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：
10647720
负责人：
Simone Krebs
金额：
$ 66.87万
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/10647720
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 Trials Complex Dose Drug Kinetics Endowment Ensure Exclusion Excretory function Exhibits Generations Goals Haptens Hepatobiliary Human Image Immune ImmunoPET Immunohistochemistry Immunologic Deficiency Syndromes In Vitro Inflammatory Inflammatory Response Pathway Kinetics Lanthanoid Series Elements Location Malignant Neoplasms Mentored Clinical Scientist Development Program 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 Transfusion Translations Treatment Efficacy Treatment Failure Variant Visualization Work Xenograft Model Xenograft procedure 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 translational approach treatment effect tumor tumor heterogeneity tumor microenvironment uptake

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细胞中表现出显着的珍贵效应 MALIGNNANC，但许多患者最近患有有限的反应和CD19阴性的肿瘤复发证明了下一代“装甲”汽车T细胞组成型表达免疫刺激分子CD40配体（CD40L）在临床前研究中表现出优质的抗肿瘤功效，但尚未在汽车抗原阴性肿瘤复发的背景下进行了充分探索。仍然需要迫切需要作为无创的体内tcells来设计他们的生物疗法，扩展和功能性，并增加汽车t -cells的杀戮能力治疗失败，我们开始开发监测体内动力学的方法基于免疫细胞射击的概念，我们首次证明了可以用DOTA抗体报告DABBR1成功转导T细胞，从而实现其体内跟踪通过宠物和SPECT。基于1个大大改善的成分1） RadioHapten Captore Reporter SCFV C825具有皮摩尔结合亲和力，以及2）优化的放射剂，下一步适用于成像和靶向α疗法（TAT）的生成蛋白酶（PR）系列该研究的目的是开发临床适用的PET成像，以b-- 细胞恶性肿瘤并进一步研究CD40L对应对合成性免疫遗传的影响 B细胞恶性肿瘤的模型。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。将采用抗原损失变体。成功转导后，我们将评估汽车和记者以及辐射托克斯城，然后是体内功能，成像敏感性以及生物疗法，并通过新颖对开发基于装甲的Car T细胞Theranostich方法 [86y] YPR/[225AC] ACPR。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细胞这样的平台将主要用于更安全，更有效的临床试验已经对我们当前的临床CD19 CAR T研究和其他计划的汽车进行了翻译相关性细胞疗法试验。