- Email: [email protected]
Towards therapeutic vaccination against cervical precancer?
Comment
Towards therapeutic vaccination against cervical precancer? In The Lancet, Cornelia Trimble and colleagues1 report the results of a double-blind, randomised controlled trial of therapeutic human papillomavirus (HPV) vaccination. Three doses of an intramuscular HPV-16 and HPV-18 plasmid vaccine significantly increased histological regression of cervical precancers caused by HPV types 16 and 18. At 36 weeks after the first dose, regression of cervical intraepithelial neoplasia 2/3 was 48·2% compared with a spontaneous rate in the placebo group of 30·0% (difference 18·2%, 95% CI 1·3–34·4). In 40% of vaccine recipients, HPV DNA became undetectable, compared with about 10% in women who received placebo. The vaccine was well tolerated. Follow-up will assess the durability of the enhanced cell-mediated immune response, and whether it protects against recurrence. Only a subset of cervical precancers progress to cancer.2 Cell-mediated immune responses are thought to play an important part in clearance of HPV infections and regression of precancerous lesions.3 Continued transcriptional activity of HPV DNA is important to the maintenance of precancer and cancer. Accordingly, research has tried to stimulate immune responses against HPV to improve viral clearance and lesion regression, but without much success so far. Trimble and colleagues’ trial1 represents a major breakthrough and proof-of-principle that therapeutic HPV vaccination is feasible. More broadly, the trial shows that it is possible to boost immune clearance of HPV among women who initially failed to control infection. The results of the trial1 suggest that, if approved by regulatory authorities, women might try a course of vaccination to treat cervical precancers positive for HPV-16 or HPV-18 (figure), before undergoing conventional treatment that excises the cancer-prone cervical transformation zone. Deep excisions of the transformation zone have been linked in rare circumstances to subsequent obstetrical complications, specifically preterm delivery.4 Thus, reducing destructive treatments might be desirable. However, as Trimble and colleagues recognise, uptake of the present vaccine formulation and protocol would be restricted to centres capable of careful clinical monitoring required to prevent invasion by precancerous tissue. Use of the present vaccine would be restricted to women testing
positive for HPV-16 or HPV-18 (which together cause about 70% of cervical cancers). Another consideration in whether to try immunotherapy would be the relatively low efficacy of the therapeutic vaccine compared with immediate destructive treatment (which typically has cure rates of more than 90%).5 Management of HPV infections found during cervical screening could be simplified. Almost all cervical cancers are caused by HPV and, as a corollary, the absence of HPV confers high reassurance against cervical cancer.6 Consequently, HPV testing is gradually replacing
Published Online September 17, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)00240-8 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)00239-1
Triage of HPV-positive women
Colposcopy and biopsy to diagnose precancer
Treatment of precancer
Population screening using HPV testing
Figure: An idealised cervical cancer prevention programme Prophylactic vaccines confer immunity against acquisition of high-risk HPV infections (light grey). As a complementary prevention strategy in incompletely protected cohorts, HPV testing can be used to reassure HPV-negative women (black) and to identify the relatively small group of HPV-positive women in the population at risk of treatable precancer (purple). However, there are too many HPV-positive women to refer all for colposcopy-guided biopsy. An optimum triage test would identify the smaller subset of infected women needing colposcopic biopsy (orange). When precancer is diagnosed (red), the therapeutic vaccine developed by Trimble and colleagues1 could successfully treat a subset, thereby somewhat reducing the need for destructive treatments. In the future, an improved vaccine might be safe, simple, inexpensive, and effective enough to treat all triage test-positive women, or even all HPV-positive women.
