Dijkgraaf Eveline M, Santegoets Saskia J A M, Reyners An K L, Goedemans Renske, Nijman Hans W, van Poelgeest Mariëtte I E, van Erkel Arien R, Smit Vincent T H B M, Daemen Toos A H H, van der Hoeven Jacobus J M, Melief Cornelis J M, Welters Marij J P, Kroep Judith R, van der Burg Sjoerd H
Department of Medical Oncology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
Department of Clinical Oncology, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands.
Oncotarget. 2015 Oct 13;6(31):32228-43. doi: 10.18632/oncotarget.4772.
Preclinical tumor models show that chemotherapy has immune modulatory properties which can be exploited in the context of immunotherapy. The purpose of this study was to determine the feasibility and immunogenicity of combinations of such an immunomodulatory chemotherapeutic agent with immunotherapy, p53 synthetic long peptide (SLP) vaccine and Pegintron (IFN-α) in patients with platinum-resistant p53-positive epithelial ovarian cancer (EOC).
This is a phase 1/2 trial in which patients sequential 6 cycles of gemcitabine (1000 mg/kg2 iv; n = 3), gemcitabine with Pegintron before and after the first gemcitabine cycle (Pegintron 1 μg/kg sc; n = 6), and gemcitabine and Pegintron combined with p53 SLP vaccine (0.3 mg/peptide, 9 peptides; n = 6). At baseline, 22 days after the 2nd and 6th cycle, blood was collected for immunomonitoring. Toxicity, CA-125, and radiologic response were evaluated after 3 and 6 cycles of chemotherapy.
None of the patients enrolled experienced dose-limiting toxicity. Predominant grade 3/4 toxicities were nausea/vomiting and dyspnea. Grade 1/2 toxicities consisted of fatigue (78%) and Pegintron-related flu-like symptoms (72%). Gemcitabine reduced myeloid-derived suppressor cells (p = 0.0005) and increased immune-supportive M1 macrophages (p = 0.04). Combination of gemcitabine and Pegintron stimulated higher frequencies of circulating proliferating CD4+ and CD8+ T-cells but not regulatory T-cells. All vaccinated patients showed strong vaccine-induced p53-specific T-cell responses.
Combination of gemcitabine, the immune modulator Pegintron and therapeutic peptide vaccination is a viable approach in the development of combined chemo-immunotherapeutic regimens to treat cancer.
临床前肿瘤模型显示化疗具有免疫调节特性，可在免疫治疗背景下加以利用。本研究旨在确定这种免疫调节化疗药物与免疫治疗药物（p53合成长肽（SLP）疫苗和派罗欣（干扰素-α））联合应用于铂耐药p53阳性上皮性卵巢癌（EOC）患者的可行性和免疫原性。
这是一项1/2期试验，患者依次接受6个周期的吉西他滨（1000mg/kg²静脉注射；n = 3）、在第一个吉西他滨周期前后使用吉西他滨与派罗欣联合治疗（派罗欣1μg/kg皮下注射；n = 6），以及吉西他滨和派罗欣与p53 SLP疫苗联合治疗（0.3mg/肽，9种肽；n = 6）。在基线、第2和第6周期后22天采集血液进行免疫监测。化疗3个周期和6个周期后评估毒性、CA - 125和放射学反应。
入组患者均未出现剂量限制性毒性。主要的3/4级毒性为恶心/呕吐和呼吸困难。1/2级毒性包括疲劳（78%）和与派罗欣相关的流感样症状（72%）。吉西他滨减少了髓源性抑制细胞（p = 0.0005）并增加了免疫支持性M1巨噬细胞（p = 0.04）。吉西他滨和派罗欣联合治疗刺激了循环中增殖性CD4⁺和CD8⁺T细胞的更高频率，但未刺激调节性T细胞。所有接种疫苗的患者均表现出强烈的疫苗诱导的p53特异性T细胞反应。
吉西他滨、免疫调节剂派罗欣和治疗性肽疫苗联合应用是开发联合化疗免疫治疗方案治疗癌症的一种可行方法。
