Romero Pedro
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
Clin Lung Cancer. 2008 Feb;9 Suppl 1:S28-36. doi: 10.3816/clc.2008.s.005.
A large variety of cancer vaccines have undergone extensive testing in early-phase clinical trials. A limited number have also been tested in randomized phase II clinical trials. Encouraging trends toward increased survival in the vaccine arms have been recently observed for 2 vaccine candidates in patients with non-small-cell lung cancer. These have provided the impetus for the initiation of phase III trials in large groups of patients with lung cancer. These vaccines target 2 antigens widely expressed in lung carcinomas: melanoma-associated antigen 3, a cancer testis antigen; and mucin 1, an antigen overexpressed in a largely deglycosylated form in advanced tumors. Therapeutic cancer vaccines aim at inducing strong CD8 and CD4 T-cell responses. The majority of vaccines recently tested in phase I clinical trials show efficacy in terms of induction of specific tumor antigen immunity. However, clinical efficacy remains to be determined but appears limited. Efforts are thus aimed at understanding the basis for this apparent lack of effect on tumors. Two major factors are involved. On one hand, current vaccines are suboptimal. Strong adjuvant agents and appropriate tumor antigens are needed. Moreover, dose, route, and schedule also need optimization. On the other hand, it is now clear that large tumors often present a tolerogenic microenvironment that hampers effective antitumor immunity. The partial understanding of the molecular pathways leading to functional inactivation of T cells at tumor sites has provided new targets for intervention. In this regard, blockade of cytotoxic T-lymphocyte antigen-4 and programmed death-1 with humanized monoclonal antibodies has reached the clinical testing stage. In the future, more potent cancer vaccines will benefit from intense research in antigen discovery and adjuvant agents. Furthermore, it is likely that vaccines need to be combined with compounds that reverse major tolerogenic pathways that are constitutively active at the tumor site. Developing these combined approaches to vaccination in cancer promises new, exciting findings and, at the same time, poses important challenges to academic research institutions and the pharmaceutical industry.
多种癌症疫苗已在早期临床试验中进行了广泛测试。少数疫苗也在随机II期临床试验中进行了测试。最近在非小细胞肺癌患者中观察到，两种候选疫苗的疫苗组出现了生存率提高的令人鼓舞的趋势。这些为在大量肺癌患者中开展III期试验提供了动力。这些疫苗靶向在肺癌中广泛表达的两种抗原：黑色素瘤相关抗原3，一种癌睾丸抗原；以及粘蛋白1，一种在晚期肿瘤中以高度去糖基化形式过度表达的抗原。治疗性癌症疫苗旨在诱导强烈的CD8和CD4 T细胞反应。最近在I期临床试验中测试的大多数疫苗在诱导特异性肿瘤抗原免疫方面显示出疗效。然而，临床疗效仍有待确定，但似乎有限。因此，努力的方向是了解这种对肿瘤明显缺乏作用的基础。涉及两个主要因素。一方面，目前的疫苗并不理想。需要强效佐剂和合适的肿瘤抗原。此外，剂量、途径和给药方案也需要优化。另一方面，现在很清楚，大肿瘤通常呈现出一种抑制免疫的微环境，阻碍有效的抗肿瘤免疫。对导致肿瘤部位T细胞功能失活的分子途径的部分理解提供了新的干预靶点。在这方面，用人源化单克隆抗体阻断细胞毒性T淋巴细胞抗原4和程序性死亡1已进入临床测试阶段。未来，更有效的癌症疫苗将受益于在抗原发现和佐剂方面的深入研究。此外，疫苗可能需要与能够逆转在肿瘤部位持续活跃的主要抑制免疫途径的化合物联合使用。开发这些癌症疫苗联合方法有望带来新的、令人兴奋的发现，同时也给学术研究机构和制药行业带来重要挑战。
