Original Article
Vaccination against HPV-16 Oncoproteins for Vulvar Intraepithelial Neoplasia
N Engl J Med 2009; 361:1838-1847November 5, 2009
- Abstract
Background
Vulvar intraepithelial neoplasia is a chronic disorder caused by high-risk types of human papillomavirus (HPV), most commonly HPV type 16 (HPV-16). Spontaneous regression occurs in less than 1.5% of patients, and the rate of recurrence after treatment is high.
Methods
We investigated the immunogenicity and efficacy of a synthetic long-peptide vaccine in women with HPV-16–positive, high-grade vulvar intraepithelial neoplasia. Twenty women with HPV-16–positive, grade 3 vulvar intraepithelial neoplasia were vaccinated three or four times with a mix of long peptides from the HPV-16 viral oncoproteins E6 and E7 in incomplete Freund's adjuvant. The end points were clinical and HPV-16–specific T-cell responses.
Results
The most common adverse events were local swelling in 100% of the patients and fever in 64% of the patients; none of these events exceeded grade 2 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute. At 3 months after the last vaccination, 12 of 20 patients (60%; 95% confidence interval [CI], 36 to 81) had clinical responses and reported relief of symptoms. Five women had complete regression of the lesions, and HPV-16 was no longer detectable in four of them. At 12 months of follow-up, 15 of 19 patients had clinical responses (79%; 95% CI, 54 to 94), with a complete response in 9 of 19 patients (47%; 95% CI, 24 to 71). The complete-response rate was maintained at 24 months of follow-up. All patients had vaccine-induced T-cell responses, and post hoc analyses suggested that patients with a complete response at 3 months had a significantly stronger interferon-γ–associated proliferative CD4+ T-cell response and a broad response of CD8+ interferon-γ T cells than did patients without a complete response.
Conclusions
Clinical responses in women with HPV-16–positive, grade 3 vulvar intraepithelial neoplasia can be achieved by vaccination with a synthetic long-peptide vaccine against the HPV-16 oncoproteins E6 and E7. Complete responses appear to be correlated with induction of HPV-16–specific immunity.
Media in This Article
Figure 1
Complete Clinical Response to Vaccination in a Patient with Grade 3 Vulvar Intraepithelial Neoplasia.Figure 2
Immune Response before and after Vaccination.Article Activity
- Article
Vulvar intraepithelial neoplasia is a chronic premalignant disorder of the vulvar skin that is caused by high-risk types of human papillomavirus (HPV); HPV type 16 (HPV-16) is involved in more than 75% of cases. 1-5 Spontaneous regression occurs in less than 1.5% of patients, and the rate of recurrence after surgical treatment is high. 6 Expression of the viral oncoproteins E6 and E7 contributes to the development of these genital lesions and their progression to invasive carcinoma.6,7
Virus-specific, interferon-γ–producing CD4+ T cells and CD8+ cytotoxic T lymphocytes are essential components in controlling chronic viral infections.8,9 In the blood of patients with high-grade (grade 3) vulvar intraepithelial neoplasia lesions, these T cells, directed against HPV-16 viral oncoproteins E6 and E7, are not detectable or are present in low numbers.10-13 Vaccination might overcome this inertia of the immune system.
Recently, we reported that in patients with cervical cancer, vaccination with synthetic long peptides, spanning the complete sequence of the two oncogenic proteins E6 and E7 of HPV-16, induces an HPV-16–specific CD4+ and CD8+ T-cell response.14,15 To assess the clinical efficacy of this vaccine, we performed a phase 2 study involving women with HPV-16–positive, grade 3 vulvar intraepithelial neoplasia.
