Bocchia M, Bronte V, Colombo M P, De Vincentiis A, Di Nicola M, Forni G, Lanata L, Lemoli R M, Massaia M, Rondelli D, Zanon P, Tura S
Department of Hematology, University of Siena, Italy.
Haematologica. 2000 Nov;85(11):1172-206.
Vaccination is an effective medical procedure of preventive medicine based on the induction of a long-lasting immunologic memory characterized by mechanisms endowed with high destructive potential and specificity. In the last few years, identification of tumor-associated antigens (TAA) has prompted the development of different strategies for antitumor vaccination, aimed at inducing specific recognition of TAA in order to elicit a persistent immune memory that may eliminate residual tumor cells and protect recipients from relapses. In this review characterization of TAA, different potential means of vaccination in experimental models and preliminary data from clinical trials in humans have been examined by the Working Group on Hematopoietic Cells.
The method employed for preparing this review was that of informal consensus development. Members of the Working Group met four times and discussed the single points, previously assigned by the chairman, in order to achieve an agreement on different opinions and approve the final manuscript. Some of the authors of the present review have been working in the field of antitumor immunotherapy and have contributed original papers to peer-reviewed journals. In addition, the material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline.
The cellular basis of antitumor immune memory consists in the generation and extended persistence of expanded populations of T- and B-lymphocytes that specifically recognize and react against TAA. The efficacy of the memory can be modulated by compounds, called "adjuvants", such as certain bacterial products and mineral oils, cytokines, chemokines, by monoclonal antibodies triggering co-stimulatory receptors. Strategies that have been shown in preclinical models to be efficient in protecting from tumor engraftment, or in preventing a tumor rechallenge, include vaccination by means of soluble proteins or peptides, recombinant viruses or bacteria as TAA genes vectors, DNA injection, tumor cells genetically modified to express co-stimulatory molecules and/or cytokines. The use of professional antigen-presenting cells, namely dendritic cells, either pulsed with TAA or transduced with tumor-specific genes, provides a useful alternative for inducing antitumor cytotoxic activity. Some of these approaches have been tested in phase I/II clinical trials in hematologic malignancies, such as lymphoproliferative diseases or chronic myeloid leukemia, and in solid tumors, such as melanoma, colon cancer, prostate cancer and renal cell carcinoma. Different types of vaccines, use of adjuvants, timing of vaccination as well as selection of patients eligible for this procedure are discussed in this review.
Experimental models demonstrate the possibility of curing cancer through the active induction of a specific immune response to TAA. However, while pre-clinical research has identified several possible targets and strategies for tumor vaccination the clinical scenario is far more complex for a number of possible reasons. Since experimental data suggest that vaccination is more likely to be effective on small tumor burden, such as a minimal residual disease after conventional treatments, or tumors at an early stage of disease, better selection of patients will allow more reliable clinical results to be obtained. Moreover, a poor correlation is frequently observed between the ability of TAA to induce a T-cell response in vitro and clinical responses. Controversial findings may also be due to the techniques used for monitoring the immune status. Therefore, the development of reliable assays for efficient monitoring of the state of immunization of cancer patients against TAA is an important goal that will markedly improve the progress of antitumor vaccines. (ABSTRACT TRUNCATED)
疫苗接种是预防医学中的一种有效医疗手段，其基于诱导持久的免疫记忆，这种免疫记忆具有高破坏潜力和特异性的机制。在过去几年中，肿瘤相关抗原（TAA）的鉴定促使了不同抗肿瘤疫苗接种策略的发展，旨在诱导对TAA的特异性识别，以引发持久的免疫记忆，从而消除残留肿瘤细胞并保护受者免于复发。造血细胞工作组在本综述中研究了TAA的特征、实验模型中不同的潜在疫苗接种方法以及人类临床试验的初步数据。
编写本综述所采用的方法是达成非正式共识。工作组成员召开了四次会议，讨论了主席预先分配的各个要点，以便就不同意见达成一致并批准最终稿件。本综述的一些作者一直在抗肿瘤免疫治疗领域工作，并在同行评审期刊上发表了原创论文。此外，本综述中审查的材料包括发表在《科学引文索引》和《医学索引》涵盖期刊上的文章和摘要。
抗肿瘤免疫记忆的细胞基础在于特异性识别并针对TAA做出反应的T淋巴细胞和B淋巴细胞扩增群体的产生和长期持续存在。记忆的功效可通过称为“佐剂”的化合物进行调节，例如某些细菌产物和矿物油、细胞因子、趋化因子，以及触发共刺激受体的单克隆抗体。在临床前模型中已证明有效的预防肿瘤植入或预防肿瘤再次攻击的策略包括通过可溶性蛋白质或肽、作为TAA基因载体的重组病毒或细菌、DNA注射、经基因改造以表达共刺激分子和/或细胞因子的肿瘤细胞进行疫苗接种。使用专业的抗原呈递细胞，即树突状细胞，用TAA脉冲或用肿瘤特异性基因转导，为诱导抗肿瘤细胞毒性活性提供了一种有用的替代方法。其中一些方法已在血液系统恶性肿瘤（如淋巴增殖性疾病或慢性粒细胞白血病）以及实体瘤（如黑色素瘤、结肠癌、前列腺癌和肾细胞癌）的I/II期临床试验中进行了测试。本综述讨论了不同类型的疫苗、佐剂的使用、疫苗接种时间以及适合该程序的患者选择。
实验模型证明了通过主动诱导对TAA的特异性免疫反应治愈癌症的可能性。然而，虽然临床前研究已经确定了几种可能的肿瘤疫苗接种靶点和策略，但由于多种可能原因，临床情况要复杂得多。由于实验数据表明疫苗接种在小肿瘤负荷（如常规治疗后的微小残留病或疾病早期的肿瘤）上更有可能有效，更好地选择患者将获得更可靠的临床结果。此外，经常观察到TAA在体外诱导T细胞反应的能力与临床反应之间相关性较差。有争议的结果也可能归因于用于监测免疫状态的技术。因此，开发可靠的检测方法以有效监测癌症患者针对TAA的免疫状态是一个重要目标，这将显著改善抗肿瘤疫苗的进展。（摘要截断）
