Mokyr M B, Kalinichenko T, Gorelik L, Bluestone J A
Department of Biochemistry and Molecular Biology, University of Illinois at Chicago, 60612, USA.
Cancer Res. 1998 Dec 1;58(23):5301-4.
CTLA-4 blockade has been shown by other investigators [D. R. Leach, et al., Science (Washington DC), 271: 1734-1736, 1996; and Y-F. Yang, et al., Cancer Res., 57: 4036-4041, 1997] to retard tumor growth in selected tumor systems. Here, we show that CTLA-4 blockade alone was ineffective in retarding tumor growth in the murine MOPC-315 tumor system. Yet, CTLA-4 blockade offered significant therapeutic benefits to MOPC-315 tumor bearers when combined with a subtherapeutic dose of the chemotherapeutic agent melphalan, which was previously shown (L. Gorelik, et al., Cancer Immunol. Immunother., 39: 117-126, 1994) to shift the cytokine profile in the tumor bearers toward type-1 cytokines. In addition, we show here that anti-CTLA-4 monoclonal antibody enhanced antitumor cytotoxicity when the anti-CTLA-4 monoclonal antibody was added to stimulation cultures of spleen cells from low-dose melphalan-treated MOPC-315 tumor-bearing mice but not from untreated tumor-bearing mice. These results suggest that the therapeutic benefits of CTLA-4 blockade depend on the ability of drugs such as melphalan to promote an immunogenic environment by altering the cytokine profile of tumor-specific T cells.
其他研究人员[D. R. 利奇等人，《科学》（华盛顿特区），271: 1734 - 1736，1996；以及杨Y - F等人，《癌症研究》，57: 4036 - 4041，1997]已表明，在特定肿瘤系统中，CTLA - 4阻断可延缓肿瘤生长。在此，我们表明，单独的CTLA - 4阻断在延缓小鼠MOPC - 315肿瘤系统中的肿瘤生长方面无效。然而，当CTLA - 4阻断与亚治疗剂量的化疗药物美法仑联合使用时，对MOPC - 315肿瘤携带者具有显著的治疗益处，此前研究表明（L. 戈雷利克等人，《癌症免疫与免疫治疗》，39: 117 - 126，1994），美法仑可使肿瘤携带者的细胞因子谱向1型细胞因子转变。此外，我们在此表明，当将抗CTLA - 4单克隆抗体添加到低剂量美法仑治疗的MOPC - 315荷瘤小鼠的脾细胞刺激培养物中时，抗CTLA - 4单克隆抗体可增强抗肿瘤细胞毒性，但添加到未治疗的荷瘤小鼠的脾细胞刺激培养物中则无此作用。这些结果表明，CTLA - 4阻断的治疗益处取决于美法仑等药物通过改变肿瘤特异性T细胞的细胞因子谱来促进免疫原性环境的能力。