Methods
Patients
Patients with histologically confirmed HPV-16–positive, grade 3 vulvar intraepithelial neoplasia were eligible for the study. Additional criteria for eligibility were a good performance status (World Health Organization performance status score of 1 or 2 [on a scale of 0 to 5, with lower scores indicating better performance status], a Karnofsky performance score of ≥60 [on a scale of 0 to 100, with higher scores indicating better performance status], or both), normal pretreatment laboratory blood values as described previously,15 and no pregnancy, immunosuppressive medication or viral diseases, or diseases associated with immunodeficiency.
Study Design
In view of the low rate of spontaneous regression of lesions in patients with grade 3 vulvar intraepithelial neoplasia,6 a single-center, single-group (noncontrolled), observational phase 2 study was designed. The end points were clinical efficacy and HPV-16–specific T-cell responses. If no clinical response was observed in the first 10 patients, the trial would be discontinued; otherwise, more patients would be enrolled, for a total of 20 patients who could be evaluated. Patients received three or four vaccinations. The vaccine was administered subcutaneously at 3-week intervals, each time in a different arm or leg. All vaccinations were performed between October 2004 and May 2007.
The study was sponsored by the Dutch Cancer Society, the European Union, and ISA Pharmaceuticals and approved by the medical ethics committee of the Leiden University Medical Center, and all patients gave written informed consent. All drafts of the manuscript were prepared by the writing committee, which consisted of three academic authors and one academic author who was also employed by the sponsor; the final draft was submitted for publication with approval by the coauthors. All authors vouch for the completeness and accuracy of the data presented.
Composition of the Vaccine
The vaccine contained nine HPV-16 E6 and four HPV-16 E7 synthetic peptides (see the Supplementary Appendix, available with the full text of this article at NEJM.org) dissolved in dimethylsulfoxide in 20 mM of phosphate-buffered saline (pH 7.5) and emulsified with incomplete Freund's adjuvant (Montanide ISA-51, Seppic); the final ratio of dimethylsulfoxide to phosphate-buffered saline to adjuvant by volume was 20:30:50. One dose of each vaccine contained 0.3 mg of each peptide in a total volume of 2.8 ml.
Assessment of Clinical Efficacy
The variables for evaluation of clinical responses were symptoms, lesion size, histologic features, and the presence or absence of HPV-16 DNA. The lesions were described in detail and measured bidimensionally by a single investigator, with the largest diameters in two dimensions recorded. In the case of a multifocal lesion, the total lesion size was determined. Symptoms were classified as none, mild to moderate (not interfering with daily life), or severe (interfering with daily life). All lesions were monitored by means of digital photography. A partial response was defined as a decrease in lesion size of 50% or more after the vaccinations. A complete clinical response was defined as complete disappearance of the lesions and symptoms of vulvar intraepithelial neoplasia. No response was defined as a reduction of less than 50% in lesion size.
Biopsy specimens of the same lesion were obtained before and 3 months after the last vaccination. For histologic analysis, the specimens were prepared in formalin and stained with hematoxylin and eosin. Grading of the lesions was performed by one experienced pathologist according to the criteria of the Armed Forces Institute of Pathology, with consensus review by two pathologists. HPV typing of paraffin-embedded sections of biopsy specimens was performed with the use of three general HPV primer sets (CPI/II, MY 9/11, and GP 5+/6+), followed by sequencing and analysis by the Basic Local Alignment Search Tool (BLAST) program of the National Center for Biotechnology Information. Beta-globin polymerase-chain-reaction product and a blank sample were included as controls.16-18 All histologic and virologic results were collected in a blinded fashion with respect to clinical outcome.
Safety and Tolerability
Monitoring for spontaneous adverse events and injection-site reactions, clinical assessments, and laboratory tests were performed after each vaccination and thereafter every 3 months for a total of 24 months of follow-up, as described previously.14 Adverse events were graded according to version 3.0 of the Common Terminology Criteria for Adverse Events (CTCAE), which grades events on a scale of 1 to 5, with higher grades indicating greater severity.14
Immunologic Monitoring of HPV-16–Specific T-Cell Responses
Peripheral-blood mononuclear cells (PBMCs) were isolated from fresh heparinized blood samples by means of Ficoll density-gradient centrifugation, with a portion of the cells subjected immediately to lymphocyte stimulation tests and the remaining cells cryopreserved. HPV-16–specific T-cell responses were determined with the use of a previously described set of complementary assays according to standard-operating-procedure protocols with predefined criteria for positive and vaccine-induced responses.15 These tests were performed by trained personnel (see the Supplementary Appendix).
