Schwaab T, Heaney J A, Schned A R, Harris R D, Cole B F, Noelle R J, Phillips D M, Stempkowski L, Ernstoff M S
Norris Cotton Cancer Center, Department of Surgery, Lebanon, New Hampshire, USA.
J Urol. 2000 Apr;163(4):1322-7. doi: 10.1016/s0022-5347(05)67771-3.
The clinical observation of spontaneous regression in patients with renal cell carcinoma (RCC) and the response to various immunotherapeutic therapies strongly suggest a role for the host immune system in this disease. Prior studies showed that sequential administration of interferon (IFN) gamma and IFN alpha to RCC patients was safe. Clinical responses as well as immune changes in the peripheral blood mononuclear cell compartment were observed. Autologous tumor cell vaccines (AV) have also demonstrated activity in renal cell carcinoma. We hypothesize that the addition of AV to sequential IFN gamma and a therapy might improve the tumor-specific immune response by providing an appropriate source of antigen in the appropriate cytokine environment. To our knowledge, this is the first trial using AV combined with IFN alpha and IFN gamma. The purpose of this study was to evaluate the feasibility of manufacturing and administering (AV) from resected tumor samples, and administration of AV with combination IFN gamma and IFN alpha therapy. Finally, the impact on immunological parameters of these treatment options was assessed.
Patients with metastatic RCC were randomly assigned to receive AV plus bCG along with a sequential administration of IFN gamma and a either together or after initiation of vaccine. Toxicity and clinical responses were evaluated. Modulations of the immune system were investigated by analyzing phenotype, cytokine mRNA expression, T cell proliferation and cytotoxicity in the peripheral blood mononuclear cell compartment.
Fourteen patients with metastatic renal cell carcinoma were enrolled in this study; 9 were available for response evaluation. In a 70 day period, 3 (33%) showed mixed responses, 5 (56%) stable disease and 1 (11%) progression of disease. Toxicities were consistent with previous clinical reports. In the flow-cytometry phenotype analysis, stimulation of distinct subsets of circulating T-lymphocytes and a decrease of CD8+ T cell subsets was demonstrated. T-cell proliferation to allogeneic tumor cell stimulation improved following treatment. IL-4 and IL-5 mRNA levels were reduced in all patients after treatment. Patients who responded to treatment did not produce any IL-4 mRNA at all, before or after treatment.
AV with IFNgamma and IFNalpha therapy might induce a MHC class-mediated cytotoxic T lymphocyte (CTL) response. We suggest that adequate therapy might direct T cell response toward a Th1 type response. We hypothesize a state of improved immune readiness in patients who might eventually respond to immunotherapy.
肾细胞癌（RCC）患者自发消退以及对各种免疫治疗的反应的临床观察强烈提示宿主免疫系统在该疾病中发挥作用。先前的研究表明，对RCC患者序贯给予γ干扰素（IFN）和α干扰素是安全的。观察到了临床反应以及外周血单核细胞区室中的免疫变化。自体肿瘤细胞疫苗（AV）在肾细胞癌中也已显示出活性。我们假设在序贯γ干扰素和一种治疗中添加AV可能通过在适当的细胞因子环境中提供合适的抗原来源来改善肿瘤特异性免疫反应。据我们所知，这是首次使用AV联合α干扰素和γ干扰素的试验。本研究的目的是评估从切除的肿瘤样本制造和施用（AV）以及将AV与γ干扰素和α干扰素联合治疗的可行性。最后，评估了这些治疗方案对免疫参数的影响。
转移性RCC患者被随机分配接受AV加卡介苗，同时序贯给予γ干扰素和α干扰素，要么一起给予，要么在疫苗开始后给予。评估毒性和临床反应。通过分析外周血单核细胞区室中的表型、细胞因子mRNA表达、T细胞增殖和细胞毒性来研究免疫系统的调节。
本研究纳入了14例转移性肾细胞癌患者；9例可进行反应评估。在70天的时间里，3例（33%）显示混合反应，5例（56%）疾病稳定，1例（11%）疾病进展。毒性与先前的临床报告一致。在流式细胞术表型分析中，证实了循环T淋巴细胞不同亚群的刺激以及CD8 + T细胞亚群的减少。治疗后对同种异体肿瘤细胞刺激的T细胞增殖有所改善。治疗后所有患者的IL - 4和IL - 5 mRNA水平均降低。对治疗有反应的患者在治疗前或治疗后根本不产生任何IL - 4 mRNA。
AV与γ干扰素和α干扰素治疗可能诱导MHC类介导的细胞毒性T淋巴细胞（CTL）反应。我们认为适当的治疗可能将T细胞反应导向Th1型反应。我们假设最终可能对免疫治疗有反应的患者的免疫准备状态有所改善。
