Interrogating the in vivo pharmacokinetics of armored CARs with radiohapten capture

通过放射性半抗原捕获来探究装甲 CAR 的体内药代动力学

基本信息

批准号：
10447176
负责人：
Simone Krebs
金额：
$ 55.17万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2021-07-07 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10447176
关键词：
Ablation Adoptive Cell Transfers Affinity Animals Antibodies Antigen Receptors Antigens Autoradiography B lymphoid malignancy Binding Biodistribution Biological Biological Assay CAR T cell therapy CD19 gene CD40 Antigens CD40 Ligand Cell Count Cell surface Cells Clinical Clinical Oncology Supplement (K12)Clinical Trials Complex Dose Drug Kinetics Ensure Excretory function Exhibits Generations Goals Haptens Hepatobiliary Human Image Immune ImmunoPET Immunohistochemistry In Vitro Inflammatory Inflammatory Response Pathway Kinetics Lanthanoid Series Elements Location Malignant Neoplasms Methodology Methods Modeling Molecular Target Monitor Mus Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Positron-Emission Tomography Proteus Radiation Toxicity Radiometry Radionuclide therapy Relapse Reporter Reporter Genes Role Safety Series Specificity System T cell therapy T-Lymphocyte Therapeutic Therapy trial Time Tissues Titrations Translations Treatment Efficacy Treatment Failure Variant Work Xenograft Model Xenograft procedure base cell killing cellular imaging chimeric antigen receptor chimeric antigen receptor T cells clinical application clinical translation clinically relevant contrast imaging cytotoxic dosimetry effector T cell engineered T cells exhaustion gene function improved in vivo in vivo monitoring insight method development molecular imaging mouse model neoplastic cell next generation novel preclinical study preservation response single photon emission computed tomography success theranostics therapeutic target tool trafficking treatment effect tumor tumor heterogeneity tumor microenvironment uptake weapons

Ablation Adoptive Cell Transfers Affinity Animals Antibodies Antigen Receptors Antigens Autoradiography B lymphoid malignancy Binding Biodistribution Biological Biological Assay CAR T cell therapy CD19 gene CD40 Antigens CD40 Ligand Cell Count Cell surface Cells Clinical Clinical Oncology Supplement (K12)Clinical Trials Complex Dose Drug Kinetics Ensure Excretory function Exhibits Generations Goals Haptens Hepatobiliary Human Image Immune ImmunoPET Immunohistochemistry In Vitro Inflammatory Inflammatory Response Pathway Kinetics Lanthanoid Series Elements Location Malignant Neoplasms Methodology Methods Modeling Molecular Target Monitor Mus Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Positron-Emission Tomography Proteus Radiation Toxicity Radiometry Radionuclide therapy Relapse Reporter Reporter Genes Role Safety Series Specificity System T cell therapy T-Lymphocyte Therapeutic Therapy trial Time Tissues Titrations Translations Treatment Efficacy Treatment Failure Variant Work Xenograft Model Xenograft procedure base cell killing cellular imaging chimeric antigen receptor chimeric antigen receptor T cells clinical application clinical translation clinically relevant contrast imaging cytotoxic dosimetry effector T cell engineered T cells exhaustion gene function improved in vivo in vivo monitoring insight method development molecular imaging mouse model neoplastic cell next generation novel preclinical study preservation response single photon emission computed tomography success theranostics therapeutic target tool trafficking treatment effect tumor tumor heterogeneity tumor microenvironment uptake weapons

