p53-Reactive T Cells Are Associated with Clinical Benefit in Patients with Platinum-Resistant Epithelial Ovarian Cancer After Treatment with a p53 Vaccine and Gemcitabine Chemotherapy.
p53-Reactive T Cells Are Associated with Clinical Benefit in Patients with Platinum-Resistant Epithelial Ovarian Cancer After Treatment with a p53 Vaccine and Gemcitabine Chemotherapy.
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DOI：
10.1158/1078-0432.ccr-17-2709
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发表时间：
2018-03-15
期刊：
影响因子：
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通讯作者：
Cristea M
中科院分区：
文献类型：
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作者：
Hardwick NR;Frankel P;Ruel C;Kilpatrick J;Tsai W;Kos F;Kaltcheva T;Leong L;Morgan R;Chung V;Tinsley R;Eng M;Wilczynski S;Ellenhorn JDI;Diamond DJ;Cristea M
在铂类耐药卵巢癌患者中进行一项改良安卡拉牛痘疫苗递送野生型人p53（p53 MVA）联合吉西他滨化疗的I期试验。在前3个化疗周期中，患者在第1天和第8天接受吉西他滨，在第15天接受p53 MVA疫苗。使用NCI通用毒性标准对毒性进行分类，并通过CT扫描评估临床反应。收集外周血样本进行免疫表型分析和监测抗p53免疫反应。对11例患者的p53 MVA/吉西他滨毒性、临床结局和免疫应答进行了评价。毒性：无DLT，但3/11例患者因吉西他滨引起的不良事件（AE）而提前退出研究。极轻微AE归因于p53 MVA疫苗接种。免疫学和临床应答：免疫后，分别在5/11和6/11例患者的CD 4+和CD 8 + T细胞区室中检测到p53肽的体外识别增强。外周血调节性T细胞（T细胞）和髓源性抑制细胞（MDSC）的变化与疫苗应答或无进展生存期（PFS）无显著相关性。治疗后p53反应性T细胞扩增最大的患者的PFS显著长于p53反应性较低的患者。4例患者出现肿瘤缩小或疾病稳定。p53 MVA耐受性良好，但吉西他滨不加类固醇预处理在某些患者中无法耐受。然而，治疗后升高的p53反应性CD 4+和CD 8 +T细胞应答与较长的PFS相关。因此，如果对p53 MVA的反应可以用替代药物增强，则可以实现上级临床反应。
To conduct a Phase I trial of a Modified Vaccinia Ankara vaccine delivering wild type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian cancer. Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses. 11 patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome and immunological response. Toxicity: There were no DLTs but 3/11 patients came off study early due to gemcitabine-attributed adverse events (AEs). Minimal AEs were attributed to p53MVA vaccination. Immunological and Clinical Response: Enhanced in vitro recognition of p53 peptides was detectable after immunization in both the CD4+ and CD8+ T cell compartments in 5/11 and 6/11 patients respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity post therapy. Tumor shrinkage or disease stabilization occurred in 4 patients. p53MVA was well tolerated, but gemcitabine without steroid pre-treatment was intolerable in some patients. However, elevated p53-reactive CD4+ and CD8+T cell responses post therapy correlated with longer PFS. Therefore, if responses to p53MVA could be enhanced with alternative agents, superior clinical responses may be achievable.