的组合细胞免疫疗法 将开发和评估血小板和CAR-T细胞。协同免疫反应 因为将评价该组合的基于细胞的免疫疗法的全身毒性。拟议的研究， 当在人体研究中成功证明时，将显著增强抗癌功效， 提高患者的生存率。这种新颖的原位生物反应策略也可能激发新的治疗方法 应用生物颗粒用于治疗剂的靶向和生物响应释放。

PROJECT SUMMARY Despite continual improvements in surgical techniques, cancer recurrence after surgical resection remains a significant challenge in cancer therapy. It has also been verified that surgery can induce promotion of cancer metastasis. In this proposal, utilizing platelet as a delivery vehicle, the team intends to develop a transformative platform for locally releasing immune checkpoint inhibitors toward post-surgical eradication of residual cancer cells. In a preliminary study, using the B16F10 melanoma tumor-bearing C57BL/6 mouse model, it has been demonstrated that the anti-PDL1 (aPDL1) attached platelets (designated P-aPDL1) could facilitate the accumulation of aPDL1 toward the surgical bed where the residual microtumors remain. Importantly, the loaded aPDL1 can be effectively released from the activated platelets mediated by the platelet-derived microparticles (PMPs) upon in situ platelet activation. Moreover, platelets can generate a local inflamed tumor microenvironment, which could boost T cells activity as well as other immune cells. Here, the team proposes to further substantiate, optimize and extend the capability of platelets as a delivery platform for checkpoints blockade-based cancer immunotherapy. The team will validate the detailed treatment mechanism of P-aPDL1 as well as optimize its physicochemical property. The capability of P-aPDL1 for treating circulating tumor cells (CTCs) will also be evaluated. In addition, the team will evaluate the potential of platelets to achieve combination delivery of aPDL1 and gemcitabine (GEM), which can upregulate both PDL1 and PD1 on tumor cells and tumor infiltrating immune cells, respectively. Furthermore, the twam will extend this platform to co-deliver different “cells”- therapeutics-loaded platelets and specific chimeric antigen receptor (CAR) T cells. Three aims will be pursued: in Aim 1, the capability of platelets for delivering checkpoint inhibitors will be validated and optimized; in Aim 2, the effectiveness of combination delivery of aPDL1 and GEM using platelets will be evaluated; in Aim 3, the innovative combination cell immunotherapy with platelets and CAR-T cells will be developed and assessed. The synergistic immune responses as well as systemic toxicity of this combination cells-based immunotherapy will be evaluated. The proposed research, when successfully demonstrated in human studies, would significantly enhance the anticancer efficacy and improving the patients’ survival. This novel in situ bio-responsive strategy may also inspire new treatments applying bio-particulates for targeting and bio-responsive release of therapeutics.