Statistical Analysis
Clinical responses are reported as the percentage of patients with a given response and the 95% confidence interval. Prespecified analyses were used for the measurement of vaccine-induced HPV-16–specific T-cell responses (see the Supplementary Appendix). A response rate of 30% was considered promising. In total, five post hoc subgroup analyses were performed and are reported here. The clinical response at 24 months was assessed according to the size of the lesion at study entry. For this analysis, the patients were divided into two groups (those with either no response or a partial response at 12 months, and those with a complete response at 12 months), and the between-group difference in the average lesion size at baseline was calculated with the use of Welch's corrected unpaired t-test. The strength of the different types of immune responses and the number of different CD8+ T-cell epitopes were compared between the group with no clinical response and the group with a complete clinical response 3 months after the last vaccination, with the use of the nonparametric Mann–Whitney test and GraphPad InStat software, version 3.00. For each type of immune assay, the strength of the immune response for no clinical response, partial clinical response, or complete clinical response was operationally defined as a combination of the magnitude and breadth (i.e., the number of different peptide pools recognized by an individual patient's T cells) of the T-cell response by taking the median number of HPV-16–specific spots (interferon-γ enzyme-linked immunosorbent spot [ELISPOT] assay), the median stimulation index (lymphocyte stimulation test), or the median amount of interferon-γ production (cytometric bead array) obtained for all six peptide pools per patient in the group (e.g., the median of 6 peptide pools × 5 patients = 30 data points in the complete-response group and 6 peptide pools × 8 patients = 48 data points in the no-response group). All reported P values are two-sided and have not been adjusted for multiple comparisons. A P value of less than 0.05 was considered to indicate statistical significance.
Results
Study Population
Characteristics of the enrolled patients are summarized in Table 1Table 1
Baseline Characteristics of the Patients.. Thirty patients were screened for the trial. Two patients withdrew (Patients 15 and 20), and one patient (Patient 24) had vaginal intraepithelial neoplasia. Five patients did not meet other inclusion criteria: in one patient (Patient 19), the lesion was not grade 3, in three patients (Patients 5, 17, and 25) the grade 3 lesion was not HPV-16–positive, and one patient (Patient 14) received immunosuppressive medication. The remaining 22 patients with histologically confirmed HPV-16–positive, grade 3 vulvar intraepithelial neoplasia were included in the study; 20 of these patients received three or four vaccinations and were evaluated. The two patients (Patients 9 and 27) who received three vaccinations declined to receive the last vaccination because of inconvenience. One patient (Patient 4) received only two vaccinations because of symptoms associated with the vaccination site in her leg. The fact that she worked as a swimming teacher and stood in water most of the day may have been associated with these symptoms. Another patient (Patient 21) received only one vaccination because she subsequently moved abroad.Adverse Events
Table 2Table 2
Systemic Adverse Events in 22 Patients Who Received at Least One Vaccination. lists all systemic adverse events assessed as possibly being associated with the vaccine in 22 patients who received at least one vaccination. All patients reported local swelling, redness, and increased skin temperature, and 95% of the patients reported local pain at the vaccination site (see the Table in the Supplementary Appendix). These symptoms and fever at night after the vaccination were the most common adverse events, as observed previously.14 Systemic adverse events, including influenza-like symptoms, chills, tiredness, or all of these symptoms, within 24 to 48 hours after vaccination, typically started after the second vaccination. No vaccine-related events exceeded grade 2 according to the CTCAE. One patient (Patient 10) died 12 months after the fourth vaccination as a result of sudden heart failure. No postmortem investigation was performed. This event was considered to be unrelated to the vaccination.Clinical Efficacy
