Lamers C H, Bolhuis R L, Warnaar S O, Stoter G, Gratama J W
Department of Clinical and Tumor Immunology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, The Netherlands.
Int J Cancer. 1997 Oct 9;73(2):211-9. doi: 10.1002/(sici)1097-0215(19971009)73:2<211::aid-ijc9>3.0.co;2-z.
We have reported a 27% overall anti-tumor response using i.p. immunotherapy of advanced ovarian carcinoma with autologous, ex vivo expanded, T lymphocytes re-targeted with bi-specific monoclonal antibody OC/TR, combined with soluble OC/TR and low-dose recombinant interleukin-2 (IL-2). This treatment had no effect on extraperitoneal disease. Therefore we studied in 13 patients whether this immunotherapeutic protocol resulted only in local or also in systemic immunomodulation. The phenotype of the ex vivo expanded lymphocytes was mainly CD3+, 4-, 8+, 16-, 56-. Their OC/TR-re-targeted cytolytic activity against Igrov-1 ovarian-carcinoma cells was approximately as high in responders as in non-responders. Following most therapeutic cycles, the immunophenotype of lymphocytes recovered from the peritoneal fluid was similar to that of the infused T cells (i.e., mainly CD3+, 4-, 8+) and they were coated with OC/TR. However, cytolytic activity of the recovered lymphocytes against Igrov- 1 cells was low in direct assays, and only slightly increased after additional in vitro re-targeting with OC/TR. Systemically, the i.p. immunotherapy resulted in a transient lymphopenia lasting for about 7 days, low (i.e., 5 to 13 ng/ml) serum concentrations of free, functional OC/TR, and very weak coating of circulating T lymphocytes with OC/TR. These peripheral-blood T lymphocytes did not exert OC/TR-re-targeted cytolytic activity. Thus, locoregional OC/TR-re-targeted cellular immunotherapy resulted in substantial local immunomodulation and anti-tumor effects but virtually no systemic immunomodulation.
我们曾报道，采用腹腔内免疫疗法治疗晚期卵巢癌，即使用双特异性单克隆抗体OC/TR对自体离体扩增的T淋巴细胞进行重新靶向，并联合可溶性OC/TR和低剂量重组白细胞介素-2（IL-2），总体抗肿瘤反应率为27%。这种治疗对腹膜外疾病无效。因此，我们对13例患者进行了研究，以确定该免疫治疗方案是否仅导致局部免疫调节，还是也会引起全身免疫调节。离体扩增淋巴细胞的表型主要为CD3+、4-、8+、16-、56-。它们对Igrov-1卵巢癌细胞的OC/TR重新靶向的溶细胞活性在应答者和非应答者中大致相同。在大多数治疗周期后，从腹腔液中回收的淋巴细胞的免疫表型与输注的T细胞相似（即主要为CD3+、4-、8+），并且它们被OC/TR包被。然而，在直接检测中，回收的淋巴细胞对Igrov-1细胞的溶细胞活性较低，在用OC/TR进行额外的体外重新靶向后仅略有增加。在全身方面，腹腔内免疫疗法导致短暂的淋巴细胞减少，持续约7天，血清中游离功能性OC/TR浓度较低（即5至13 ng/ml），循环T淋巴细胞被OC/TR包被的程度非常弱。这些外周血T淋巴细胞未发挥OC/TR重新靶向的溶细胞活性。因此，局部区域OC/TR重新靶向的细胞免疫疗法导致了显著的局部免疫调节和抗肿瘤作用，但几乎没有全身免疫调节。
