点击显示 收起
July 22, 2008 — 首次有报导指出，癌症临床预后与接受治疗性疫苗后T细胞反应性之间，有渐进性的关连。在7月15日的癌症研究期刊中，来自加州洛杉矶Cedars-Sinai医学中心的研究者们报导，在进行治疗性疫苗接种后，罹患神经胶母细胞瘤病患的T细胞反应与临床预后有直接相关。
第一作者、Cedars-Sinai医学中心Maxine Dunitz神经外科机构的研究科学家Christopher Wheeler博士向Medscape肿瘤学表示，我们可以自信地说，这是这种癌症疫苗首次以我们所预期的方式产生作用，且疫苗所产生的免疫反应越强，病患的好处越多。
对疫苗有反应的病患，不论是存活时间（TTS）或是肿瘤恶化时间（TTP）都显著较长，目前这项研究倾向支持早先研究显示树突疫苗接种与化学治疗共同加成性地作用，且可以改善预后。接种疫苗后接着进行化学治疗，相较于仅接受疫苗接种，TTP显著增加，同时，TTP显著增加的情形并不局限于对疫苗有反应者；作者表示，这可能代表在此病患族群中，化学治疗的临床效果比接种疫苗好，或是这个研究所筛选出来的病患族群与一般族群不同。
Wheeler医师表示，化学治疗对大部分神经胶母细胞瘤并没有效果，我们正设法取得比传统化学治疗更有效、且能延长病患生命的治疗方式；我们认为疫苗可能增强化学治疗的疗效，我们已经在神经胶母细胞瘤的实验中取得相关证据。
神经胶母细胞瘤占所有原发性脑部肿瘤的一半，且约占所有成人中神经系统肿瘤的21%，一般来说，它的预后是非常差的，可以存活超过两年的病患不到28%；目前最有效的治疗，是外科手术加上放射线治疗与temozolamide化学治疗，但也只能提供平均约15个月的存活时间，因此，我们需要更有效的治疗。
【细胞激素反应】
这项研究族群包括34位罹患神经胶母细胞瘤的成人病患，其中32位（21位再发与11位新诊断的病例）都接受免疫功能评估；在这项第二期研究中，所有受试者都接受四次疫苗注射，每次900 μg的自体肿瘤碎片，这来自10到40 x 106自体树突细胞。接着，研究者在疫苗接种前与后的周边单核细胞中，评估树突细胞/碎片刺激细胞激素反应（干扰素-γ）。
研究者发现，抗原延生的IFN-γ产生，在疫苗接种后逐渐增加，在接种疫苗两次后达到统计上显著差异，且在第三次疫苗接种后达到最高。已有报告指出IFN-γ的产生达到注射疫苗前的1.5倍，而这是癌症病患疫苗反应阳性的证据。根据这个条件，34位罹患神经胶母细胞瘤病患中有17位在三次的疫苗接种后有阳性反应。然而，IFN-产生超过注射疫苗前1.5倍的病患，在注射疫苗后，并没有比较可能有相似的效果（无反应病患有20%、具反应病患有25%）。
【具反应者的存活时间与恶化所需时间较长】
研究者观察到有反应者病患的TTS是无反应者的7倍（642天比上430天）；TTP的增加也是显著较长的，对疫苗有反应者比无反应者长了4.5个月（308天比上167天）；有反应者的效果较好，不一定是病患误差造成；有反应者与无反应的治疗前预后因子是相差不多的。
存活至少在两年以上的疫苗反应者有41%，但无反应者存活超过两年仅7%，整体而言，疫苗反应者的临床预后比无反应者佳；这样的趋势显然与反应程度有关。作者表示，有反应者中，疫苗所产生的反应以及治疗后存活与接种疫苗后IFN-反应成对数性相关；这项观察与疫苗透过T细胞产生第一型细胞激素反应，而成比例地改善神经胶母细胞瘤病患存活的想法相符。
【疫苗与后续化学治疗的加乘作用】
当检视树突细胞疫苗与化学治疗之间的加乘作用时，研究者比较仅接受疫苗与接受疫苗以及后续化学治疗病患的TTP，结果显示，接受疫苗后进行化学治疗的病患，其平均TTP比仅接受疫苗病患长188天，且至少有3位病患（1位无反应者、2位有反应者）在接种疫苗后接受化学治疗达到完全消退。第4位反应者在接种疫苗与化学治疗之间达到消退反应。
疫苗反应与横跨化学治疗的TTP之间关连，比疫苗反应与TTS之间关联强；作者写道，这些观察显示疫苗诱发的反应，主要是透过肿瘤对化学治疗产生反应，来达到治疗上的好处。
在一项声明中，Cedars-Sinai神经肿瘤学主任、同时也是该临床研究主要研究者的John S. Yu医师表示，如果我们可以改善疫苗的免疫反应率，我们同样能预期将有临床上的好处，这致使我们能将我们的疫苗以更即时的方式进行微调。
树突疫苗科技特定股权与相对应的智慧财产权已经由Cedars-Sinai转移给ImmunoCellular Therapeutics有限公司。Wheeler医师是专利拥有人；试验共同作者Keith L. Black医师，来自Maxine Duitz神经外科机构，拥有Immune Therapeutics公司的股份；而Yu博士，同样来自Maxine Duitz神经外科机构，他接受MGI Pharma公司商业研究经费，同时也担任ImmunoCellular Therapueitcs有限公司发言人与领取酬金。该研究由Maxine Duitz神经外科研究经费赞助。
Novel Vaccine Boosts Survival in Glioblastoma Patients
By Roxanne Nelson
Medscape Medical News
July 22, 2008 — For the first time, a progressive correlation between cancer clinical outcome and T?cell responsiveness after therapeutic vaccination has been reported. In the July 15 issue of Cancer Research, researchers from Cedars-Sinai Medical Center, in Los Angeles, California, reported that the T?cell response seen after therapeutic vaccination for glioblastoma multiforme is directly related to clinical outcome.