www.thelancet.com Published online September 17, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00240-8
1
Comment
cytology as the main cervical screening strategy.7 Although testing negative is very reassuring, we are not yet sure how to manage the 5–15% of women who test HPV positive.7 Up to 90% of infections clear within a few years;8 these infections are benign and could be safely ignored. However, when the immune system fails to control HPV, persistent infection with a high-risk HPV type increases risk of neoplastic transformation. Various triage tests are being considered to predict the risk of HPV infections.7 Some of these triage tests are already available (eg, cytology and HPV genotyping), and others are in final testing (eg, p16/Ki67 cytology) or in early development (eg, viral and host DNA methylation). However, none is clearly optimum and all add to costs and complexity of management. Furthermore, colposcopy and biopsy have restricted reproducibility and accuracy in distinguishing signs of HPV infection from early precancer;9 many women are found not to have evident precancer, but they must still be followed due to continued elevated risk.10 Therapeutic vaccination could become the proper treatment not only for women diagnosed with precancer, but for all women with HPV persistence past an accepted waiting period. HPV screen-and-treat strategies could be improved in low-resource regions. Almost 90% of cervical cancer deaths occur in low-resource regions and, thus, we must aim to adapt new developments in cervical cancer prevention to the settings in which the disease most often occurs.11 Low-cost, accurate HPV screening tests are already technically feasible and mainly restricted by lack of a matching low-cost, easy, and effective treatment. A single-dose therapeutic vaccine would be ideal. To be broadly useful in addressing the global cervical cancer problem, antiviral treatment would have to work against an extended set of carcinogenic types with excellent safety and low morbidity, and would need to be lower cost and more practical than destructive options based on cooling, heating, or excision. Trimble and colleagues’ results1 should encourage researchers to intensify research into improving immunotherapy targeting the genetically related group of about 13 HPV types that can cause anogenital and oropharyngeal cancers. If immunotherapy of underlying
2
persistent HPV infection can be further improved and simplified, some crucial clinical needs could be met. For example, treatment of anal precancer could be made less morbid, because surgical treatment of anal precancer is considerably more difficult than cervical treatment.12 Therapeutic vaccination could be a very welcome alternative to surgery in patients with anal precancer. The path from the proof-of-principle vaccine developed by Trimble and colleagues1 to the ideal immunotherapy, permitting us to make optimum use of the sensitivity of HPV screening, is obviously not straightforward. But it is encouraging to see that the first step has been taken. *Mark Schiffman, Nicolas Wentzensen Division of Cancer Epidemiology & Genetics, National Cancer Institute, Bethesda, MD 20892, USA schiff[email protected] We declare no competing interests. 1
2
3
4
5
6
7 8
9 10
11
12
Trimble CL, Morrow MP, Kraynyak KA, et al. Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial. Lancet 2015; published online Sept 17. http://dx.doi. org/10.1016/S0140-6736(15)00239-1. McCredie MR, Sharples KJ, Paul C, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol 2008; 9: 425–34. Kadish AS, Timmins P, Wang Y, et al. Regression of cervical intraepithelial neoplasia and loss of human papillomavirus (HPV) infection is associated with cell-mediated immune responses to an HPV type 16 E7 peptide. Cancer Epidemiol Biomarkers Prev 2002; 11: 483–88. Heinonen A, Gissler M, Riska A, Paavonen J, Tapper AM, Jakobsson M. Loop electrosurgical excision procedure and the risk for preterm delivery. Obstet Gynecol 2013; 121: 1063–68. Hellberg D, Nilsson S. 20-year experience of follow-up of the abnormal smear with colposcopy and histology and treatment by conization or cryosurgery. Gynecol Oncol 1990; 38: 166–69. Gage JC, Schiffman M, Katki HA, et al. Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test. J Natl Cancer Inst 2014; 106: dju153. Schiffman M, Wentzensen N. Transitioning to a new era in cervical cancer screening. Gynecol Oncol 2015; 136: 175–77. Rodriguez AC, Schiffman M, Herrero R, et al. Longitudinal study of human papillomavirus persistence and cervical intraepithelial neoplasia grade 2/3: critical role of duration of infection. J Natl Cancer Inst 2010; 102: 315–24. Wentzensen N, Walker JL, Gold MA, et al. Multiple biopsies and detection of cervical cancer precursors at colposcopy. J Clin Oncol 2015; 33: 83–89. Katki HA, Gage JC, Schiffman M, et al. Follow-up testing after colposcopy: five-year risk of CIN 2+ after a colposcopic diagnosis of CIN 1 or less. J Low Genit Tract Dis 2013; 17 (5 suppl 1): S69–77. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136: E359–86. Park IU, Palefsky JM. Evaluation and management of anal intraepithelial neoplasia in HIV-negative and HIV-positive men who have sex with men. Curr Infect Dis Rep 2010; 12: 126–33.
