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

用于术后癌症免疫治疗的血小板介导的检查点抑制剂递送

• 批准号: 10668316
• 负责人: Song Li
• 金额: $ 39.49万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10668316
• 关键词: 4T1; Acceleration; Antigen-Presenting Cells; Area; Autoimmune Diseases; B-Lymphocytes; Beds; Blood Platelets; C57BL/6 Mouse; Carcinoma; Cell membrane; Cells; Cellular immunotherapy; Chemotherapy and/or radiation; Clinical Data; Combined Modality Therapy; Development; Dose; Effectiveness; Encapsulated; Engraftment; Evaluation; Excision; Frequencies; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunotherapy; In Situ; In Vitro; Inflammation; Ligands; Malignant Neoplasms; Mediating; Methods; Modeling; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Operative Surgical Procedures; Particulate; Pathway interactions; Patients; Perioperative; Pharmaceutical Preparations; Platelet Activation; Property; Recurrent Malignant Neoplasm; Recurrent tumor; Relapse; Research; Residual Cancers; Residual Neoplasm; Residual state; Site; Solid Neoplasm; T cell infiltration; T-Lymphocyte; Techniques; Testing; Therapeutic; Toxic effect; Transfusion; Trauma; Treatment Efficacy; Tumor Cell Invasion; Tumor Promotion; Tumor-infiltrating immune cells; Work; anti-CTLA4; anti-PD-1; anti-PD-L1; anti-PD-L1 antibodies; anti-cancer; cancer cell; cancer immunotherapy; cancer recurrence; cancer therapy; cancer type; chimeric antigen receptor; chimeric antigen receptor T cells; delivery vehicle; effectiveness evaluation; gemcitabine; high risk; immune checkpoint blockade; immunogenic; improved; in vivo; innovation; interest; melanoma; mouse model; multidisciplinary; neoplastic cell; novel; objective response rate; particle; prevent; programmed cell death ligand 1; programmed cell death protein 1; recruit; sialogangliosides; side effect; small molecule; success; systemic toxicity; targeted delivery; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

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.

项目概要 尽管手术技术不断改进，但手术切除后癌症复发仍然是一个难题 癌症治疗中的重大挑战也已被证实，手术可以促进癌症的发生。 在该提案中，该团队打算利用血小板作为输送载体开发一种转移药物。 用于局部释放免疫检查点抑制剂以实现术后根除的变革性平台 在一项初步研究中，使用携带 B16F10 黑色素瘤的 C57BL/6 小鼠。 模型中，已证明抗 PDL1 (aPDL1) 附着的血小板（称为 P-aPDL1）可以 促进aPDL1向残留微肿瘤残留的手术床积聚。 重要的是，负载的aPDL1可以通过介导的介导有效地从活化的血小板中释放出来。 血小板原位活化后的血小板衍生微粒（PMP）此外，血小板可以产生血小板。 局部发炎的肿瘤微环境，可以增强 T 细胞以及其他免疫细胞的活性。 该团队建议进一步证实、优化和扩展血小板作为输送平台的能力 对于基于检查点封锁的癌症免疫疗法，该团队将验证详细的治疗方法。 P-aPDL1 的作用机制并优化其理化性质。 此外，该团队还将评估治疗循环肿瘤细胞（CTC）的潜力。 血小板以实现 aPDL1 和吉西他滨 (GEM) 的联合递送，这可以上调两者 PDL1和PD1分别作用于肿瘤细胞和肿瘤浸润免疫细胞此外，twam将。 扩展该平台以共同输送不同的“细胞”——载有治疗药物的血小板和特定的嵌合抗原 受体（CAR）T细胞将追求三个目标：目标1，血小板的输送能力。 检查点抑制剂将得到验证和优化；在目标 2 中，联合给药的有效性 将在创新的组合细胞免疫疗法 Aim 3 中评估使用血小板的 aPDL1 和 GEM； 还将开发和评估血小板和 CAR-T 细胞的协同免疫反应。 由于将评估这种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，将显着增强抗癌功​​效 这种新颖的原位生物响应策略也可能激发新的治疗方法。 应用生物颗粒进行治疗药物的靶向和生物响应释放。

项目成果

Cryo-shocked cancer cells for targeted drug delivery and vaccination.

冷冻休克癌细胞用于靶向药物输送和疫苗接种。

• 发表时间: 2020
• 影响因子: 13.6
• 作者: Ci, Tianyuan;Li, Hongjun;Chen, Guojun;Wang, Zejun;Wang, Jinqiang;Abdou, Peter;Tu, Yiming;Dotti, Gianpietro;Gu, Zhen
• 通讯作者: Gu, Zhen

Adipocytes Encapsulating Telratolimod Recruit and Polarize Tumor-Associated Macrophages for Cancer Immunotherapy.

封装 Telratolimod 的脂肪细胞招募并极化肿瘤相关巨噬细胞，用于癌症免疫治疗。

• 发表时间: 2023-02
• 作者: Wen, Di;Liang, Tingxizi;Chen, Guojun;Li, Hongjun;Wang, Zejun;Wang, Jinqiang;Fu, Ruxing;Han, Xiao;Ci, Tianyuan;Zhang, Yuqi;Abdou, Peter;Li, Ruoxin;Bu, Linlin;Dotti, Gianpietro;Gu, Zhen
• 通讯作者: Gu, Zhen

Tailoring Materials for Modulation of Macrophage Fate.

用于调节巨噬细胞命运的定制材料。

• 发表时间: 2021-03
• 作者: Li, Jinhua;Jiang, Xinquan;Li, Hongjun;Gelinsky, Michael;Gu, Zhen
• 通讯作者: Gu, Zhen

Disrupting tumour vasculature and recruitment of aPDL1-loaded platelets control tumour metastasis.

破坏肿瘤脉管系统和招募载有 aPDL1 的血小板可控制肿瘤转移。

• 发表时间: 2021
• 影响因子: 16.6
• 作者: Li, Hongjun;Wang, Zejun;Chen, Zhaowei;Ci, Tianyuan;Chen, Guojun;Wen, Di;Li, Ruoxin;Wang, Jinqiang;Meng, Huan;Bryan Bell, R;Gu, Zhifeng;Dotti, Gianpietro;Gu, Zhen
• 通讯作者: Gu, Zhen

Immunotherapy in head and neck squamous cell carcinoma: a narrative review.

头颈鳞状细胞癌的免疫治疗：叙述性回顾。

• 发表时间: 2022-09
• 作者: Sharon, Shay;Bell, R Bryan
• 通讯作者: Bell, R Bryan