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July 5, 2007 — 检验癌症疫苗是否有效的研究通常是令人失望的，过去专家报告接受疫苗的病患倾向活得比较久、且对于之后的治疗反应较佳；马里兰班赛斯达国家癌症机构肿瘤免疫与生物学实验室主任Jeffrey Schlom博士向记者表示，尽管研究显示，疫苗无法诱发免疫系统使肿瘤缩小，但临床研究数据提供病患在接受疫苗接种后活得比较久的证据；这些研究数据显示，科学界与有关当局应该重新思考癌症疫苗研究的设计、以及我们目前用于评估疫苗疗效的方式。
该团队的回顾性文章发表于7月1日的临床癌症研究期刊上。研究者解释，思考疫苗对于病患反应的作用，或许会比检验疫苗对于肿瘤的作用要来得好；作者表示，而 RECIST（the Response Criteria in Solid Tumors）实验性标准在评估对肿瘤有毒性的疗法上，例如放射线治疗或是化学治疗，是一样有用的，但对于评估免疫反应的全身作用上就不是那么有效。
在发表这项研究结果的记者会中，Schlom医师表示，证据显示疫苗最主要的作用在于免疫系统，他指出，疫苗并非被动的，疫苗会诱发免疫系统的动态反应，在许多案例中，可能控制肿瘤且增强对于接下来治疗的反应。
截至目前，美国食品药物管理局并未核准任何治疗性的癌症疫苗，目前这篇回顾性文章涵盖五种摄护腺癌疫苗研究，显示接受疫苗接种病患显然对于接下来的化学治疗或是荷尔蒙治疗较有反应，但这些研究的试验终点并未包括长期存活率、且是针对肿瘤本身的治疗反应；根据研究者所述，尽管这些疫苗具有延长存活时间的治疗价值，但他们并未达到主要试验终点，这些疫苗可能被弃置不用。
【疫苗可以延长存活时间吗？】
不像其他预防性疫苗，例如流行性感冒疫苗或是那些被发展来对抗人类乳突病毒的疫苗，癌症疫苗是治疗现存的疾病，这项回顾性文章中针对的是两种疫苗以细胞为主的疫苗，分别是sipuleucel-T（Provenge，Dendreon集团）与Cell Genesys公司的GVAX，这些研究中有三项评估基因工程痘病毒载体。
研究者指出，他们仅针对少数具有临床好处证据的疫苗；异源性全肿瘤细胞、胜肽或是蛋白加上抗原表现细胞（包括树突细胞）、基因重组DNA与病毒载体、以及基因重组Saccharomyces（霉菌）目前都在临床研究发展中。
他们补充道，最近有一系列新被定义与肿瘤相关、且其中包括肿瘤及肿瘤发展过程的标的，被拿来发展癌症疫苗，当这些癌症疫苗疗法的领域成熟，将会了解其长期的安全性；在这个时刻，他们建议疫苗可作为某些癌症前期的辅助疗法。
当回顾摄护腺癌疫苗时，研究员表示，这些试验，如淋巴瘤、黑色素细胞瘤及胰脏、肺脏及其他类型癌症，是相似的疫苗疗法持续进展的例子。为什么疫苗可提高之后疗法的反应？研究员推测可能与几个因素相关。
这些后续疗法可能：
* 减少抑制型细胞，加强之前T细胞的反应；
* 溶解某些肿瘤细胞，然后活化相对休眠的T细胞去达到抗肿瘤反应的结果；
* 加强宿主T细胞的活性；
* 改变肿瘤细胞的表现型。
Schlom博士与其团队表示，怀疑是科学过程的一个重要部分，且这应该是发展新治疗方法缺一不可的元素；许多人该有警觉，举例来说，十年前对于单株抗体治疗癌症存疑及说风凉话，但目前已有七种单株抗体用来治疗癌症，这也许能发展出癌症疫苗；虽然存疑是重要的，但也必须了解开拓疫苗合并疗法及分析病患在存活率（与最低毒性）方面的好处，才是适当的临床试验终点。
Clin Cancer Res. 2007;13:3376-3782.
