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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结尽管外科手术技术在不断改进，但手术切除后的癌症复发仍然是一种癌症治疗中的重大挑战。手术也被证实可以促进癌症的发生。转移。在这个提案中，利用PLATE作为一种交付工具，团队打算开发一种为手术后根除局部释放免疫检查点抑制剂提供变革性平台残留的癌细胞。在一项初步研究中，使用B16F10黑色素瘤C57BL/6小鼠模型研究表明，抗PDL1(APDL1)结合的血小板(命名为P-aPDL1)可以促进aPDL1向残留微肿瘤的外科床积累。重要的是，负载的aPDL1可以有效地从活化的血小板中释放出来血小板衍生微粒(PMPs)对原位激活血小板的影响。此外，血小板可以产生一种局部炎症的肿瘤微环境，可促进T细胞和其他免疫细胞的活性。这里, 该团队建议进一步充实、优化和扩展血小板作为递送平台的能力用于检查站封锁为基础的癌症免疫治疗。该团队将验证详细的治疗方案探讨了P-aPDL1的作用机理，并优化了其理化性质。P-aPDL1的性能治疗循环肿瘤细胞(CTCs)也将得到评估。此外，该团队将评估潜在的以实现PDL1和吉西他滨(GEM)的联合传递，这可以上调两者的表达 PDL1和PD1分别作用于肿瘤细胞和肿瘤浸润性免疫细胞。此外，这对双胞胎还会扩展这一平台以共同传递不同的“细胞”--负载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：在目标1中，血小板传递的能力将验证和优化检查点抑制剂；在目标2中，联合提供将评估使用血小板的aPDL1和GEM；在目标3中，创新的组合细胞免疫疗法将对血小板和CAR-T细胞进行开发和评估。还有协同免疫反应由于这种组合的全身毒性，将对基于细胞的免疫疗法进行评估。拟议的研究，当在人体研究中成功证明时，将显著增强抗癌效果和提高患者的存活率。这种新的原位生物反应策略也可能激发新的治疗方法将生物微粒应用于治疗药物的靶向和生物响应释放。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

DOI：
10.1002/advs.202206001
发表时间：
2023-02
期刊：
ADVANCED SCIENCE
影响因子：
15.1
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

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

DOI：
10.1038/s41467-021-22674-3
发表时间：
2021-05-13
期刊：
Nature communications
影响因子：
16.6
作者：
Li H;Wang Z;Chen Z;Ci T;Chen G;Wen D;Li R;Wang J;Meng H;Bryan Bell R;Gu Z;Dotti G;Gu Z
通讯作者：
Gu Z

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