Vaccination strategies for the prevention of cervical cancer

Infection with high-risk human papillomaviruses (HPVs) is an essential step in the multistep process leading to cervical cancer. There are approximately 120 different types of HPV identified: of these, 18 are high-risk types associated with cervical cancer, with HPV-16 being the dominant type in most parts of the world. The major capsid protein of papillomavirus, produced in a number of expression systems, self assembles to form virus-like particles. Virus-like particles are the basis of the first generation of HPV vaccines presently being tested in clinical trials. Virus-like particles are highly immunogenic and afford protection from infection both in animal models and in Phase IIb clinical trials. A number of Phase III trials are in progress to determine if the vaccine will protect against cervical disease and, in some cases, genital warts. However, it is predicted that these vaccines will be too expensive for the developing world, where they are desperately needed. Another problem is that they will be type specific. Novel approaches to the production of virus-like particles in plants, second-generation vaccine approaches including viral and bacterial vaccine vectors and DNA vaccines, as well as different routes of immunization, are also reviewed.     

Human papillomavirus therapy for the prevention and treatment of cervical cancer

Opinion statement Cervical carcinoma is associated with human papillomavirus infection. Proliferation of cancer cells depends on the continual expression of the E6 and E7 viral oncogenes. This article includes treatment strategies that can interfere with expression or function of the proteins and immunotherapeutic approaches that can eliminate cells that express E6 and E7 proteins.     

Vaccination against cervical cancer

Globally, carcinomas of the anogenital tract, in particular cervical cancer, remain some of the most common cancers in women, cervical cancer represents the second most frequent gynecological malignancy and the third leading cause of cancer-related death in women worldwide. The causal relationship between human papillomavirus (HPV) infection and anogenital cancer has prompted substantial interest in the development of both preventive and therapeutic vaccines against high-risk HPV types. In the past decade, several groups have shown encouraging results using experimental vaccination systems in animal models and these results have led to several current prophylactic and therapeutic vaccine clinical trials in humans. Prophylactic vaccination focuses on the induction of high titer neutralizing antibodies that are potentially protective against incident and persistent HPV infection. Two major phase II clinical trials conducted by pharmaceutical companies have demonstrated that their vaccines have 100% efficacy in preventing persistent viral DNA and its associated cellular abnormalities; however, whether they induce long-lasting protective immunity is yet to be determined. At least one US FDA approved prophylactic vaccine targeting the two most common high-risk HPVs is expected to be on the market within the next 2–3 years. Nevertheless, significant reductions in the frequency and onset of cytologic screening and incidences of HPV-related lesions are not expected to become apparent for decades due to the fact that there will be women who are already infected with HPV, the long latency period between infection and development of high-grade lesions, and lesions associated with other high-risk HPV types not being included in the vaccines. Therapeutic vaccines aim to control HPV-associated malignancies by stimulating cellular immune responses that target established HPV infections via viral proteins. Progress in the field of HPV immunotherapy has remained elusive, with clinical trials being limited to small numbers of patients. Potential treatment of precancerous lesions is unique to HPV-associated infection and cancer because of cytologic monitoring and HPV typing. Unlike more common surgical treatments for cervical lesions, active immunotherapy has the potential to address HPV persistence as the cause of lesion development in addition to leaving the patient with long-term immunity that can be reactivated if and when the patient becomes reinfected.     

宫颈癌精准防治的研究新进展

宫颈癌是女性生殖系统三大恶性肿瘤之一,发病机制尚未完全阐明,但高危型人乳头状瘤病毒(high-risk human papillomavirus, HR-HPV) 持续性感染以及病毒整合到人类基因组被认为是宫颈癌的重要发病机制。精准医学的崛起,依赖于现代遗传学技术、分子诊断、生物信息学和大数据的快速发展,是现阶段医学发展的高峰。本文从宫颈癌的易感性、发病机制和治疗等方面,对宫颈癌的精准防治进行综述。     

