Combination antigen sensing engineered T cell for precise recognition and enhanced elimination of solid tumors

组合抗原传感工程 T 细胞可精确识别并增强实体瘤的消除

• 批准号: 10651062
• 负责人: BIN LIU
• 金额: $ 66.61万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-04 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651062
• 关键词: Address; Affinity; Alkaline Phosphatase; Antibodies; Antigen Targeting; Antigens; B lymphoid malignancy; Bacteriophages; Binding; Biological Markers; CAR T cell therapy; CAR receptor; CD8B1 gene; Cell Therapy; Cell surface; Clinic; Clinical; Collaborations; Credentialing; DNA Binding Domain; Development; Engineering; Family; Generations; Genes; Goals; Human; Immune; Immune response; Immunoglobulin Fragments; In Vitro; Laboratories; Libraries; Logic; Malignant Neoplasms; Malignant mesothelioma; Mesothelioma; Modeling; Nature; Normal tissue morphology; Patient-Focused Outcomes; Patients; Placenta; Preclinical Testing; Prognosis; Proteolysis; Rare Diseases; Refractory; Relapse; Reporting; Research; Sampling; Seminoma; Signal Transduction; Site; Solid Neoplasm; Specificity; Specimen; Surface Antigens; System; T cell therapy; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Tissues; Toxic effect; Transactivation; Transcriptional Activation; Translations; Treatment Efficacy; Tumor Antigens; Viral Proteins; Work; Xenograft Model; antibody engineering; antigen binding; chimeric antigen receptor T cells; clinical efficacy; clinical translation; cytokine; design; engineered T cells; exhaustion; extracellular; flexibility; human DNA; human monoclonal antibodies; human tissue; immunoregulation; improved; in vivo; member; mesothelin; neoplastic cell; notch protein; novel; novel strategies; novel therapeutics; patient biomarkers; patient stratification; receptor; research clinical testing; success; synthetic antibodies; therapeutic development; translational potential; trophoblast; tumor; tumor microenvironment; yeast protein

Abstract: The goal of this proposal is to develop an engineered T cell therapy with potential of translation into human testing. We will develop a clinically optimized combination antigen sensing prime-and-kill circuit T cell for precise recognition and enhanced elimination of mesothelioma, a rare disease with poor prognosis. The work is built on our recent progress in T cell engineering and novel tumor antigen discovery: (1) a prime-and-kill dual antigen AND-gated circuit with fully human components (dubbed as SNIPR for SyNthetic Intramembrane Proteolysis Receptors) that facilitate clinical translation. (2) A novel tumor specific cell surface antigen ALPPL2 (aka ALPG) that is expressed in mesothelioma but not any of the normal human tissues except for the placenta. Paired with the credentialed mesothelioma antigen mesothelin, the ALPPL2 SNIPR → CAR circuit T cell enables precise temporal and spatial control of T cell activation at the site of the tumor, minimizes on-target off-tumor toxicity, reduces tonic signaling and T cell exhaustion, and maintains multifunctional T cell states. The circuit design is modular and flexible and can be induced to locally deliver additional immune modulatory payloads such as cytokines to further improve efficacy. In addition, our research has shown that SNIPR → CAR circuit T cells are capable of effectively targeting antigens that are heterogeneously expressed in tumors, a common pitfall for therapeutic efficacy. We propose to perform translation-enabling studies: (Aim 1) Optimize antibodies for SNIPR T cell construction, and develop biomarker for patient stratification. (Aim 2) Engineer and evaluate humanized clinical grade SNIPR → AND logic T cells in vitro and in vivo. (Aim 3) Evaluate SNIPR-engineered prime-and- kill circuit T cells in killing tumor with heterogeneous target antigen expression. Successful completion of the project will enable us to move the SNIPR → CAR circuit T cell to translational development and identify via the biomarker appropriate mesothelioma patients for clinical testing.

摘要： 该提案的目标是开发一种具有翻译成人类的潜力的工程化T细胞疗法。 试验.我们将开发一种临床优化的组合抗原感应引发和杀伤电路T细胞，用于精确的免疫治疗。 间皮瘤是一种罕见的预后不良的疾病，这项工作是建立在 我们在T细胞工程和新肿瘤抗原发现方面的最新进展：（1）一种致敏-杀伤双重抗原 与门电路与全人类组件（称为SNIPR的合成膜内蛋白水解 受体），促进临床翻译。(2)一种新的肿瘤特异性细胞表面抗原ALPPL 2（aka ALPG） 在间皮瘤中表达，但在除胎盘外的任何正常人体组织中均不表达。搭配 有资格的间皮瘤抗原间皮素，ALPPL 2 SNIPR → CAR电路T细胞使精确的 在肿瘤部位的T细胞活化的时间和空间控制，最小化靶向肿瘤外毒性， 减少紧张性信号传导和T细胞耗竭，并维持多功能T细胞状态。电路设计 并且可以被诱导以局部递送另外的免疫调节有效载荷， 细胞因子以进一步提高功效。此外，我们的研究表明，SNIPR → CAR电路T细胞是 能够有效地靶向在肿瘤中异质表达的抗原，这是肿瘤治疗的常见缺陷。 疗效我们建议进行预防性研究：（目的1）优化SNIPR抗体 T细胞构建，并开发用于患者分层的生物标志物。(Aim 2）人性化设计与评价 临床级SNIPR → AND逻辑T细胞的体外和体内研究。(Aim 3）评估SNIPR工程化的引物-和- 杀伤回路T细胞杀伤具有异质性靶抗原表达的肿瘤。成功完成 该项目将使我们能够将SNIPR → CAR电路T细胞转移到翻译开发中，并通过 适合间皮瘤患者的生物标志物进行临床检测。