Franzén Alexander Sebastian, Boulifa Abdelhadi, Radecke Clarissa, Stintzing Sebastian, Raftery Martin J, Pecher Gabriele
Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Competence Center of Immuno-Oncology and Translational Cell Therapy (KITZ), Department of Hematology, Oncology and Tumor Immunology, CCM, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Cancers (Basel). 2024 Jan 16;16(2):388. doi: 10.3390/cancers16020388.
Colorectal carcinoma (CRC) presents a formidable medical challenge, demanding innovative therapeutic strategies. Chimeric antigen receptor (CAR) natural killer (NK) cell therapy has emerged as a promising alternative to CAR T-cell therapy for cancer. A suitable tumor antigen target on CRC is carcinoembryonic antigen (CEA), given its widespread expression and role in tumorigenesis and metastasis. CEA is known to be prolifically shed from tumor cells in a soluble form, thus hindering CAR recognition of tumors and migration through the TME. We have developed a next-generation CAR construct exclusively targeting cell-associated CEA, incorporating a PD1-checkpoint inhibitor and a CCR4 chemokine receptor to enhance homing and infiltration of the CAR-NK-92 cell line through the TME, and which does not induce fratricidal killing of CAR-NK-92-cells. To evaluate this therapeutic approach, we harnessed intricate 3D multicellular tumor spheroid models (MCTS), which emulate key elements of the TME. Our results demonstrate the effective cytotoxicity of CEA-CAR-NK-92 cells against CRC in colorectal cell lines and MCTS models. Importantly, minimal off-target activity against non-cancerous cell lines underscores the precision of this therapy. Furthermore, the integration of the CCR4 migration receptor augments homing by recognizing target ligands, CCL17 and CCL22. Notably, our CAR design results in no significant trogocytosis-induced fratricide. In summary, the proposed CEA-targeting CAR-NK cell therapy could offer a promising solution for CRC treatment, combining precision and efficacy in a tailored approach.
结直肠癌(CRC)是一项严峻的医学挑战,需要创新的治疗策略。嵌合抗原受体(CAR)自然杀伤(NK)细胞疗法已成为一种有前景的替代CAR T细胞疗法的癌症治疗方法。鉴于癌胚抗原(CEA)在结直肠癌中广泛表达且在肿瘤发生和转移中起作用,它是结直肠癌合适的肿瘤抗原靶点。已知CEA以可溶性形式从肿瘤细胞中大量脱落,从而阻碍CAR对肿瘤的识别以及通过肿瘤微环境(TME)的迁移。我们开发了一种专门靶向细胞相关CEA的下一代CAR构建体,它整合了PD1检查点抑制剂和CCR4趋化因子受体,以增强CAR-NK-92细胞系通过TME的归巢和浸润,并且不会诱导CAR-NK-92细胞的自相残杀。为了评估这种治疗方法,我们利用了复杂的3D多细胞肿瘤球体模型(MCTS),该模型模拟了TME的关键要素。我们的结果表明,CEA-CAR-NK-92细胞在结直肠癌细胞系和MCTS模型中对CRC具有有效的细胞毒性。重要的是,对非癌细胞系的脱靶活性极小,突出了这种疗法的精确性。此外,CCR4迁移受体的整合通过识别靶配体CCL17和CCL22增强了归巢。值得注意的是,我们的CAR设计不会导致明显的由胞啃作用诱导的自相残杀。总之,所提出的靶向CEA的CAR-NK细胞疗法可能为CRC治疗提供一种有前景的解决方案,以量身定制的方法将精确性和有效性结合起来。
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