Vaccination strategies in the treatment of lymphomas

Malignant lymphomas are clonal neoplasms of lymphoid origin. By definition, all cells of the malignant clone have undergone the same rearrangement of antigen receptor genes and express identical antigen receptor molecules (immunoglobulin for B cell lymphomas, T cell receptor for T cell lymphomas). The hypervariable stretches within the variable regions of these receptors are considered true tumor-specific antigens ('idiotypes'). In several animal models, protective humoral or cellular immunity can be induced against the malignant lymphoma by vaccination with the tumor-derived idiotype. Successful experimental immunization strategies in animals include idiotype protein vaccines combined with various adjuvants, genetically or immunologically modified lymphoma cells, idiotype-presenting dendritic cells, idiotype-encoding viral vectors, and DNA immunization. Firm evidence for the induction of lymphoma-specific immunity has also been obtained from human idiotype vaccination trials. Furthermore, some trials have provided strong but hitherto formally unproven evidence for clinical benefit of idiotype-vaccinated patients. Alternative vaccination approaches are based on immunologically modified tumor cells. Current research efforts concentrate on the identification of the most efficacious vaccination route, on definitive proof of clinical efficacy, and on the development of convenient methods to manufacture individual idiotype vaccines.     

Vaccination and screening programs: harmonizing prevention strategies for HPV-related diseases

Background

In nuclear medicine, liquid radiopharmaceuticals for diagnostic or therapeutic purposes are administered to patients by using various types of syringes with different volumes. The activity of each "dose" must be carefully measured and documented prior to administration using an activity calibrator.

Methods

Calibrator response is a function of the measurement geometry and, in particular, it depends on the syringe type and filling volume. To minimize the uncertainty associated with the measured activity of the syringe, it is necessary to calculate a calibration curve depending on filling volume for each syringe type. This curve can be obtained by fitting experimentally determined volume correction factors.

Results

A theoretical evaluation of volume correction factors for syringes is reported for three different experimental methods. The aim is to determine the most accurate experimental method among those considered, by examining the expression of uncertainty for the correction factor. This theoretical analysis was then tested experimentally.

Conclusion

The agreement between the experimental data obtained in the constant activity method and gravimetric method at constant specific activity and the small associated uncertainties show the accuracy of these two procedures; while the volumetric method at constant specific activity could lead to a wrong evaluation of the correction factors.     

Epidemiology, prevention and treatment of cervical cancer in the Philippines

Cervical cancer remains to be one of the leading malignancies among Filipino women. High-risk human papillomavirus (HPV) types, such as 16 and 18, are consistently identified in Filipino women with cervical cancer. Factors identified to increase the likelihood of HPV infection and subsequent development of cervical cancer include young age at first intercourse, low socioeconomic status, high parity, smoking, use of oral contraception and risky sexual behaviors. Cancer screening programs presently available in the Philippines include Pap smears, single visit approach utilizing visual inspection with acetic acid followed by cryotherapy, as well as colposcopy. However, the uptake of screening remains low and is further compounded by the lack of basic knowledge women have regarding screening as an opportunity for prevention of cervical cancer. Prophylactic HPV vaccination of both quadrivalent and bivalent vaccines has already been approved in the Philippines and is gaining popularity among the Filipinos. However, there has been no national or government vaccination policy implemented as of yet. The standard of treatment of cervical cancer is radiotherapy concurrent with chemotherapy. Current researches are directed towards improving availability of both preventive and curative measures of cervical cancer management.     

The use of vaccines in the prevention and treatment of cervical cancer

The close association between high risk HPV infection and cervical carcinoma has provided the impetus for the development of prophylactic and therapeutic vaccination schedules. An effective prophylactic vaccine would obviate the need for population-based cervical screening programmes, while therapeutic vaccination might provide an effective adjunct to or replacement for conventional treatment for benign and malignant cervical disease. While the challenges associated with the design and implemention of immunotherapies are numerous, optimism remains high and it is expected that the next few decades will witness a revolutionary change in the way we treat cervical cancer and its premalignant lesions. A papillomavirus vaccine that prevented HPV infection on the one hand and acted against established disease on the other, would have a profound impact on one of the major cancers affecting women globally.     

Vaccination strategies for lymphomas

Vaccination strategies for lymphomas were developed along with one of the first recognized tumor-specific targets, the clonal antigen receptor, composed of unique variable regions known as idiotypes. Human clinical trials of idiotype vaccination have benefited from highly concordant animal models, leading to sequential improvements in design. Evidence of the clinical benefit of idiotype vaccines is strong but formally unproven. Significant progress has been made in our understanding of the basic mechanisms underlying the induction of immune responses, which has led to a proliferation of rationally designed immunotherapeutic strategies. Current research efforts include the development of more convenient methods to produce individual idiotype vaccines, the establishment of definitive proof for clinical efficacy, and the implementation of alternative vaccination strategies, including genetic vaccination and genetically or immunologically modified autologous tumor cells and dendritic cells.     

