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Novel Drug for Cancer Immunotherapy that Targets Phosphatidylserine

针对磷脂酰丝氨酸的癌症免疫治疗新药

基本信息

批准号：
10254727
负责人：
RICHARD B BANKERT
金额：
$ 29.32万
依托单位：
IMMUNE MODULATORY THERAPIES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-11 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10254727
关键词：
Address Adoptive Transfer Animal Model Antitumor Response Apoptotic Avidity Binding Biological Availability Blocking Antibodies Cancer Patient Cell membrane Cells Clinical Data Clinical Research Clinical Trials Combined Modality Therapy Data Dose Drug Kinetics Foundations Future Goals Growth Human Immune Immune Targeting Immunodeficient Mouse Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Injections Lead Link Lipid Bilayers Malignant Neoplasms Malignant neoplasm of ovary Measures Mediating Methods Modeling Monoclonal Antibodies Mus Names Nature Neoplasm Metastasis Oncology Operative Surgical Procedures Ovarian Patients Pharmaceutical Preparations Pharmacodynamics Phase Phosphatidylserines Preclinical Testing Radiation therapy Recurrence Reporting Schedule Surface T cell response T cell therapy T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Therapeutic Studies Toxic effect Treatment Efficacy Tumor Burden Tumor Suppression Tumor-Derived Validation Vesicle Virus Work Xenograft Model Xenograft procedure anti-tumor immune response base cancer cell cancer immunotherapy cancer therapy chemotherapy design efficacy testing exosome extracellular vesicles immune checkpoint immune checkpoint blockade improved improved outcome in vivo in vivo evaluation melanoma mouse model nanosized neoantigens neoplastic cell new therapeutic target novel novel anticancer drug ovarian neoplasm pharmacokinetic model pharmacokinetics and pharmacodynamics phase 1 study phase 2 study pre-clinical pre-clinical therapy response success therapeutic target treatment strategy tumor tumor microenvironment tumor progression tumor xenograft

项目摘要

Abstract Phosphatidylserine (PS) is emerging as an attractive immunotherapeutic target in the light of mounting evidence highlighting its causal link to immune suppression. We have established that exosomes derived from melanoma and ovarian tumor microenvironments express PS on their surfaces and suppress multiple activation endpoints of T cells triggered through the T cell receptor. Studies have also shown that expression of PS on the surface of many non-apoptotic cancer cells lead to immunosuppression. Recent clinical studies in melanoma patients demonstrated that exosomes that are released from patient tumors suppress T cell tumor killing and contribute to tumor progression. We have designed and synthesized a new compound, Zn-DPA)6-DP-15K (ExoBlock) that binds to phosphatidylserine with high avidity. ExoBlock was shown to consistently and significantly block the immune suppressive activity of exosomes derived from melanoma and ovarian tumor microenvironments in vitro. Based upon these findings, we predicted that ExoBlock would enhance the killing of tumor cells by T cells in tumor xenografts due to its binding to PS on the exosomes, tumor and apoptotic cells, representing a multi- pronged approach. We tested this prediction using two different human tumor xenograft models: a) the previously validated in-house developed omental tumor xenograft (OTX) model established using patient-derived ovarian tumors, and b) the recently developed and validated Xenomimetic mouse (X-mouse) model that allows us to quantify and establish the efficacy of multiple T cell-stimulating immune-based therapies pre-clinically. This model uses melanoma patient-derived tumor-specific T cells that are adoptively transferred into immunodeficient mice bearing melanoma xenografts expressing tumor neo-antigens recognized by the T cells. The therapeutic efficacy of ExoBlock was next established by significantly enhancing tumor suppression in both the OTX and X- mouse models, and was found to be comparable to anti-PD-1 therapy in X-mouse model. Together, these results have laid the foundation and rationale for our work proposed in the Phase I application. Additional toxicity and pharmacokinetic (PK) studies are proposed for ExoBlock in Aim 1. The PK studies will help to determine the optimal dose, schedule and delivery method of ExoBlock that will be tested in aim 2. In Aim 2 ExoBlock will be tested in vivo for its therapeutic efficacy in omental tumor xenograft (OTX) model consisting of patient-derived ovarian tumor and syngeneic mouse melanoma model with B16-F10 tumor. Our rationale for using both a human and mouse tumor model is discussed in the Approach. The results of this Phase 1 study will lay the foundation for a more extensive study in a future phase 2 study that will lead to an IND and clinical trial of ExoBlock.

摘要

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exosomes Represent an Immune Suppressive T Cell Checkpoint in Human Chronic Inflammatory Microenvironments.

DOI：
10.1080/08820139.2020.1748047
发表时间：
2020-10
期刊：
Immunological investigations
影响因子：
2.8
作者：
Shenoy GN;Bhatta M;Loyall JL;Kelleher RJ Jr;Bernstein JM;Bankert RB
通讯作者：
Bankert RB

Tumor-Associated Exosomes: A Potential Therapeutic Target for Restoring Anti-Tumor T Cell Responses in Human Tumor Microenvironments.

DOI：
10.3390/cells10113155
发表时间：
2021-11-13
期刊：
Cells
影响因子：
6
作者：
Shenoy GN;Bhatta M;Bankert RB
通讯作者：
Bankert RB

Sialic Acid-Dependent Inhibition of T Cells by Exosomal Ganglioside GD3 in Ovarian Tumor Microenvironments.

DOI：
10.4049/jimmunol.1801041
发表时间：
2018-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Shenoy GN;Loyall J;Berenson CS;Kelleher RJ Jr;Iyer V;Balu-Iyer SV;Odunsi K;Bankert RB
通讯作者：
Bankert RB