"We can convincingly say for the first time that this form of cancer vaccine is working the way we think it should — the more immune activity the vaccine induces, the greater the benefit to the patient," first author Christopher Wheeler, PhD, a research scientist for the Maxine Dunitz Neurosurgical Institute at Cedars-Sinai Medical Center, told Medscape Oncology.
Both time to survival (TTS) and time to tumor progression (TTP) were significantly longer in patients who responded to the vaccine. The current study lends support to earlier research that suggested dendritic cell vaccination and chemotherapy work synergistically to improve outcomes. TTP increased significantly when vaccination was followed by chemotherapy, compared with vaccination alone. This increase was not limited to vaccine responders, the authors noted, and could be indicative of the fact that the clinical efficacy of chemotherapy is greater than that of vaccination in the study population, or that the patient subpopulation selected had a clinical disease course distinct from the general population.
"Chemotherapy is not that effective against most glioblastoma multiforme, and we're getting a much bigger effect and in a greater span of patients than conventional chemotherapy alone," said Dr. Wheeler. "We think the vaccine is probably enhancing the efficacy of chemotherapy. We also have evidence of this in experimental models of glioblastoma."
Glioblastoma multiforme accounts for about half of all primary brain tumors and 21% of all central nervous system tumors in adults. Prognosis is usually very poor, with less than 28% of patients surviving 2 years. The most effective treatment, which offers a median survival of only 15 months, is currently surgical resection followed by radiation and temozolamide chemotherapy. Therefore, more effective therapies are needed.
Cytokine Responses
The study cohort consisted of 34 adult patients with glioblastoma multiforme, of whom 32 (21 recurrent and 11 newly diagnosed) were available for an immunologic evaluation. In this phase?2 trial, all participants received 4 vaccines of 900?μg autologous tumor lysate/10 to 40 × 106 autologous dendritic cells. The researchers then assessed cytokine (interferon -γ) responsiveness after the dendritic cell/lysate stimulation of both prevaccine and postvaccine peripheral blood mononuclear cells.
The researchers found that antigen-directed IFN-γ production progressively increased after vaccination, reached statistical significance after 2 vaccinations, and reached maximal levels after 3 vaccinations. IFN-γ production 1.5 times the prevaccine level has been reported and is evidence of a positive vaccine response in cancer patients. Using this criterion, 17 of 34 patients with glioblastoma exhibited a positive response after 3 vaccinations. However, patients with IFN-γ production 1.5 or more times higher than the prevaccine level were not more likely to experience the same after receiving the vaccines (20% of nonresponders and 25% of responders).
Longer Time to Survival and Time to Progression in Responders
The researchers observed that TTS among responders was about 7 months longer than it was for nonresponders (642 days vs 430 days). The increase in TTP was also significantly longer, by more than 4.5 months, in patients who had responded to the vaccine (308 days vs 167 days). The more favorable response seen in vaccine responders did not appear to be due to patient bias; pretreatment prognostic factors were similar between vaccine responders and nonresponders.
A total of 41% of the vaccine responders survived at least 2 years, whereas only 7% of nonresponders did. Overall, vaccine responders showed more favorable clinical outcomes than nonresponders; this trend appeared to be dependent on the level of response. Vaccine-elicited responses and posttreatment survival correlated logarithmically with the magnitude of postvaccine IFN-γ responses seen exclusively in responders; this observation is consistent with the idea that vaccine-elicited type?1 cytokine responses by T cells proportionally improve survival in glioblastoma patients, the authors note.
Synergy Between Vaccine and Subsequent Chemotherapy
When examining the synergy between the dendritic cell vaccine and chemotherapy, the researchers compared TTP in patients who received vaccine alone and in those who received both the vaccine and subsequent chemotherapy. Mean TTP was 188 days longer during the postvaccine chemotherapy interval than during the vaccine interval, and at least 3 patients (1 nonresponder, 2 responders) experienced a complete regression during the postvaccine chemotherapy interval. A fourth responder experienced a regression during the interval that spanned vaccination and chemotherapy.
The correlation between vaccine response and TTP that spanned chemotherapy was stronger than that between vaccine response and TTS. These observations suggest that vaccine-induced responses elicit therapeutic benefits primarily by sensitizing tumors to chemotherapy, the authors write.
In a statement, John S. Yu, MD, director of surgical neuro-oncology at Cedars-Sinai and the principal investigator of the clinical trial, noted that "if we can improve the immune response of our vaccine, we can anticipate that the clinical benefit will be improved as well. This allows us to fine-tune our vaccine in more of a real-time way,"
Certain rights in the dendritic cell vaccine technology and corresponding intellectual property have been exclusively licensed by Cedars-Sinai to ImmunoCellular Therapeutics, Inc. Dr. Wheeler is a patent holder; study coauthor Keith L. Black, MD, from the Maxine Dunitz Neurosurgical Institute, has an ownership interest in Immune Therapeutics; and Dr. Yu, also from the Maxine Dunitz Neurosurgical Institute, has received a commercial research grant from MGI Pharma and speakers bureau/honoraria from ImmunoCellular Therapeutics. The study was supported by a grant from the Maxine Dunitz Neurosurgical research fund.
Cancer Res. 2008;68:5955-5964. Abstract