Translational strategies for cancer prevention in liver

Unlike many other types of human cancer, the aetiology of liver cancer is well understood. Infection with hepatitis viruses, coupled with dietary exposure to the fungal toxin aflatoxin, increases the risk of the disease. Although primary prevention, based on vaccination and avoiding exposure to these agents, is an appealing option, such strategies will require considerable investment of time and resources to be successful. In the developing world--where the burden of liver cancer is highest--immediate, practical and economical approaches are essential. So, targeted chemoprevention might be most appropriate for the present generation of individuals at risk.     

人乳头瘤病毒分型检测在宫颈癌及癌前病变防治中的应用

人乳头瘤病毒(HPV)与宫颈癌及宫颈癌前病变的发生密切相关,并且HPV亚型不同,其致癌力、宫颈癌病理分型以及宫颈癌的预后均有所不同.早期发现官颈高危型HPV感染与准确分型,及时进行早期干预治疗,是提高宫颈癌防治效果的有效途径,临床HPV分型检测对宫颈癌及癌前病变的防治有重要意义.     

人乳头瘤病毒疫苗防治宫颈癌研究的新进展

宫颈癌的发病率在女性恶性肿瘤居第二位,人乳头状瘤病毒(HPV)感染已被证实为宫颈癌发生的主要因素,采用HPV疫苗防治HPV感染和宫颈癌是最根本的病因治疗方法,其中HPV疫苗分为预防性疫苗和治疗性疫苗两大类,本文综述了近几年关于HPV疫苗的研究成果.     

HPV vaccines and the prevention of cervical cancer

Cervical cancer is the second commonest causes of cancer death among women worldwide. Uniquely amongst human cancers, it is entirely attributable to infection. Persisting infection of anogenital epithelium with one of a limited subset of human papillomaviruses (HPVs) is necessary for the development of cervical cancer. Several recent large clinical trials have shown that prophylactic vaccines, based on PV virus particles produced using recombinant DNA technology, provide long lasting immunity against infection with the incorporated PV genotypes, and against premalignant conditions caused by these infections. Effective deployment of these vaccines, which have excellent safety and efficacy profiles, could eventually reduce the global burden of cervical cancer by up to 70% through universal immunisation of preadolescent girls. Vaccine use will supplement rather than replace cervical cancer screening programs, where these programs already exist.     

Novel strategies for the early detection and prevention of lung cancer

Lung cancer is the leading cause of cancer death in the United States. Despite evidence of molecular abnormalities in biological specimens, progress in this disease is hampered by the lack of diagnostic markers useful for clinical practice. The majority of patients with lung cancer are still diagnosed at an advanced stage, when prognosis is poor. This article reviews new strategies being studied for the early detection of lung cancer. These strategies involve new methods of imaging (including low-dose computed tomography [CT] scanning), DNA analysis, and proteomic-based techniques. These strategies have not only improved our understanding of lung cancer but show promise in offering better survival to patients with this deadly disease. Of paramount importance in the search for methods of early detection is the need for the identification of the ideal population to screen, a multidisciplinary approach, and validation of promising techniques.     

Papillomavirus vaccination for prevention and treatment of cervical carcinoma

Some human cancers are associated with human papillomaviruses, particularly cervical carcinoma, representing the second most frequent cancer in women worldwide, and with an increasing incidence in women of childbearing age in developed countries. The association to some viral types as human papillomavirus (HPV) 16 makes it feasible to develop prophylactic or therapeutic vaccines that can have an efficacy of at least 70%. The combination of epitopes from the L1 and E7 proteins are the most immunogenic, inducing neutralising antibodies to control virus spread, as well as cytolytic T cells, which are detectable in the genital tract. These vaccines have no side effects and have passed phase II clinical trials. Phase III clinical trials are underway in several countries where viral infection and highgrade lesions are used as endpoints parameters for vaccine evaluation in the follow-up.      

靶向表皮生长因子受体的抗肿瘤治疗

表皮生长因子受体(EGFR)与恶性肿瘤的发生和发展密切相关.目前针对EGFR已经开发出多种单克隆抗体、酪氨酸激酶小分子抑制剂等药物应用于临床,在对多种晚期和耐药肿瘤的治疗中取得良好效果.     

