Lum Lawrence G, LeFever Ann V, Treisman Jonathan S, Garlie Nina K, Hanson John P
Cancer Immunotherapy Program, Roger Williams Cancer Center, Providence, Rhode Island; and Immunotherapy Research and Treatment Institute, Milwaukee, Wisconsin, U.S.A.
J Immunother (1991). 2001 Sep-Oct;24(5):408-419.
Anti-CD3/anti-CD28 monoclonal antibody-coactivated T cells (COACTs) proliferate, secrete tumoricidal cytokines, and mediate non-major histocompatibility complex (MHC)-restricted cytotoxicity. This phase I study was done to determine the safety, maximum tolerated dose, technical limits of expansion, and modulation of immune functions in cancer patients given COACTs. Coactivated T cells were produced by stimulating peripheral blood mononuclear cells (PBMCs) with OKT3 anti-CD3 and 9.3 (anti-CD28)-coated beads in the presence of 100 IU interleukin (IL)-2 per milliliter for 14 days. The beads were removed after 4 days of culture. Ten courses of COACTs were given to eight patients with renal cell (1), ovarian (2), breast (1), and colorectal (4) carcinomas; two patients received two courses of COACTs. Patients were given up to 10 x 10 9 COACTs twice a week for 3 weeks without dose-limiting toxicities. Patients at the first and second dose levels received a mean total of 17.6 and 42.4 x 10 9 COACTs, respectively. After 14 days of culture, the COACTs contained a mean of 57.5% CD4 + cells and 42.5% CD8 + cells, exhibited non-MHC-restricted cytotoxicity, and produced significant amounts of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and granulocyte macrophage colony-stimulating factor (GM-CSF). Infusions were safe and induced measurable serum levels of IFNgamma, TNFalpha, and IL-4 in two patients. Peripheral blood mononuclear cells from patients who received COACTs secreted higher amounts of IFNgamma and GM-CSF on in vitro anti-CD3/anti-CD28 restimulation than PBMCs obtained before immunotherapy. The detection of cytokines in patient sera and enhanced in vitro production of cytokines by anti-CD3/anti-CD28-stimulated patient PBMCs after COACT infusions suggest that COACTs were modulating immune responses in cancer patients.
抗CD3/抗CD28单克隆抗体共激活的T细胞（COACTs）能够增殖、分泌杀肿瘤细胞因子，并介导非主要组织相容性复合体（MHC）限制的细胞毒性作用。本I期研究旨在确定给予癌症患者COACTs后的安全性、最大耐受剂量、扩增的技术限制以及免疫功能的调节情况。共激活的T细胞是通过在每毫升含100国际单位白细胞介素（IL）-2的条件下，用OKT3抗CD3和9.3（抗CD28）包被的磁珠刺激外周血单个核细胞（PBMCs）14天而产生的。培养4天后去除磁珠。对8例肾细胞癌（1例）、卵巢癌（2例）、乳腺癌（1例）和结直肠癌（4例）患者给予10个疗程的COACTs；2例患者接受了2个疗程的COACTs。患者每周两次给予高达10×10⁹个COACTs，共3周，未出现剂量限制性毒性反应。第一和第二剂量水平的患者分别平均接受了17.6×10⁹和42.4×10⁹个COACTs。培养14天后，COACTs平均含有57.5%的CD4⁺细胞和42.5%的CD8⁺细胞，表现出非MHC限制的细胞毒性，并产生大量的干扰素（IFN）-γ、肿瘤坏死因子（TNF）-α和粒细胞巨噬细胞集落刺激因子（GM-CSF）。输注是安全的，并且在2例患者中诱导出可测量的血清IFNγ、TNFα和IL-4水平。接受COACTs的患者的外周血单个核细胞在体外抗CD3/抗CD28再刺激时比免疫治疗前获得的PBMCs分泌更高量的IFNγ和GM-CSF。在COACTs输注后患者血清中细胞因子的检测以及抗CD3/抗CD28刺激的患者PBMCs体外细胞因子产生的增强表明COACTs正在调节癌症患者的免疫反应。
