1] Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany [2] Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.
Mol Ther. 2013 Dec;21(12):2268-77. doi: 10.1038/mt.2013.192. Epub 2013 Aug 28.
Cytokine-induced killer (CIK) cells raised interest for use in cellular antitumor therapy due to their capability to recognize and destroy autologous tumor cells in a HLA-independent fashion. The antitumor attack of CIK cells, predominantly consisting of terminally differentiated CD8(+)CD56(+) cells, can be improved by redirecting by a chimeric antigen receptor (CAR) that recognizes the tumor cell and triggers CIK cell activation. The requirements for CIK cell activation were, however, so far less explored and are likely to be different from those of "younger" T cells. We revealed that CD28 and OX40 CARs produced higher interferon- secretion as compared with the first-generation ζ-CAR; CD28-ζ and the third-generation CD28-ζ-OX40 CAR, however, performed similar in modulating most CIK cell effector functions. Compared with the CD28-ζ CAR, however, the CD28-ζ-OX40 CAR accelerated terminal maturation of CD56(+) CIK cells producing high frequencies in activation-induced cell death (AICD) and reduced antitumor efficiency in vivo. Consequently, CD28-ζ CAR CIK cells of CD56(-) phenotype were superior in redirected tumor cell elimination. CAR-mediated CIK cell activation also increased antigen-independent target cell lysis; the CD28-ζ CAR was more efficient than the CD28-ζ-OX40 CAR. Translated into therapeutic strategies, CAR-redirected CIK cells benefit from CD28 costimulation; "super-costimulation" by the CD28-ζ-OX40 CAR, however, performed less in antitumor efficacy due to increased AICD.
细胞因子诱导的杀伤（CIK）细胞因其能够以 HLA 非依赖性方式识别和破坏自体肿瘤细胞而引起人们对其在细胞抗肿瘤治疗中的应用的兴趣。CIK 细胞的抗肿瘤攻击主要由终末分化的 CD8(+)CD56(+)细胞组成，可以通过识别肿瘤细胞并触发 CIK 细胞激活的嵌合抗原受体（CAR）进行重定向来改善。然而，CIK 细胞激活的要求迄今为止研究较少，并且可能与“年轻”T 细胞的要求不同。我们发现 CD28 和 OX40 CAR 产生的干扰素分泌高于第一代 ζ-CAR；然而，CD28-ζ 和第三代 CD28-ζ-OX40 CAR 在调节大多数 CIK 细胞效应功能方面表现相似。然而，与 CD28-ζ CAR 相比，CD28-ζ-OX40 CAR 加速了 CD56(+)CIK 细胞的终末成熟，在激活诱导的细胞死亡（AICD）中产生高频率，并降低了体内的抗肿瘤效率。因此，CD56(-)表型的 CD28-ζ CAR CIK 细胞在重定向肿瘤细胞消除方面具有优势。CAR 介导的 CIK 细胞激活也增加了抗原非依赖性靶细胞裂解；CD28-ζ CAR 比 CD28-ζ-OX40 CAR 更有效。转化为治疗策略，CAR 重定向的 CIK 细胞受益于 CD28 共刺激；然而，由于 AICD 的增加，CD28-ζ-OX40 CAR 的“超级共刺激”在抗肿瘤疗效方面表现较差。