Are Cancer Vaccine Trials Being Disregarded Too Quickly?
By Allison Gandey
Medscape Medical News
July 5, 2007 — Results of trials testing cancer vaccines have been largely disappointing, yet experts report that patients receiving immunization tend to survive longer and respond better to subsequent therapy. "Clinical data are providing evidence that patients are living longer following vaccination, despite the fact that trials do not show the vaccines can induce the immune system into shrinking tumors," lead author Jeffrey Schlom, PhD, chief of the laboratory of tumor immunology and biology at the National Cancer Institute, in Bethesda, Maryland, told reporters. "The data suggest that the scientific community and regulatory committees ought to rethink the design of clinical vaccine trials and our current approach to measuring the effectiveness of a cancer vaccine."
The group's review article appears in the July 1 issue of Clinical Cancer Research. The investigators explain that it may be more useful to think of the effectiveness of a vaccine in terms of the response of the patient rather than the effect on the tumor. While the Response Criteria in Solid Tumors (RECIST) experimental standards work well in evaluating therapies that are toxic to tumors such as radiation or chemotherapy, they are less effective in measuring more subtle systemic effects of immune response, the authors suggest.
In a news release highlighting the findings, Dr. Schlom said the evidence suggests that vaccines are in effect priming the immune system. "Vaccines are not passive," he noted. "They induce a dynamic process of immune response that, in many cases, may keep the tumor in check and enhance the effectiveness of subsequent therapies."
No therapeutic cancer vaccine has been approved to date by the US Food and Drug Administration. The current review covered 5 prostate cancer vaccine trials and showed that patients who are immunized appear to respond better to subsequent chemotherapy or hormone treatment. But the end points of the trials did not include long-term survival and focused instead on the effect of treatment on the tumor itself. According to the researchers, since they didn not achieve their primary end points, these vaccines may be abandoned despite their real therapeutic value in prolonging survival.
Will Vaccines Prolong Survival?
Unlike preventive vaccines such as the flu shot or those developed to protect against human papillomavirus, cancer vaccines treat existing disease. Included in the review were 2 cell-based vaccines — sipuleucel-T (Provenge, Dendreon Corp) and Cell Genesys Inc's GVAX. Three of the trials evaluated engineered poxvirus vectors.
The researchers point out that they looked at only a small number of vaccines showing evidence of clinical benefit. Allogeneic whole-tumor cells, peptide- or protein-pulsed antigen-presenting cells (including dendritic cells), recombinant DNA and viral vectors, and recombinant Saccharomyces (yeast) are all currently in active clinical-trial development.
There is a wide array of newly defined potential tumor-associated targets primed for cancer vaccine development, including neoplastic or tumor progression processes, they add. As the field of cancer-vaccine therapy matures, long-term safety profiles of several of these agents will most likely be realized. At that juncture, vaccines may well also be used in neoadjuvant settings and in certain preneoplastic conditions, they suggest.
While the review focused on prostate cancer vaccines, the researchers say these trials are examples of ongoing progress in similar vaccine therapies for lymphoma, melanoma, and pancreatic, lung, and other types of cancer. Why are vaccines enhancing outcome to subsequent therapies? The investigators suggest this may be due to several factors. The subsequent therapy may:
Reduce suppressor cell populations, allowing for enhancement of prior established T-cell responses.
Lyse some tumor cells that are then, as a consequence of cross priming, activating relatively dormant T cells to elicit an antitumor response.
Enhance host T-cell activity.
Alter the phenotype of tumor cells.
"Skepticism is an important component of the scientific process, and it should be an integral component in the development of any potential new therapy," write Dr. Schlom and his team. "Many are very much aware, for instance, of those skeptics and 'naysayers' who, for a decade, dismissed monoclonal antibody-mediated cancer therapy." There are now 7 monoclonals approved for cancer management. "This too may well be the case for cancer vaccines. Although skepticism is important, there are also those who realize the need for paradigm shifts in both exploiting vaccine combination therapy and analysis of patient benefit in terms of survival (with minimal toxicity) as the appropriate clinical trial end point."