Therapeutic HPV vaccination for stage IB1 cervical cancer

描述（由申请方提供）：宫颈人乳头瘤病毒（HPV）相关瘤形成提供了一个测试抗原特异性疫苗接种的令人信服的机会，因为两种非自身病毒抗原E6和E7的表达在功能上共同需要启动和维持肿瘤病变，包括高度异型增生（CIN 2/3），浸润性癌症的前兆和癌症。这项I期临床试验将评估靶向HPV 16 E7抗原的DNA疫苗pNGVL 4a-CRT-E7（detox）的颗粒介导表皮递送（PMED）在与HPV 16相关的可手术IB 1期宫颈癌患者中的安全性、耐受性和免疫原性，HPV 16是最常见的与疾病相关的HPV基因型。临床级疫苗已由NCI RAID生产，并已配制用于PMED疫苗接种。这项试验也将提供一个独特的机会，以评估在标准治疗性切除时获得的标本中肿瘤隔室的免疫调节机制的分子证据。尽管设计免疫应答策略的中心假设是引发对肿瘤相关抗原特异性的效应免疫应答将导致临床应答，但从HPV疾病患者中HPV特异性免疫应答的测量结果可以清楚地看出，外周血中免疫应答的存在并不总是与结果相关。因此，在本试验中，我们不仅将评估该患者队列中疫苗接种的安全性和免疫原性，还将确定肿瘤区室中的免疫调节措施是否与疫苗接种应答能力相关。我们在这一患者人群的临床试验设计和执行方面有着良好的记录，这一人群中不成比例地包括无法有效获得医疗保健系统的少数民族妇女。该协议将转化由NCI SPORE机制支持的早期开发，并利用与亚拉巴马大学GOG研究人员的长期合作。该I期临床试验将在患有可手术的IB 1期宫颈癌的患者中测试用治疗性HPV疫苗pNGVL 4a-CRT-E7（detox）进行无针颗粒介导的疫苗接种的安全性、可行性和免疫原性。这项试验也将提供一个独特的机会，以评估在标准治疗性切除时获得的标本中肿瘤隔室的免疫调节机制的证据。临床级疫苗由NCI RAID与PowderMed合作生产。该试验是SPORE-GOG合作。

DESCRIPTION (provided by applicant): Human papillomavirus (HPV)-associated neoplasia of the cervix presents a compelling opportunity to test antigen-specific vaccination because expression of two nonself, viral antigens, E6 and E7, are together functionally required to initiate and maintain neoplastic lesions, both high grade dysplasia (CIN2/3), the precursor to invasive cancer, and cancer. This phase I clinical trial will assess the safety, tolerability, and immunogenicity of particle-mediated epidermal delivery (PMED) of a DNA vaccine which is targeted at the HPV16 E7 antigen, pNGVL4a-CRT-E7(detox), in patients with operable Stage IB1 cervical cancer associated with HPV16, the HPV genotype most commonly associated with disease. Clinical grade vaccine has been manufactured by NCI RAID, and has been formulated for PMED vaccination. This trial will also present a unique opportunity to assess the tumor compartment for molecular evidence of mechanisms of immune regulation, in specimens obtained at the time of standard therapeutic resection. Although the central assumption in designing immunotherapeutic strategies is that eliciting effector immune responses specific for tumor associated antigens will result in clinical response, it is clear from measures of HPV-specific immune responses in patients with HPV disease that the presence of immune responses in the peripheral blood does not always correlate with outcome. Therefore in this trial we will assess not only the safety and immunogenicity of vaccination in this patient cohort, but also determine whether measures of immune regulation in the tumor compartment correlate with ability to respond to vaccination. We have a demonstrated track record in clinical trial design and execution in this patient population, which is disproportionately comprised of minority women who do not access the medical care system effectively. This protocol will translate early development supported by the NCI SPORE mechanism, and take advantage of a longstanding collaboration with GOG investigators at the University of Alabama. This phase I clinical trial will test safety, feasibility, and immunogenicity of needle- free particle-mediated vaccination with a therapeutic HPV vaccine, pNGVL4a- CRT-E7(detox), in patients with operable Stage IB1 cervical cancer. This trial will also present a unique opportunity to assess the tumor compartment for evidence of mechanisms of immune regulation, in specimens obtained at the time of standard therapeutic resection. Clinical grade vaccine has been manufactured by NCI RAID, in collaboration with PowderMed. This trial is a SPORE-GOG collaboration.