Freedman R S, Kudelka A P, Kavanagh J J, Verschraegen C, Edwards C L, Nash M, Levy L, Atkinson E N, Zhang H Z, Melichar B, Patenia R, Templin S, Scott W, Platsoucas C D
Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Clin Cancer Res. 2000 Jun;6(6):2268-78.
To identify strategies that enhance tumor-specific immunity in patients with ovarian carcinoma, 22 patients received four to six doses of i.p. recombinant IFN-gamma (rIFN-gamma), 200 microg/m2 on days 1, 3, 5, 8, 10, and 12, and i.p. recombinant interleukin 2 (rIL-2), either 6.0 x 10(5) IU/m2 (group A) or 1.0 x 10(5) IU/m2 (group B), on days 9, 10, and 11. Two patients in group A also received T-cell lines expanded from peritoneal tumor-infiltrating lymphocytes (TILs) obtained after i.p. rIFN-gamma/rIL-2 administration. Toxicity was manageable and included five nonhematological grade 3 or 4 events in 22 patients (23%). A patient had normalization of CA-125 values and a progression-free interval of 18 months, after receiving i.p. rIFN-gamma/rIL-2 without TILs. Another patient who received i.p. rIFN-gamma/rIL-2 plus TILs had stabilization of ascites and intra-abdominal tumors and >50% reduction in serum CA-125 values over 6 months. A third patient who received i.p. rIFN-gamma/rIL-2 had stabilization of intra-abdominal tumors and ascites accompanied by CA-125 values of 50 to 100 units over 6 months. T-cell lines for adoptive immunotherapy were developed for only 3 of 20 patients who were treated with rIFN-gamma/rIL-2. Large numbers of CD3- CD56+ adherent cells were expanded in rIL-2 in the remaining patients, precluding the development of T-cell lines. i.p. rIFN-gamma, either alone or followed by rIL-2, increased proportions of human leukocyte antigen (HLA) class I+ and class II+ tumor cells and increased HLA class I staining intensity on peritoneal carcinoma cells. i.p. rIFN-gamma plus rIL-2 also enhanced cytotoxic activity against Daudi and K562 cells and against allogeneic ovarian tumor cells. Increased cytotoxic activity was associated with an increase in the proportion of CD56+ cells. IFN-gamma and IL-2 transcripts were expressed more frequently after rIFN-gamma and rIL-2 treatment. In addition, the proportions of CD45RA+ (naive lymphocytes) were increased, and CD8+ DR+ lymphocytes were increased relative to CD8+ CD69+ cells, which were decreased. IL-10 concentrations in peritoneal fluids were increased after treatment with rIFN-gamma and the higher rIL-2 dosing (group A) but not in those treated with rIFN-gamma and the lower rIL-2 dosing (group B). These results demonstrated that patients with ovarian carcinoma can tolerate treatment with rIFN-gamma and rIL-2 and that rIFN-gamma alone or rIFN-gamma combined with rIL-2 enhances the expression of HLA class I and class II antigens on ovarian tumor cells, although immunosuppressive cytokines, such as transforming growth factor-beta and IL-10, may persist. Treatment with rIFN-gamma/rIL-2 i.p. did not facilitate the production of TIL-derived T-cell lines ex vivo.
为了确定增强卵巢癌患者肿瘤特异性免疫的策略，22例患者接受了4至6剂腹腔内重组干扰素-γ（rIFN-γ），剂量为200μg/m²，分别于第1、3、5、8、10和12天给药，同时在第9、10和11天腹腔内注射重组白细胞介素2（rIL-2），A组剂量为6.0×10⁵IU/m²，B组剂量为1.0×10⁵IU/m²。A组中有2例患者还接受了从腹腔内注射rIFN-γ/rIL-2后获得的腹膜肿瘤浸润淋巴细胞（TILs）扩增的T细胞系。毒性是可控的，22例患者中有5例发生了5次非血液学3级或4级事件（23%）。1例患者在接受腹腔内rIFN-γ/rIL-2但未接受TILs治疗后，CA-125值恢复正常，无进展生存期为18个月。另1例接受腹腔内rIFN-γ/rIL-2加TILs治疗的患者，腹水和腹腔内肿瘤稳定，血清CA-125值在6个月内降低了50%以上。第3例接受腹腔内rIFN-γ/rIL-2治疗的患者，腹腔内肿瘤和腹水稳定，6个月内CA-125值为50至100单位。在接受rIFN-γ/rIL-2治疗的20例患者中，仅为3例患者制备了用于过继免疫治疗的T细胞系。其余患者在rIL-2中大量扩增了CD3⁻CD56⁺贴壁细胞，从而无法制备T细胞系。单独腹腔内注射rIFN-γ或先注射rIFN-γ后再注射rIL-2，均可增加人白细胞抗原（HLA）I类和II类阳性肿瘤细胞的比例，并增强腹膜癌细胞上HLA I类的染色强度。腹腔内注射rIFN-γ加rIL-2还可增强对Daudi和K562细胞以及同种异体卵巢肿瘤细胞的细胞毒性活性。细胞毒性活性的增加与CD56⁺细胞比例的增加有关。rIFN-γ和rIL-2治疗后，IFN-γ和IL-2转录本的表达更为频繁。此外，CD45RA⁺（初始淋巴细胞）的比例增加，相对于减少的CD8⁺CD69⁺细胞，CD8⁺DR⁺淋巴细胞增加。用rIFN-γ和较高剂量的rIL-2（A组）治疗后，腹腔液中IL-10浓度升高，但用rIFN-γ和较低剂量的rIL-2（B组）治疗的患者则未升高。这些结果表明，卵巢癌患者能够耐受rIFN-γ和rIL-2治疗，并且单独使用rIFN-γ或rIFN-γ与rIL-2联合使用均可增强卵巢肿瘤细胞上HLA I类和II类抗原的表达，尽管免疫抑制细胞因子如转化生长因子-β和IL-10可能仍然存在。腹腔内注射rIFN-γ/rIL-2并不能促进体外制备TIL来源的T细胞系。
