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癌症治疗中的重大挑战。还已经证实，手术可以诱导癌症促进转移。在此建议中，使用血小板作为送货工具，团队打算开发一个用于局部释放免疫切除点抑制剂的变革平台残留的癌细胞。在一项初步研究中，使用B16F10黑色素瘤肿瘤C57BL/6小鼠模型，已经证明抗PDL1（APDL1）附着的血小板（指定的P-APDL1）可以促进APDL1的积累朝着残留的微型肿块保留的手术床的积累。重要的是，加载的APDL1可以有效地从由激活的血小板中释放原位血小板激活后，血小板衍生的微粒（PMP）。此外，血小板可以生成一个局部发炎的肿瘤微环境，可以增强T细胞的活性以及其他免疫细胞。这里，团队的建议，以进一步证实，优化和扩展血小板作为交付平台的能力用于检查点基于封锁的癌症免疫疗法。团队将验证详细的治疗 P-APDL1的机理以及优化其物理化学特性。 p-apdl1的功能还将评估处理循环肿瘤细胞（CTC）。此外，团队将评估潜力血小板以实现APDL1和Gemcitabine（GEM）的组合交付，可以更新两者肿瘤细胞和肿瘤上的PDL1和PD1分别浸润免疫细胞。此外，摇动将将此平台扩展到不同的“细胞” - 疗法的血小板和特定的嵌合抗原接收器（CAR）T细胞。将追求三个目标：在AIM 1中，血小板的传递能力检查点抑制剂将得到验证和优化；在AIM 2中，结合交付的有效性将评估使用血小板的APDL1和GEM；在AIM 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。也有协同免疫复杂由于该组合细胞的全身毒性将评估。拟议的研究，当在人类研究中成功证明时，将显着提高抗癌效率和改善患者的生存。这部小说原位生物响应策略也可能激发新疗法应用生物局部用于靶向和生物响应性释放治疗。

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

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

DOI：
10.1126/sciadv.abc3013
发表时间：
2020-12
期刊：
Science advances
影响因子：
13.6
作者：
Ci T;Li H;Chen G;Wang Z;Wang J;Abdou P;Tu Y;Dotti G;Gu Z
通讯作者：
Gu Z

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

Local and Targeted Delivery of Immune Checkpoint Blockade Therapeutics.