A novel 4D ex vivo human lymphoma model to assess CAR T and NK cell efficacy

一种新型 4D 离体人类淋巴瘤模型，用于评估 CAR T 和 NK 细胞功效

• 批准号: 505726814
• 负责人: Professor Dr. Martin-Leo Hansmann
• 金额: --
• 依托单位: Dr. Senckenbergisches Institut für Pathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/505726814?language=en
• 关键词: novel; 4D; ex; vivo; human

Adoptive transfer of T and natural killer (NK) cells expressing chimeric antigen receptors (CARs) has shown remarkable clinical efficacy against advanced B cell malignancies. However, many patients do not benefit from this treatment either because they do not respond or subsequently relapse. It is therefore of paramount importance to understand the mechanisms of tumour resistance to CAR T/NK cells. Prior to initiating clinical trials, model systems in which engineered immune cells can be characterized and tested for their potency and safety should be in place. To date, few models perfectly recapitulate the human immune system and tumour microenvironment, and some models have revealed CAR T/NK limitations that were contradicted or missed entirely in other models. Thus, careful model selection is a crucial step in evaluating CAR T/NK cell treatment and a major issue in the field of cancer immunotherapy. In this project, innovative preclinical human models that have been developed over the last years by our will be implemented and optimized to enable advanced monitoring of CAR T/NK cell efficacy that we generate. These assays include an ex vivo 4D human model that fully preserves the lymphoma environment and a microchannel system that enables to dissect engineered T and NK cell motility. Using these two models, our objectives are to monitor, using confocal fluorescent imaging techniques, early and late CD19 CAR T/NK cell responses as well as their abilities to kill malignant cells. The role played by suppressive cells and components contained within the lymphoma environment on CAR T/NK cell responses will also be investigated. Thus, we believe to significantly enrich the current state of the art approaches for the evaluation and prediction of specific CAR immune cell-based therapeutics and to overcome resistance mechanisms. Finally, the results obtained during this project will allow further optimization of personalized immune cell-based therapy of lymphoma.

表达嵌合抗原受体（CARs）的T细胞和自然杀伤细胞（NK）过继转移治疗晚期B细胞恶性肿瘤显示出显著的临床疗效。然而，许多患者没有从这种治疗中获益，因为他们没有反应或随后复发。因此，了解肿瘤抵抗CAR - T/NK细胞的机制至关重要。在开始临床试验之前，应该有模型系统，其中可以对工程免疫细胞进行表征并测试其效力和安全性。迄今为止，很少有模型完美地概括了人类免疫系统和肿瘤微环境，一些模型揭示了CAR T/NK的局限性，而这些局限性在其他模型中是相互矛盾或完全遗漏的。因此，谨慎的模型选择是评估CAR - T/NK细胞治疗的关键步骤，也是癌症免疫治疗领域的一个主要问题。在这个项目中，我们将实施和优化过去几年开发的创新临床前人体模型，以便对我们产生的CAR T/NK细胞功效进行高级监测。这些实验包括一个完全保留淋巴瘤环境的离体4D人体模型和一个能够解剖工程T和NK细胞运动的微通道系统。使用这两种模型，我们的目标是使用共聚焦荧光成像技术监测早期和晚期CD19 CAR T/NK细胞反应以及它们杀死恶性细胞的能力。抑制细胞和淋巴瘤环境中包含的成分对CAR - T/NK细胞反应的作用也将被研究。因此，我们相信这将极大地丰富当前最先进的方法，以评估和预测特异性CAR免疫细胞治疗方法，并克服耐药机制。最后，本项目获得的结果将进一步优化淋巴瘤的个性化免疫细胞治疗。