展开

项目摘要

Project Summary/Abstract CD19-targeted chimeric antigen receptor (CAR) T cell therapy has shown remarkable treatment effects in B-cell malignancies, but many patients suffer from limited response and CD19-negative tumor relapse. Recently, we demonstrated that next-generation “armored” CAR T cells constitutively expressing the immune-stimulatory molecule CD40 ligand (CD40L) exhibited superior antitumor efficacy in preclinical studies but have not yet been fully explored in the context of CAR antigen-negative tumor relapse. There remains an urgent need for the non-invasive in vivo tracking of transfused T cells to determine their biodistribution, expansion, and functionality and to increase the CAR T cells’ killing capacity in case of imminent treatment failure. To overcome these limitations, we began developing methods for monitoring the in vivo kinetics of CAR T cells based on the concept of immune cell radiohapten capture. We demonstrated for the first time that T cells can be successfully transduced with a DOTA-antibody reporter, the DAbR1, enabling their in vivo tracking via PET and SPECT. In the current proposal, we build on this work and optimize our approach for translation of immune cell radiohapten capture from animals to patients, based on greatly improved components of 1) radiohapten capture reporter scFv C825 with picomolar binding affinity, and 2) optimized radiohaptens, the next- generation Proteus-DOTA (Pr) series suitable for imaging and targeted alpha therapy (TAT). The primary objectives of this study are to develop a clinically applicable PET imaging strategy of CAR T cell trafficking in B- cell malignancies and further study the effect of CD40L on counteracting the immune inhibition in syngeneic models of B-cell malignancies. The secondary objectives are to deliver TAT to enhance T cells’ killing capacity in cases of imminent treatment failure and improve the potency of CAR T cell therapies. We project to achieve our aims by generating second-generation and armored CD 19 CAR T cells expressing cell-surface anchored scFv C825. Syngeneic and immunodeficient xenograft murine models of CD19+ B cell malignancies including antigen-loss variants will be employed. After successful transduction, we will assess in vitro functionality of the CAR and the reporter, as well as radiation toxicity, followed by in vivo functionality, imaging sensitivity, and biodistribution, and develop an armored CAR T cell-based theranostic approach with the novel pair [86Y]YPr/[225Ac]AcPr. Finally, as a prerequisite to clinical translation of this novel platform, we will conduct studies using human second-generation and armored CAR T cells in clinically relevant xenograft models. The availability of such a single platform would provide crucial information for safer, more effective clinical trials. The aims thus have immediate translational relevance for our current clinical CD19 CAR T studies and other planned CAR T cell therapy trials.

项目摘要/摘要 CD19靶向的嵌合抗原受体（CAR）T细胞疗法在B细胞中显示出显着的治疗效果恶性肿瘤，但许多患者的反应有限和CD19阴性肿瘤缓解。最近，我们证明了下一代“装甲”汽车T细胞组成性表达免疫刺激性分子CD40配体（CD40L）在临床前研究中暴露了上等抗肿瘤效率，但尚未是在汽车抗原阴性肿瘤缓解的背景下进行了充分探索。迫切需要对输血T细胞的非侵入性体内跟踪来确定其生物分布，扩展和功能，并在迫在眉睫的情况下增加汽车T细胞的杀伤能力治疗失败。为了克服这些限制，我们开始开发用于监测体内动力学的方法基于免疫细胞射量捕获的概念的CAR T细胞。我们第一次证明可以使用DOTA抗体报告DABR1成功传输T细胞，从而实现其体内跟踪通过PET和SPECT。在当前的建议中，我们以这项工作为基础，并优化了我们的翻译方法基于1个大大改善的成分，免疫细胞的捕获从动物到患者的捕获）带有皮摩尔结合亲和力的RadioHapten捕获记者SCFV C825，以及2）优化的放射性适用于成像和靶向α疗法（TAT）的生成proteus-dota（PR）系列。主要这项研究的目标是制定b-中汽车T细胞运输的临床适用的PET成像策略细胞恶性肿瘤并进一步研究CD40L对应对合成性免疫抑制作用的影响 B细胞恶性肿瘤的模型。次要目标是提供TAT以增强T细胞的杀戮能力在迫在眉睫的治疗失败并提高CAR T细胞疗法的效力的情况下。我们计划实现我们的目的是通过产生第二代和装甲CD 19车T细胞，表达细胞表面的锚固 SCFV C825。 CD19+ B细胞恶性肿瘤的合成和免疫缺陷的异种移植鼠模型包括将雇用抗原损坏变体。成功翻译后，我们将评估汽车和记者以及辐射毒性，然后体内功能，成像敏感性和生物分布，并通过新颖对开发一种基于装甲的汽车T细胞的疗法方法 [86Y] YPR/[225AC] ACPR。最后，作为这个新型平台的临床翻译的先决条件，我们将进行研究在临床上相关的异种移植模型中，使用人类的第二代和装甲车T细胞。可用性这样的单个平台将为更安全，更有效的临床试验提供至关重要的信息。因此的目的与我们当前的临床CD19 CAR T研究和其他计划的汽车具有直接的翻译相关性细胞疗法试验。