Marshall Julia A, Forster Trevor H, Purdie David M, Lanagan Catherine M, O'Connor Linda E, O'Rourke Michael G E, Johnson Maree K, See Janet L, Ellem Kay A O, Martinez Nathan R, López J Alejandro, Schmidt Christopher W
Cancer and Cell Biology Division, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
Immunol Cell Biol. 2006 Jun;84(3):295-302. doi: 10.1111/j.1440-1711.2006.01445.x.
Current treatment options for advanced metastatic melanoma are limited to experimental regimen that provide poor survival outcomes. Immunotherapy is a promising alternative and we recently reported a clinical trial in which 6 out of 19 patients enrolled had objective clinical responses to a fully autologous melanoma/dendritic cell vaccine. The mechanism of the vaccine is not well understood, but we hypothesized that general immunocompetence may be a determinant of clinical response. We therefore examined the immune status of an expanded series of 21 patients who displayed varying clinical responses to the melanoma/dendritic cell vaccine. Immunocompetence was assessed using in vitro assays of lymphocyte function: survival, proliferation and cytokine responses to mitogen stimulation as well as T-cell receptor zeta expression and lymphocyte subset analysis. Although lymphocytes from patients mostly performed comparably to age-matched and sex-matched controls, in some assays we identified significant differences between complete clinical responders and other patients, both before and following vaccination. Surprisingly, before vaccination, only lymphocytes from clinical responder patients showed impaired in vitro survival. Following vaccination, T lymphocyte survival improved and cells recovered their ability to produce the Th1-associated cytokines TNF and IFN-gamma in response to anti-CD3 stimulation in vitro. No increase in Th1 cytokine production was observed in lymphocytes from patients who experienced partial clinical responses or progressive disease. We conclude that, before vaccination, patients who go on to have complete responses have immune characteristics suggestive of high cell turnover and low Th1-associated cytokine production, and that these can be reversed with vaccination. These results have potential implications for future immunotherapeutic strategies.
晚期转移性黑色素瘤目前的治疗选择仅限于疗效不佳的实验性方案。免疫疗法是一种有前景的替代方法，我们最近报道了一项临床试验，19名入组患者中有6名对完全自体黑色素瘤/树突状细胞疫苗有客观临床反应。该疫苗的作用机制尚不完全清楚，但我们推测一般免疫能力可能是临床反应的一个决定因素。因此，我们检查了21名对黑色素瘤/树突状细胞疫苗表现出不同临床反应的患者的免疫状态。通过淋巴细胞功能的体外检测来评估免疫能力：淋巴细胞对丝裂原刺激的存活、增殖和细胞因子反应，以及T细胞受体ζ链表达和淋巴细胞亚群分析。尽管患者的淋巴细胞大多与年龄和性别匹配的对照组表现相当，但在一些检测中，我们发现在接种疫苗前后，完全临床缓解者与其他患者之间存在显著差异。令人惊讶的是，在接种疫苗前，只有临床缓解者的淋巴细胞在体外存活能力受损。接种疫苗后，T淋巴细胞存活率提高，细胞在体外对抗CD3刺激产生与Th1相关的细胞因子TNF和IFN-γ的能力恢复。部分临床缓解或疾病进展患者的淋巴细胞中未观察到Th1细胞因子产生增加。我们得出结论，在接种疫苗前，能够实现完全缓解的患者具有提示高细胞更新率和低Th1相关细胞因子产生的免疫特征，而这些特征可通过接种疫苗得到逆转。这些结果对未来的免疫治疗策略具有潜在意义。