www.thelancet.com Published online September 17, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00240-8
Towards therapeutic vaccination against cervical precancer? In The Lancet, Cornelia Trimble and colleagues1 report the results of a double-blind, randomised controlled trial of therapeutic human papillomavirus (HPV) vaccination. Three doses of an intramuscular HPV-16 and HPV-18 plasmid vaccine significantly increased histological regression of cervical precancers caused by HPV types 16 and 18. At 36 weeks after the first dose, regression of cervical intraepithelial neoplasia 2/3 was 48·2% compared with a spontaneous rate in the placebo group of 30·0% (difference 18·2%, 95% CI 1·3–34·4). In 40% of vaccine recipients, HPV DNA became undetectable, compared with about 10% in women who received placebo. The vaccine was well tolerated. Follow-up will assess the durability of the enhanced cell-mediated immune response, and whether it protects against recurrence. Only a subset of cervical precancers progress to cancer.2 Cell-mediated immune responses are thought to play an important part in clearance of HPV infections and regression of precancerous lesions.3 Continued transcriptional activity of HPV DNA is important to the maintenance of precancer and cancer. Accordingly, research has tried to stimulate immune responses against HPV to improve viral clearance and lesion regression, but without much success so far. Trimble and colleagues’ trial1 represents a major breakthrough and proof-of-principle that therapeutic HPV vaccination is feasible. More broadly, the trial shows that it is possible to boost immune clearance of HPV among women who initially failed to control infection. The results of the trial1 suggest that, if approved by regulatory authorities, women might try a course of vaccination to treat cervical precancers positive for HPV-16 or HPV-18 (figure), before undergoing conventional treatment that excises the cancer-prone cervical transformation zone. Deep excisions of the transformation zone have been linked in rare circumstances to subsequent obstetrical complications, specifically preterm delivery.4 Thus, reducing destructive treatments might be desirable. However, as Trimble and colleagues recognise, uptake of the present vaccine formulation and protocol would be restricted to centres capable of careful clinical monitoring required to prevent invasion by precancerous tissue. Use of the present vaccine would be restricted to women testing
positive for HPV-16 or HPV-18 (which together cause about 70% of cervical cancers). Another consideration in whether to try immunotherapy would be the relatively low efficacy of the therapeutic vaccine compared with immediate destructive treatment (which typically has cure rates of more than 90%).5 Management of HPV infections found during cervical screening could be simplified. Almost all cervical cancers are caused by HPV and, as a corollary, the absence of HPV confers high reassurance against cervical cancer.6 Consequently, HPV testing is gradually replacing
Published Online September 17, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)00240-8 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)00239-1
Triage of HPV-positive women
Colposcopy and biopsy to diagnose precancer
Treatment of precancer
Population screening using HPV testing
Figure: An idealised cervical cancer prevention programme Prophylactic vaccines confer immunity against acquisition of high-risk HPV infections (light grey). As a complementary prevention strategy in incompletely protected cohorts, HPV testing can be used to reassure HPV-negative women (black) and to identify the relatively small group of HPV-positive women in the population at risk of treatable precancer (purple). However, there are too many HPV-positive women to refer all for colposcopy-guided biopsy. An optimum triage test would identify the smaller subset of infected women needing colposcopic biopsy (orange). When precancer is diagnosed (red), the therapeutic vaccine developed by Trimble and colleagues1 could successfully treat a subset, thereby somewhat reducing the need for destructive treatments. In the future, an improved vaccine might be safe, simple, inexpensive, and effective enough to treat all triage test-positive women, or even all HPV-positive women.