At 3 months of follow-up (range, 2.5 to 4.0), symptom relief was reported by 11 patients; 5 of 20 patients had a complete clinical and histologic response (25%; 95% confidence interval [CI], 9 to 49) (Figure 1Figure 1
Complete Clinical Response to Vaccination in a Patient with Grade 3 Vulvar Intraepithelial Neoplasia.), and 7 other patients (35%; 95% CI, 15 to 59) had a partial response. Concomitant loss of HPV-16 from the original lesion sites was observed in four of the patients who had a complete response (Table 3Table 3
Clinical Results at 3, 12, and 24 Months after the Last Vaccination.).At 12 months of follow-up, 15 of 19 patients (79%; 95% CI, 54 to 94) had an objective clinical response: the number of patients with a complete response increased to 9 (47%; 95% CI, 24 to 71), a partial response was seen in 6 patients (32%; 95% CI, 13 to 57), and no response was seen in 3 patients (16%; 95% CI, 3 to 40). Invasive carcinoma developed in one patient (Patient 2) at 6 months of follow-up. One patient died. Symptom relief was reported by 12 patients (63%; 95% CI, 38 to 84) (Table 3).
All patients with a complete response were still free of disease at 24 months of follow-up, whereas microinvasion was observed in one patient with a partial response (Patient 23). A carcinoma developed in two other patients (Patients 1 and 3) 3.5 and 2.5 years, respectively, after the last vaccination.
Post hoc analysis of the mean (±SD) lesion size at study entry and clinical outcome at 12 months suggested that, on average, the lesions were smaller in the complete-response group than in the group with no response or a partial response (6.4±3.1 cm2 vs. 17.2±11 cm2, (P=0.01).
Immunologic Responses
After they received the last vaccination, 85% of the patients had circulating vaccine-induced HPV-16–specific T cells, which proliferated when stimulated with E6, E7, or both. Proliferation was accompanied by the production of both T-helper type 1 (Th1) and T-helper type 2 (Th2) cytokines, mostly interferon-γ and interleukin-5 (Table 4Table 4
Immunologic Response Rate on Stimulation with HPV-16 Oncoproteins E6, E7, or Both, According to Immunologic Assay.) and, to a lesser extent, by tumor necrosis factor α, interleukin-4, interleukin-10, or all of these cytokines. In addition, 83% of the patients had a T-cell response against HPV-16, as determined by interferon-γ ELISPOT assay. Some preexisting HPV-16 T-cell immunity that was E6-specific, E7-specific, or both was detected in six patients (including three patients who had a complete response); this immunity was boosted by vaccination and coincided with enhanced interferon-γ production. No boost was observed in one patient, and she did not have an immunologic response to the vaccine. We were able to obtain blood samples from a number of patients 1 to 2 years after the last vaccination. In 12 of 14 patients, strong HPV-16–specific proliferative responses were still detectable. Analyses of PBMCs after one round of in vitro stimulation by multiparameter flow cytometry revealed the presence of vaccine-induced HPV-16–specific CD4+ T cells in all 20 patients and of CD8+ T cells in 83% of the patients. The CD8+ T-cell responses were predominantly against the HPV-16 oncoprotein E6 (Table 4).The immunologic analysis in which PBMCs were tested against four different pools of overlapping E6 peptides and two pools of E7 peptides not only measured the presence of a vaccine-induced T-cell response but also allowed the calculation of the strength of the immune response, operationally defined as a combination of the magnitude and breadth of the T-cell response to all six peptide pools. To assess the correlation between the strength of the vaccine-induced immune response and the clinical outcome, the patients were classified as having no response, a partial response, or a complete response according to their clinical status at the predetermined clinical-evaluation point of 3 months of follow-up. We focused on the eight patients with no response and the five patients with a complete response, since these groups were clinically well segregated and a comparison of them was therefore likely to reveal any potential correlation with immunity. Our post hoc subgroup analyses showed that as compared with the patients who had no clinical response, the group of patients with a complete response had a significantly higher number of interferon-γ–producing CD4+ T cells (P=0.001) (Figure 2AFigure 2
