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

• 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
• 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

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 越来越多的证据表明，磷脂酰丝氨酸（PS）正成为一个有吸引力的免疫靶点 强调了它与免疫抑制的因果关系。我们已经确定黑色素瘤来源的外泌体 卵巢肿瘤微环境在其表面表达PS并抑制多个活化终点 通过T细胞受体触发的T细胞。研究还表明，PS在细胞表面的表达， 许多非凋亡癌细胞导致免疫抑制。黑色素瘤患者的最新临床研究 研究表明，从患者肿瘤释放的外泌体抑制T细胞肿瘤杀伤， 与肿瘤进展有关。我们设计并合成了一种新的化合物Zn-DPA）6-DP-15K（ExoBlock）， 以高亲合力与磷脂酰丝氨酸结合。ExoBlock被证明可以持续且显著地阻断 源自黑素瘤和卵巢肿瘤微环境的外来体的免疫抑制活性。 基于这些发现，我们预测ExoBlock将增强T细胞对肿瘤细胞的杀伤， 肿瘤异种移植物，由于其与外泌体、肿瘤和凋亡细胞上的PS结合，代表了多 pronged方法.我们使用两种不同的人类肿瘤异种移植模型测试了这一预测： 使用患者来源的卵巢癌细胞建立的经验证的内部开发的网膜肿瘤异种移植物（OTX）模型 肿瘤，和B）最近开发和验证的拟异种小鼠（X-小鼠）模型，使我们能够 在临床前量化和确定多种T细胞刺激免疫疗法的功效。这 该模型使用黑色素瘤患者来源的肿瘤特异性T细胞，其过继转移到免疫缺陷的 携带表达T细胞识别的肿瘤新抗原的黑素瘤异种移植物的小鼠。治疗 ExoBlock的功效接下来通过显著增强OTX和X-细胞中的肿瘤抑制来确定。 在小鼠模型中，发现与抗PD-1疗法相当。这些结果一起 为我们在第一阶段申请中提出的工作奠定了基础和理论基础。其他毒性和 在目的1中提出了ExoBlock的药代动力学（PK）研究。PK研究将有助于确定 将在目标2中测试的ExoBlock的最佳剂量、时间表和递送方法。在Aim 2 ExoBlock中， 体内测试其在由患者来源的抗肿瘤药物组成的网膜肿瘤异种移植（OTX）模型中的治疗功效。 卵巢肿瘤和具有B16-F10肿瘤的同基因小鼠黑素瘤模型。我们的理论是， 并对小鼠肿瘤模型进行了探讨。第一阶段研究的结果将为 在未来的2期研究中进行更广泛的研究，这将导致ExoBlock的IND和临床试验。

项目成果

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)
• 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