www.thelancet.com Published online September 17, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00240-8
1
Comment
cytology as the main cervical screening strategy.7 Although testing negative is very reassuring, we are not yet sure how to manage the 5–15% of women who test HPV positive.7 Up to 90% of infections clear within a few years;8 these infections are benign and could be safely ignored. However, when the immune system fails to control HPV, persistent infection with a high-risk HPV type increases risk of neoplastic transformation. Various triage tests are being considered to predict the risk of HPV infections.7 Some of these triage tests are already available (eg, cytology and HPV genotyping), and others are in final testing (eg, p16/Ki67 cytology) or in early development (eg, viral and host DNA methylation). However, none is clearly optimum and all add to costs and complexity of management. Furthermore, colposcopy and biopsy have restricted reproducibility and accuracy in distinguishing signs of HPV infection from early precancer;9 many women are found not to have evident precancer, but they must still be followed due to continued elevated risk.10 Therapeutic vaccination could become the proper treatment not only for women diagnosed with precancer, but for all women with HPV persistence past an accepted waiting period. HPV screen-and-treat strategies could be improved in low-resource regions. Almost 90% of cervical cancer deaths occur in low-resource regions and, thus, we must aim to adapt new developments in cervical cancer prevention to the settings in which the disease most often occurs.11 Low-cost, accurate HPV screening tests are already technically feasible and mainly restricted by lack of a matching low-cost, easy, and effective treatment. A single-dose therapeutic vaccine would be ideal. To be broadly useful in addressing the global cervical cancer problem, antiviral treatment would have to work against an extended set of carcinogenic types with excellent safety and low morbidity, and would need to be lower cost and more practical than destructive options based on cooling, heating, or excision. Trimble and colleagues’ results1 should encourage researchers to intensify research into improving immunotherapy targeting the genetically related group of about 13 HPV types that can cause anogenital and oropharyngeal cancers. If immunotherapy of underlying
2
persistent HPV infection can be further improved and simplified, some crucial clinical needs could be met. For example, treatment of anal precancer could be made less morbid, because surgical treatment of anal precancer is considerably more difficult than cervical treatment.12 Therapeutic vaccination could be a very welcome alternative to surgery in patients with anal precancer. The path from the proof-of-principle vaccine developed by Trimble and colleagues1 to the ideal immunotherapy, permitting us to make optimum use of the sensitivity of HPV screening, is obviously not straightforward. But it is encouraging to see that the first step has been taken. *Mark Schiffman, Nicolas Wentzensen Division of Cancer Epidemiology & Genetics, National Cancer Institute, Bethesda, MD 20892, USA schiff[email protected] We declare no competing interests. 1
2
3
4
5
6
7 8
9 10
11
12
Trimble CL, Morrow MP, Kraynyak KA, et al. Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial. Lancet 2015; published online Sept 17. http://dx.doi. org/10.1016/S0140-6736(15)00239-1. McCredie MR, Sharples KJ, Paul C, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol 2008; 9: 425–34. Kadish AS, Timmins P, Wang Y, et al. Regression of cervical intraepithelial neoplasia and loss of human papillomavirus (HPV) infection is associated with cell-mediated immune responses to an HPV type 16 E7 peptide. Cancer Epidemiol Biomarkers Prev 2002; 11: 483–88. Heinonen A, Gissler M, Riska A, Paavonen J, Tapper AM, Jakobsson M. Loop electrosurgical excision procedure and the risk for preterm delivery. Obstet Gynecol 2013; 121: 1063–68. Hellberg D, Nilsson S. 20-year experience of follow-up of the abnormal smear with colposcopy and histology and treatment by conization or cryosurgery. Gynecol Oncol 1990; 38: 166–69. Gage JC, Schiffman M, Katki HA, et al. Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test. J Natl Cancer Inst 2014; 106: dju153. Schiffman M, Wentzensen N. Transitioning to a new era in cervical cancer screening. Gynecol Oncol 2015; 136: 175–77. Rodriguez AC, Schiffman M, Herrero R, et al. Longitudinal study of human papillomavirus persistence and cervical intraepithelial neoplasia grade 2/3: critical role of duration of infection. J Natl Cancer Inst 2010; 102: 315–24. Wentzensen N, Walker JL, Gold MA, et al. Multiple biopsies and detection of cervical cancer precursors at colposcopy. J Clin Oncol 2015; 33: 83–89. Katki HA, Gage JC, Schiffman M, et al. Follow-up testing after colposcopy: five-year risk of CIN 2+ after a colposcopic diagnosis of CIN 1 or less. J Low Genit Tract Dis 2013; 17 (5 suppl 1): S69–77. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136: E359–86. Park IU, Palefsky JM. Evaluation and management of anal intraepithelial neoplasia in HIV-negative and HIV-positive men who have sex with men. Curr Infect Dis Rep 2010; 12: 126–33.
www.thelancet.com Published online September 17, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00240-8