Optimizing treatment for cervical cancer

There are a number of ways in which surgery, radiation therapy, and more recently chemotherapy have been employed in the treatment of locally advanced cervical cancer. The evidence in favor of chemoradiation in cervical cancer was summarized in a meta-analysis of 19 trials which showed improvement with the concomitant administration of chemotherapy and radiation (CRT), not only in survival (by >10% at 5 years) but also in both local and distant recurrence rates. These results validate the National Cancer Institute Alert (USA) in February 1999, which was based on preliminary evidence from five randomized trials, and stated that concomitant chemoradiotherapy should be considered for the majority of patients with cervical cancer. However, patients with locally advanced disease with negative para-aortic nodes accounted for the majority of those selected for these trials, and the benefits of the addition of chemotherapy to radiation were clearer in stages I and II disease. Acute and late toxicity remain areas of concern. The role of surgery is also undergoing re-evaluation, both in early disease where surgery may offer equal survival to radiation with reduced morbidity, and in more locally advanced cases where recent data have shown surgery preceded by chemotherapy achieves similar gaines in absolute survival compared with radiation alone. The trials involving CRT differed in size, design, accrual period and chemotherapeutic agent used, and there has been extensive debate about optimization of the radiation dose and whether chemotherapy in some of the trials compensates for inadequate radiation dose. However, these factors would not account for the improvement in distant relapse rates observed. Similarly, surgical expertise has been shown to be a major factor affecting outcome in radical procedures, and recent developments in more conservative surgery also improve morbidity in selected cases. The alternative strategy of neoadjuvant chemotherapy prior to surgery (NACT-S) has been evaluated extensively in South America and Italy in groups similar to those in which CRT has been shown to be effective. Although the data are promising, the evidence base for outcome compared with radiation alone is much smaller, and there have been no direct comparisons with CRT. The chemotherapy in CRT may be acting predominantly through a cytotoxic effect as distinct from having a sensitization effect, and hence the rationale for these two approaches (CRT and NACT-S) may be broadly similar, that is, early control of systemic disease as well as additional local control to that achieved by either surgery or radiation alone. The sequential use of further chemotherapy after these strategies is under development. In early disease, surgery and radiation therapy are comparable in terms of efficacy, and the preference for surgery is based on reduced morbidity and the potential to preserve fertility. The addition of platinum-based chemotherapy, either prior to surgery or with radiation improves survival and distant recurrence rates in more locally advanced cases up to stage IIb, or in those patients with adverse risk factors. The available data are insufficient to recommend routine adoption of CRT in earlier (stage Ia2) or more advanced cases (stages III or IV). However, with the enrolment of over 4000 women in randomized trials and mature follow-up, chemoradiation has become an established treatment.     

The road ahead for cervical cancer prevention and control

Since the early 1950s, Papanicolaou (“Pap”) cytology screening has dramatically reduced cervical cancer mortality in most high-income settings. Currently, human papillomavirus (hpv) vaccination has the greatest potential to reduce the global burden of cervical cancer and precancerous lesions. However, as the prevalence of precancerous lesions declines, maintaining cytology as the primary screening test in settings with established programs might become less efficient. A reduction in test performance (sensitivity, specificity, and positive predictive value) would lead to an increase in unnecessary colposcopy referrals. Fortunately, hpv dna testing has emerged as a suitable candidate to replace cytology. Compared with the Pap test, hpv testing is less specific but much more sensitive in detecting high-grade precancerous lesions, less prone to human error, and more reproducible across settings. Linkage of hpv vaccination and screening registries could serve the added role of monitoring vaccine efficacy. As a triage test, cytology is expected to perform with sufficient accuracy because most hpv-positive smears would contain relevant abnormalities. This approach and others—for example, hpv testing followed by genotyping—are being evaluated in large population studies and have already been recommended in some settings. Other specific biomarkers that might perform well for screening and triage include hpv E6/E7 messenger rna testing, methylation of host or viral genes, and p16^INK4a staining. Considering the rapid pace of major discoveries and the anticipated arrival of a nonavalent hpv vaccine (currently in phase iii trials), the evidence base in this field has become an elusive target and will continue to be an obstacle for policymakers.