Santin Alessandro D, Bellone Stefania, Palmieri Michela, Ravaggi Antonella, Romani Chiara, Tassi Renata, Roman Juan J, Burnett Alexander, Pecorelli Sergio, Cannon Martin J
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Arkansas for Medical Sciences, 4301 W. Markham, Little Rock, AR 72205-7199, USA.
Gynecol Oncol. 2006 Mar;100(3):469-78. doi: 10.1016/j.ygyno.2005.09.040. Epub 2005 Oct 24.
To evaluate the potential of human papillomavirus (HPV) type 16 and 18 E7 antigen-loaded autologous dendritic cells (DC) as a therapeutic cellular vaccine in a case series of cervical cancer patients harboring recurrent/metastatic disease refractory to standard treatment modalities.
Autologous monocyte-derived DC were pulsed with recombinant HPV16 E7 or HPV18 E7 oncoproteins and administered to 4 cervical cancer patients. Vaccinations were followed by subcutaneous administration twice daily of low doses of human recombinant interleukin-2 (1 x 10(6) IU/m2) from day 3 to day 7. Safety, toxicity, delayed type hypersensitivity reactions (DTH), clinical responses, and induction of serological and cellular immunity against HPV16/18 E7 were monitored.
The vaccine was well-tolerated in all patients and no local or systemic side effects or toxicity were recorded. Three out of four patients were found to be significantly immunocompromised before starting the vaccination treatment, as assessed by DTH with a panel of recall antigens. Specific humoral and cellular CD4+ T cell responses to the E7 vaccine were detected in 2 patients, as detected by ELISA and by IFN-gamma ELISpot assays, respectively. Increased numbers of E7-specific IFN-gamma secreting CD8+ T cells were detected in all patients after vaccination. Swelling and induration (i.e., a positive DTH response) to the intradermal injection of HPV E7 oncoprotein and/or irradiated autologous tumor cells were detected in two patients after six vaccinations. No objective clinical responses were observed. However, both patients who developed a positive DTH to the vaccine experienced a slow tumor progression (i.e., 13 months survival) while DTH unresponsive patients died within 5 months from the beginning of therapy.
Autologous DC pulsed with HPV16/18 E7 proteins can induce systemic B and T cell responses in patients unresponsive to standard treatment modalities. However, treatment-induced immunosuppression may impose severe limitations on the efficacy of active vaccination strategies in late stage cervical cancer patients. DC-based vaccination trials are warranted in immunocompetent cervical cancer patients with early stage disease and/or limited tumor burden, and at significant risk for tumor recurrence or disease progression.
在一系列对标准治疗方法难治的复发性/转移性宫颈癌患者病例中，评估负载人乳头瘤病毒（HPV）16型和18型E7抗原的自体树突状细胞（DC）作为治疗性细胞疫苗的潜力。
用重组HPV16 E7或HPV18 E7癌蛋白脉冲处理自体单核细胞来源的DC，并将其给予4例宫颈癌患者。从第3天至第7天，每天两次皮下注射低剂量的重组人白细胞介素-2（1×10⁶IU/m²），随后进行疫苗接种。监测安全性、毒性、迟发型超敏反应（DTH）、临床反应以及针对HPV16/18 E7的血清学和细胞免疫诱导情况。
所有患者对该疫苗耐受性良好，未记录到局部或全身副作用或毒性。通过一组回忆抗原进行DTH评估发现，4名患者中有3名在开始疫苗接种治疗前存在明显免疫功能低下。分别通过ELISA和IFN-γ ELISpot检测，在2例患者中检测到对E7疫苗的特异性体液和细胞CD4⁺ T细胞反应。接种疫苗后，在所有患者中均检测到E7特异性IFN-γ分泌性CD8⁺ T细胞数量增加。6次接种后，在2例患者中检测到对皮内注射HPV E7癌蛋白和/或照射的自体肿瘤细胞出现肿胀和硬结（即阳性DTH反应）。未观察到客观临床反应。然而，对疫苗产生阳性DTH反应的2例患者肿瘤进展缓慢（即存活13个月），而对DTH无反应的患者在治疗开始后5个月内死亡。
用HPV16/18 E7蛋白脉冲处理的自体DC可在对标准治疗方法无反应的患者中诱导全身性B细胞和T细胞反应。然而，治疗诱导的免疫抑制可能对晚期宫颈癌患者主动疫苗接种策略的疗效造成严重限制。对于免疫功能正常、处于疾病早期和/或肿瘤负荷有限且有肿瘤复发或疾病进展重大风险的宫颈癌患者，有必要进行基于DC的疫苗接种试验。