Immune Response before and after Vaccination.) and stronger proliferative responses (P=0.005) (Figure 2B), which were associated with the production of larger amounts of interferon-γ (P=0.02) (Figure 2C). Moreover, all patients with a complete response had an HPV-16–specific CD8+ T-cell response, although the mean number of T-cell epitopes detected in this group was not significantly higher than in patients with no response (P=0.17) (Figure 2D). Patient 2, in whom an invasive carcinoma developed, had an HPV-16–specific proliferative response that was associated with the production of only low amounts of interferon-γ (mean, 160 pg per milliliter) and no other Th1 and Th2 cytokines. These results suggest that the clinical efficacy of a therapeutic HPV-16 vaccine may be determined by its capacity to induce a strong and broad multifunctional immune response to the HPV-16 oncoproteins E6 and E7.Discussion
This study shows that vaccination with synthetic long peptides that represent the entire length of the two oncoproteins E6 and E7 of HPV-16 is effective over a period of 12 to 24 months for the treatment of high-grade vulvar intraepithelial neoplasia lesions. This clinical efficacy is probably related to a vaccine-induced HPV-16–specific T-cell response.
Therapeutic vaccination targeting an established, persistent viral infection had a clinical benefit in a number of our patients with grade 3 vulvar intraepithelial neoplasia. Regression of HPV-16–positive lesions was noted in the majority of patients (79%), and complete regression was observed in 47% of patients 1 year after the last dose of vaccine. The number of complete responses increased from five to nine between 3 and 12 months after the last vaccination, and this response was maintained at 24 months. Since the rate of spontaneous regression of lesions in patients with grade 3 vulvar intraepithelial neoplasia is low (<1.5%),6,19 the high response rate observed in the current trial is probably related to the vaccination.
Topical treatment with imiquimod cream was shown to induce complete regression of lesions in 9 of 26 patients with grade 3 vulvar intraepithelial neoplasia (35%).19 Subgroup evaluations of these patients revealed a significant correlation between the presence of circulating, preexisting HPV-16–specific, interferon-γ–producing T cells and regression of the HPV-16–positive lesions13; this correlation suggests that the clinical benefit of topical imiquimod cream may depend on the presence of interferon-γ–producing, HPV-16–specific T cells and that the use of imiquimod cream after vaccination may further increase the complete-response rate.
Like cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia is caused by persistent infection with a high-risk type of HPV and can progress to invasive carcinoma.20-24 Virus-specific T cells are essential components in the immune response to chronic viral infection.8,9 As compared with patients, healthy subjects with evidence of previous exposure to HPV-16 have relatively strong recall T-cell responses against the early viral proteins; these responses are characterized by CD4+ T cells producing mixed cytokines, including interferon-γ and interleukin-5.25-28 In addition, most patients clearing HPV-16 have a CD8+ cytotoxic T-lymphocyte response that is specific for the HPV-16 oncoprotein E6.29,30 The notion that the lack of generation of interferon-γ–producing T cells allows persistent virus infection is strengthened by our finding that such T-cell responses are weak or lacking in patients with cervical cancer,28 cervical intraepithelial neoplasia,28,31,32 or grade 3 vulvar intraepithelial neoplasia.10-13 The idea that these interferon-γ–producing T cells exert therapeutic activity is supported by our post hoc analyses of subgroups of patients with grade 3 vulvar intraepithelial neoplasia, which showed a significant correlation between vaccine-induced complete regression of lesions and higher numbers of HPV-specific CD4+ T cells producing large amounts of interferon-γ in patients with a complete response than in patients with no response. Furthermore, vaccine-induced CD8+ T-cell responses were predominantly directed against HPV-16 oncoprotein E6. This finding is consistent with the association between spontaneous clearance of HPV infection and detection of CD8+ T-cell responses that are specific for HPV-16 oncoprotein E6.29,30,33
