Goedegebuure P S, Douville L M, Li H, Richmond G C, Schoof D D, Scavone M, Eberlein T J
Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
J Clin Oncol. 1995 Aug;13(8):1939-49. doi: 10.1200/JCO.1995.13.8.1939.
The objective of this study was to determine the tolerance and effect of moderate-dose recombinant human interleukin-2 (rHu IL-2) and tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma (MM) or renal cell carcinoma (RCC) refractory to standard therapy.
Twenty-six patients (18 MM and eight RCC) were entered onto this pilot study. TIL were isolated from fresh biopsy material and activated with anti-CD3 antibody, OKT3, for 48 hours and expanded in 100 IU/mL r-methionyl Hu IL-2 alanine 125 (r-met Hu IL-2 [ala-125]). At least 10(10) TIL were reinfused intravenously in three divided injections on days 2, 4, and 6 of the protocol. A maximum dose of 30,000 U/kg of IL-2 per injection was administered every 8 hours from day 2 through day 11 for a total of 28 doses.
Sixteen melanoma patients completed the study. Of these, three (19%) showed a durable complete response (CR), nine (56%) had no response (NR), and four (25%) had progressive disease (PD). One nonresponder demonstrated complete tumor regression within 1 year of treatment. Of four assessable RCC patients, two experienced a minor response (MR) and two showed NR. All TIL cultures showed comparably high cytotoxic activity as determined by antibody-redirected lysis (ARL). More importantly, melanoma TIL from responders possessed significantly higher cytotoxicity against autologous tumor cells than TIL from nonresponders (P < .05). Production of granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-gamma), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and IL-4 was similar for TIL from melanoma responders and nonresponders, or TIL from RCC patients.
Immunotherapy with polyclonally activated TIL and moderate-dose IL-2 could be successfully used for the treatment of immunogenic tumors with less toxicity and lower costs as compared with high-dose IL-2 protocols.
本研究的目的是确定中等剂量重组人白细胞介素-2（rHu IL-2）和肿瘤浸润淋巴细胞（TIL）对标准治疗难治的转移性黑色素瘤（MM）或肾细胞癌（RCC）患者的耐受性和疗效。
26例患者（18例MM和8例RCC）进入该初步研究。从新鲜活检材料中分离出TIL，并用抗CD3抗体OKT3激活48小时，然后在100 IU/mL的r-甲硫氨酰人白细胞介素-2丙氨酸125（r-甲硫氨酰人白细胞介素-2 [ala-125]）中扩增。在方案的第2、4和6天，分三次静脉注射至少10(10)个TIL。从第2天到第11天，每8小时注射一次，每次最大剂量为30,000 U/kg的IL-2，共28剂。
16例黑色素瘤患者完成了研究。其中，3例（19%）显示持久完全缓解（CR），9例（56%）无反应（NR），4例（25%）疾病进展（PD）。1例无反应者在治疗1年内肿瘤完全消退。4例可评估的RCC患者中，2例有轻微反应（MR），2例无反应。所有TIL培养物经抗体导向裂解（ARL）测定均显示出相当高的细胞毒性活性。更重要的是，反应者的黑色素瘤TIL对自体肿瘤细胞的细胞毒性明显高于无反应者（P <.05）。黑色素瘤反应者和无反应者的TIL，或RCC患者的TIL，粒细胞-巨噬细胞集落刺激因子（GM-CSF）、干扰素γ（IFN-γ）、白细胞介素-6（IL-6）、肿瘤坏死因子α（TNF-α）和IL-4的产生相似。
与高剂量IL-2方案相比，多克隆激活的TIL和中等剂量IL-2的免疫疗法可成功用于治疗免疫原性肿瘤，毒性较小且成本较低。
