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:
- 金额:$ 29.32万
- 依托单位:
- 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:
- 关键词:AddressAdoptive TransferAnimal ModelAntitumor ResponseApoptoticAvidityBindingBiological AvailabilityBlocking AntibodiesCancer PatientCell membraneCellsClinical DataClinical ResearchClinical TrialsCombined Modality TherapyDataDoseDrug KineticsFoundationsFutureGoalsGrowthHumanImmuneImmune TargetingImmunodeficient MouseImmunosuppressionImmunotherapeutic agentImmunotherapyIn VitroInjectionsLeadLinkLipid BilayersMalignant NeoplasmsMalignant neoplasm of ovaryMeasuresMediatingMethodsModelingMonoclonal AntibodiesMusNamesNatureNeoplasm MetastasisOncologyOperative Surgical ProceduresOvarianPatientsPharmaceutical PreparationsPharmacodynamicsPhasePhosphatidylserinesPreclinical TestingRadiation therapyRecurrenceReportingScheduleSurfaceT cell responseT cell therapyT-Cell ActivationT-Cell ReceptorT-LymphocyteTestingTherapeuticTherapeutic StudiesToxic effectTreatment EfficacyTumor BurdenTumor SuppressionTumor-DerivedValidationVesicleVirusWorkXenograft ModelXenograft procedureanti-tumor immune responsebasecancer cellcancer immunotherapycancer therapychemotherapydesignefficacy testingexosomeextracellular vesiclesimmune checkpointimmune checkpoint blockadeimprovedimproved outcomein vivoin vivo evaluationmelanomamouse modelnanosizedneoantigensneoplastic cellnew therapeutic targetnovelnovel anticancer drugovarian neoplasmpharmacokinetic modelpharmacokinetics and pharmacodynamicsphase 1 studyphase 2 studypre-clinicalpre-clinical therapyresponsesuccesstherapeutic targettreatment strategytumortumor microenvironmenttumor progressiontumor 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.
抽象的
鉴于越来越多的证据,磷脂酰丝氨酸(PS)正在成为一个有吸引力的免疫治疗靶点
强调其与免疫抑制的因果关系。我们已经确定源自黑色素瘤的外泌体
和卵巢肿瘤微环境在其表面表达 PS 并抑制多个激活终点
通过 T 细胞受体触发的 T 细胞。研究还表明PS表面的表达
许多非凋亡癌细胞会导致免疫抑制。黑色素瘤患者的最新临床研究
证明从患者肿瘤释放的外泌体可抑制 T 细胞肿瘤杀伤并有助于
到肿瘤进展。我们设计并合成了一种新化合物 Zn-DPA)6-DP-15K (ExoBlock),
以高亲和力与磷脂酰丝氨酸结合。 ExoBlock 被证明能够持续且显着地阻止
源自黑色素瘤和卵巢肿瘤微环境的外泌体的体外免疫抑制活性。
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作用
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
多管齐下。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:a) 之前的模型
使用患者来源的卵巢建立经过验证的内部开发的网膜肿瘤异种移植(OTX)模型
肿瘤,以及 b) 最近开发和验证的 Xenomimetic 小鼠 (X-mouse) 模型,使我们能够
在临床前量化并确定多种 T 细胞刺激免疫疗法的功效。这
该模型使用源自黑色素瘤患者的肿瘤特异性 T 细胞,这些 T 细胞被过继转移到免疫缺陷中
携带黑色素瘤异种移植物的小鼠表达 T 细胞识别的肿瘤新抗原。治疗性的
接下来通过显着增强 OTX 和 X-肿瘤抑制来确定 ExoBlock 的功效
小鼠模型,并被发现与 X 小鼠模型中的抗 PD-1 疗法相当。综合起来,这些结果
为我们在第一阶段申请中提出的工作奠定了基础和理由。额外的毒性和
目标 1 中建议对 ExoBlock 进行药代动力学 (PK) 研究。PK 研究将有助于确定
ExoBlock 的最佳剂量、时间表和递送方法将在目标 2 中进行测试。在目标 2 中,ExoBlock 将
体内测试其在大网膜肿瘤异种移植(OTX)模型中的治疗效果,该模型由患者来源的
卵巢肿瘤和具有 B16-F10 肿瘤的同基因小鼠黑色素瘤模型。我们使用人类的理由
方法中讨论了小鼠肿瘤模型。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
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:
- 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:
- 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:
- 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
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RICHARD B BANKERT其他文献
RICHARD B BANKERT的其他文献
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{{ truncateString('RICHARD B BANKERT', 18)}}的其他基金
Role of Memory T Cells in Pathogenesis and Resolution of Inflammatory Diseases
记忆 T 细胞在炎症性疾病发病机制和解决中的作用
- 批准号:
8018802 - 财政年份:2010
- 资助金额:
$ 29.32万 - 项目类别:
Re-activating Memory T Cells in the Microenvironment of Human Tumors
重新激活人类肿瘤微环境中的记忆 T 细胞
- 批准号:
9065674 - 财政年份:2007
- 资助金额:
$ 29.32万 - 项目类别:
Re-activating Memory T Cells in the Microenvironment of Human Tumors
重新激活人类肿瘤微环境中的记忆 T 细胞
- 批准号:
8576662 - 财政年份:2007
- 资助金额:
$ 29.32万 - 项目类别:
Re-activating Memory T Cells in the Microenvironment of Human Tumors
重新激活人类肿瘤微环境中的记忆 T 细胞
- 批准号:
7990409 - 财政年份:2007
- 资助金额:
$ 29.32万 - 项目类别:
Re-activating Memory T Cells in the Microenvironment of Human Tumors
重新激活人类肿瘤微环境中的记忆 T 细胞
- 批准号:
8196768 - 财政年份:2007
- 资助金额:
$ 29.32万 - 项目类别:
Re-activating Memory T Cells in the Microenvironment of Human Tumors
重新激活人类肿瘤微环境中的记忆 T 细胞
- 批准号:
7544973 - 财政年份:2007
- 资助金额:
$ 29.32万 - 项目类别:
Re-activating Memory T Cells in the Microenvironment of Human Tumors
重新激活人类肿瘤微环境中的记忆 T 细胞
- 批准号:
7353638 - 财政年份:2007
- 资助金额:
$ 29.32万 - 项目类别:
Re-activating Memory T Cells in the Microenvironment of Human Tumors
重新激活人类肿瘤微环境中的记忆 T 细胞
- 批准号:
8848784 - 财政年份:2007
- 资助金额:
$ 29.32万 - 项目类别:
Re-activating Memory T Cells in the Microenvironment of Human Tumors
重新激活人类肿瘤微环境中的记忆 T 细胞
- 批准号:
8723760 - 财政年份:2007
- 资助金额:
$ 29.32万 - 项目类别:
Re-activating Memory T Cells in the Microenvironment of Human Tumors
重新激活人类肿瘤微环境中的记忆 T 细胞
- 批准号:
7741732 - 财政年份:2007
- 资助金额:
$ 29.32万 - 项目类别:
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