Wheeler Christopher J, Das Asha, Liu Gentao, Yu John S, Black Keith L
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Clin Cancer Res. 2004 Aug 15;10(16):5316-26. doi: 10.1158/1078-0432.CCR-04-0497.
Although the development of immune-based therapies for various cancers including malignant glioma has been heralded with much hope and optimism, objective clinical improvements in most vaccinated cancer patients have not been realized. To broaden the search for vaccine-induced benefits, we examined synergy of vaccines with conventional chemotherapy.
Survival and progression times were analyzed retrospectively in 25 vaccinated (13 with and 12 without subsequent chemotherapy) and 13 nonvaccinated de novo glioblastoma (GBM) patients receiving chemotherapy. Immune responsiveness and T-cell receptor excision circle (TREC) content within CD8+ T cells (CD8+ TRECs) was determined in vaccinated patients.
Vaccinated patients receiving subsequent chemotherapy exhibited significantly longer times to tumor recurrence after chemotherapy relative to their own previous recurrence times, as well as significantly longer postchemotherapy recurrence times and survival relative to patients receiving isolated vaccination or chemotherapy. Patients exhibiting objective (>50%) tumor regression, extremely rare in de novo GBM, were also confined to the vaccine + chemotherapy group. Prior tumor behavior, demographic factors, other treatment variables, distribution of vaccine responders, and patients with high CD8+ TRECs all failed to account for these differences in clinical outcome. Within all GBM patients receiving post-vaccine chemotherapy, however, CD8+ TRECs predicted significantly longer chemotherapeutic responses, revealing a strong link between the predominant T-cell effectors in GBM and tumor chemosensitivity.
We propose that therapeutic vaccination synergizes with subsequent chemotherapy to elicit tangible clinical benefits for GBM patients.
尽管包括恶性胶质瘤在内的各种癌症的免疫疗法的发展带来了诸多希望和乐观情绪，但大多数接受疫苗接种的癌症患者并未实现客观的临床改善。为了更广泛地寻找疫苗诱导的益处，我们研究了疫苗与传统化疗的协同作用。
回顾性分析了25例接受疫苗接种的（13例随后接受化疗，12例未接受化疗）和13例初发胶质母细胞瘤（GBM）且未接种疫苗并接受化疗的患者的生存时间和疾病进展时间。测定了接种疫苗患者CD8 + T细胞内的免疫反应性和T细胞受体切除环（TREC）含量（CD8 + TRECs）。
与自身先前的复发时间相比，接受后续化疗的接种疫苗患者化疗后肿瘤复发时间显著延长，与接受单纯疫苗接种或化疗的患者相比，化疗后复发时间和生存期也显著延长。出现客观（> 50%）肿瘤消退的患者（在初发GBM中极为罕见）也仅限于疫苗+化疗组。先前的肿瘤行为、人口统计学因素、其他治疗变量、疫苗反应者的分布以及CD8 + TRECs高的患者均无法解释这些临床结果差异。然而，在所有接受疫苗接种后化疗的GBM患者中，CD8 + TRECs预示化疗反应显著延长，揭示了GBM中主要T细胞效应器与肿瘤化疗敏感性之间的紧密联系。
我们提出治疗性疫苗接种与后续化疗协同作用可为GBM患者带来切实的临床益处。
