T-cell Biofactories for targeting interstitial fluid pressure

针对间质液压力的 T 细胞生物工厂

• 批准号: 9906864
• 负责人: Parijat Bhatnagar
• 金额: $ 26万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-04 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906864
• 关键词: Affect; Biological Assay; Biological Availability; Biological Markers; Biology; Blood Circulation; Breast; CCL4 gene; Cachexia; Calcium; Calcium Channel; Cells; Clinic; Colon; Connective Tissue; Cues; Cytotoxic T-Lymphocytes; Desmoplastic; Disease; Disease model; Drug resistance; Engineering; Environment; Enzymes; Extracellular Matrix; FDA approved; Glycoside Hydrolases; Goals; Growth; Half-Life; Hyaluronan; Hyaluronidase; Immune system; Immunosuppression; Immunotherapy; Impairment; In Situ; In Vitro; Infusion procedures; Intercellular Fluid; Investigation; Ion Channel; Knowledge; Laboratories; Lead; Light; Malignant Neoplasms; Malignant neoplasm of pancreas; Mission; Molecular; Monitor; Normal tissue morphology; Outcome; Ovarian; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathology; Perfusion; Phase; Prostate; Proteins; Public Health; Research; Research Personnel; Resistance development; Safety; Signal Pathway; Signal Transduction; Site; Solid Neoplasm; Source; Stomach; Stress; T-Cell Activation; T-Lymphocyte; TRPV1 gene; Technology; Therapeutic; Tissues; Toxic effect; Transcriptional Activation; Treatment outcome; Tumor Pathology; Work; antitumor agent; base; cancer therapy; chemotherapy; dosage; engineered T cells; enzyme therapy; improved; in vivo; innovation; molecular marker; neoplastic cell; pressure; response; rituximab; side effect; skeletal; standard of care; success; technology development; transgene expression; tumor; tumor microenvironment

PROJECT SUMMARY The focus of this proposal is to develop pressure-sensitive T cells that can activate in response to the high interstitial fluid pressure (IFP) in many solid tumors and release an engineered enzyme to neutralize its source. The dense fibrous extracellular matrix (ECM) tissue growth common in many solid tumors presents a physical barrier to the current standard of care chemotherapies and immunotherapies. It leads to the compressive stresses that cause high interstitial fluid pressure (IFP) (>100 mmHg) as compared to that within normal tissues (-4 to -6 mmHg). Together, the ECM barrier and IFP resist the influx of therapeutics into tumor sites. The ECM also harbors the tumor microenvironment (TME) that causes drug resistance and immunosuppression. Hence, the challenge is to selectively break down the ECM at the tumor site to enable the entry of therapeutic cytolytic T cells without affecting the normal connective tissues. Here, the investigators propose that T cells can be engineered to provide a solution to this challenge by selectively degrading the ECM. The investigators' long-term goal is to develop new treatments by harnessing the cell's potential to interact with the in vivo environment and target the underlying mechanisms in the disease pathology. The objective of this project, toward this long-term goal, is to engineer the T cells to synthesize and release the ECM degrading enzymes upon sensing increased IFP. To achieve this objective, their strategy is to engineer the T cells with an artificial cell signaling cascade that upregulates the desired proteins in situ. This work is supported by their preliminary work on engineering the T cells and use of a new assay to simulate IFP in vitro. The rationale for this effort is that it will lead to a cellular technology to locally disrupt the tumor ECM and reduce IFP to assist the influx of antitumor agents for improved treatment outcome. The investigators have described specific milestones with quantitative metric of success and will use the following parallel aims to conduct the investigations: Engineering of T cells with pressure-sensitive trigger (Aim 1); Engineering of T cell for pressure-induced expression of ECM degrading enzyme (Aim 2). This effort is expected to lead to a broad- spectrum technology that has the potential for high-impact. This is because there is no known molecular biomarker to target either the ECM or IFP. The proposed approach is innovative because it challenges the status quo by engineering the T cells to actively traffic to the TME and synthesize an ECM-degrading enzyme in situ. This will mitigate the IFP and enable perfusion of engineered cytolytic T cells to kill tumor cells; as well as alter the continuously evolving TME to overcome drug resistance and immunosuppression.

项目摘要 该提案的重点是开发对高响应高的压力敏感的T细胞 在许多实体瘤中的间质流体压力（IFP）并释放工程酶以中和其源。 在许多实体瘤中，致密的纤维纤维细胞外基质（ECM）组织的生长呈现出物理 当前护理化疗和免疫疗法的障碍。它导致压缩 与正常情况相比 组织（-4至-6 mmHg）。 ECM屏障和IFP一起抵抗了疗法涌入肿瘤部位。 ECM还具有引起耐药性和的肿瘤微环境（TME） 免疫抑制。因此，挑战是选择性分解肿瘤部位的ECM以实现 治疗性细胞溶解T细胞的进入而不影响正常结缔组织。在这里，调查人员 建议可以通过选择性地降解T细胞来设计T细胞以提供解决此挑战的解决方案 ECM。调查人员的长期目标是通过利用细胞的潜力来开发新的治疗方法 与体内环境相互作用，并针对疾病病理学中的潜在机制。这 实现这一长期目标的该项目的目的是设计T细胞，以合成并释放 传感时，ECM降解酶会增加IFP。为了实现这一目标，他们的策略是设计 带有人造细胞信号级联的T细胞上调原位所需的蛋白质。这项工作是 由他们在工程上进行T细胞的初步工作以及使用新测定法在体外模拟IFP的支持。 这项工作的理由是，它将导致一种细胞技术，以局部破坏肿瘤ECM和 减少IFP以帮助抗肿瘤剂的涌入以改善治疗结果。调查人员有 描述了具有定量成功指标的特定里程碑，并将使用以下平行目的 进行研究：具有压敏触发器的T细胞工程（AIM 1）； T细胞的工程 用于压力诱导的ECM降解酶的表达（AIM 2）。预计这项努力将导致广泛的 具有高影响力的频谱技术。这是因为没有已知的分子 生物标志物靶向ECM或IFP。提出的方法是创新的，因为它挑战了 通过设计T细胞来主动访问TME并合成ECM降解酶来实现现状 原位。这将减轻IFP，并使工程溶细胞T细胞的灌注杀死肿瘤细胞。也是如此 随着改变不断发展的TME，以克服耐药性和免疫抑制。