Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Eur J Immunol. 2021 May;51(5):1218-1233. doi: 10.1002/eji.202048885. Epub 2021 Mar 9.
Monoclonal antibodies (mAbs) have revolutionized clinical medicine, especially in the field of cancer immunotherapy. The challenge now is to improve the response rates, as immunotherapy still fails for many patients. Strategies to enhance tumor cell death is a fundamental aim, but relevant model systems for human tumor immunology are lacking. Herein, we have developed a preclinical human immune - three-dimensional (3D) tumor model (spheroids) to map the efficiency of tumor-specific isotypes for improved tumor cell killing. Different anti-CD20 Rituximab (RTX) isotypes alone or in combination, were evaluated for mediating complement-dependent cytotoxicity and antibody-dependent phagocytosis by human monocytic cells in 3D spheroids, in parallel with monolayer cultures, of human CD20 B-cell lymphomas. We demonstrate that the IgG3 variant of RTX has the greatest tumoricidal effect over other isotypes, and when combined with apoptosis-inducing RTX-IgG2 isotype the therapeutic effect can be substantially enhanced. The results show further that the treatment outcome by RTX isotypes is influenced by tumor morphology and expression of the complement inhibitor CD59. Hence, the human immune-3D tumor model is a clinical relevant and attractive ex vivo system to predict mAbs for best efficacy in cancer immunotherapy.
单克隆抗体（mAbs）彻底改变了临床医学，尤其是在癌症免疫治疗领域。现在的挑战是提高反应率，因为免疫疗法仍然对许多患者无效。增强肿瘤细胞死亡的策略是一个基本目标，但缺乏用于人类肿瘤免疫学的相关模型系统。在此，我们开发了一种临床前人类免疫-三维（3D）肿瘤模型（球体），以绘制肿瘤特异性同种型的效率图，以提高肿瘤细胞杀伤作用。单独或组合使用不同的抗 CD20 利妥昔单抗（RTX）同种型，在 3D 球体和单层培养物中评估其介导补体依赖性细胞毒性和抗体依赖性吞噬作用，用于人类 CD20 B 细胞淋巴瘤。我们证明 RTX 的 IgG3 变体比其他同种型具有更大的杀肿瘤作用，并且当与诱导细胞凋亡的 RTX-IgG2 同种型联合使用时，治疗效果可以大大增强。结果还表明，RTX 同种型的治疗效果受肿瘤形态和补体抑制剂 CD59 的表达影响。因此，人类免疫-3D 肿瘤模型是一种临床相关且有吸引力的体外系统，可以预测癌症免疫治疗中最佳疗效的 mAbs。