Our results underscore the importance of studying immunity to the antigen of interest in protected and nonprotected persons to identify assays that are likely to yield correlates of protection after vaccination — in our case, the interferon-γ ELISPOT assay, proliferation assays, and interferon-γ enzyme-linked immunosorbent assays.10-13,25-28 Although vaccination with HPV peptides did not prevent the development of carcinoma in all patients, no carcinomas were seen in the group of patients who had a complete response. Moreover, all the patients in whom carcinomas developed had had vulvar intraepithelial neoplasia for more than 10 years (Table 1). In studies of other vaccines against HPV-16 oncoproteins E6 and E7, some clinical benefit was observed, but a durable complete response was observed only occasionally.10-12 We ascribe the potent T-cell response induced by the vaccine to efficient dendritic-cell targeting, the absence of antigenic competition from viral vectors, and the high dose of specific antigen.34 The therapeutic activity of this vaccine is consistent with our findings in rodent models, in which vaccination with long peptides induced strong, long-lasting, virus-specific T-cell immunity that was associated with regression of lesions35,36 and suppression of persistent viral infection.35
Dr. Melief reports having a stock-appreciation right that is the equivalent of a stock option in 1% of the issued share capital of ISA Pharmaceuticals and being named as an inventor on the patent for the use of synthetic long peptides as vaccine and serving as a member of the steering committee of ISA Pharmaceuticals; Drs. Kenter, Oostendorp, and Drijfhout, serving as nonpaid members of the strategy team of ISA Pharmaceuticals and holding no financial interest in the company; Dr. Offringa, being named as one of the inventors on the patent for the use of synthetic long peptides as vaccine but holding no financial interest and being involved in the study before he was employed by Genentech; and Dr. van der Burg, being named as one of the inventors on the patent for the use of synthetic long peptides as vaccine but holding no financial interest and serving as a nonpaid member of the steering committee of ISA Pharmaceuticals. No other potential conflict of interest relevant to this article was reported.
Drs. Kenter and Welters contributed equally to this article.
Supported by grants from the Dutch Cancer Society (RUL 2000-2200), the European Union Integrated Project Cancer Immunotherapy (LSHC-CT-2006-518234), the European Union Network of Excellence DC-THERA (LSHB-CT-2004-512074), and ISA Pharmaceuticals. This study was conducted by the Leiden University Medical Center (LUMC), which holds a patent on the use of synthetic long peptides as vaccine (U.S. patent number 7,202,034). The LUMC does not share the financial benefit from this patent with its employees. ISA Pharmaceuticals, a biotechnology company, has licensed the patent from the LUMC.
We thank the patients who participated in the study as well as their referring physicians; C.L.M.C. Franken (Leiden University Medical Center, the Netherlands) for preparing the recombinant human proteins used; and Dr. V.T.B.H.M. Smit for kindly reviewing the pathological samples.
Source Information
From the Departments of Gynecology (G.G.K., M.J.G.L., D.M.A.B.M.), Immunohematology and Blood Transfusion (M.J.P.W., A.P.G.V., F.E., R.O., J.W.D., C.J.M.M.), Clinical Pharmacy and Toxicology (A.R.P.M.V., L.M.F., A.R.W., J.O.), Pathology (G.J.F.), and Clinical Oncology (S.H.B.), Leiden University Medical Center, Leiden; and ISA Pharmaceuticals, Bilthoven (C.J.M.M., F.E.) — both in the Netherlands.
Address reprint requests to Dr. Kenter at the Department of Gynecology, Leiden University Medical Center, Mailbox 9600, 2300 RC Leiden, the Netherlands, or at g.g.kenter@lumc.nl.
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