HspE7 Treatment of Pediatric Recurrent Respiratory Papillomatosis: Final Results of an Open-Label Trial

Derkay, Craig S.; Smith, Richard J.H.; McClay, John E.; Burik, Jo Anne H. Van; Wiatrak, Brian J.; Arnold, James E.; Berger, Bruce W.; Neefe, John R.

doi:10.1177/000348940511400913

Cited by 77 publications

(40 citation statements)

References 27 publications

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“…Similar to results of other HspE7 trials for other HPV-associated neoplasms [21][22][23]30], there was no difference in responses (pathologic or colposcopic) to HspE7 in patients without HPV 16 infection at any visit compared to those who were infected with HPV 16 (22/25 or 88% vs. 23/33 or 70%, p=0.12). Also, there was no difference in the clinical responses of women who were infected with one HPV type compared to those infected with multiple HPV types (data not shown), but this may be due to the small sample size.…”

Section: Response To Treatmentsupporting

confidence: 82%

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Heat shock fusion protein-based immunotherapy for treatment of cervical intraepithelial neoplasia III

Einstein

Kadish

Burk

et al. 2007

Gynecologic Oncology

129

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Objectives-SGN-00101 (HspE7, Nventa, San Diego, CA) is a novel therapeutic vaccine consisting of a fusion protein containing an M. bovis BCG heat shock protein (Hsp65) covalently linked to the entire sequence of HPV 16 E7. This trial was designed to evaluate the efficacy and toxicities of HspE7 in women with CIN III.Methods-HIV (−) women with biopsy-proven CIN III were eligible. Two cohorts were accrued; one cohort to establish efficacy and a second cohort with a longer follow-up period to improve the precision of the trial to estimate response rates. Each patient underwent 3 monthly subcutaneous vaccinations with 500 µg of HspE7 followed by monthly colposcopic follow-up for 1 month in cohort 1 and an extended observation period (2 months) in cohort 2. All patients then underwent a LEEP or cone biopsy of the cervix. A complete pathologic response (pCR) was defined as no evidence of CIN or CIN I (only HPV changes). A partial response (PR) was defined as colposcopic lesion regression of >50% in size. Cervicovaginal lavage samples were obtained at each visit for HPV typing using MY09/ MY11 HPV PCR.Results-Seventy-two patients were registered and screened, of whom 64 were eligible. Fifty-eight patients completed the trial and were evaluable (31 in cohort 1, 27 in cohort 2). There were no significant epidemiologic or HPV type differences between the 2 cohorts so responses were combined for analysis. Of the 58 evaluable patients, 13 (22.5%) had a pCR; 32 (55%) had a PR and 11 (19%) had stable disease. Two (3.5%) patients in cohort 2 had microinvasive disease and were defined as progressive disease. Thirty-three of 58 (57%) of the patients were infected with HPV 16 prior to vaccination or in subsequent visits. There was no significant difference in regression in women infected with HPV 16 compared to those without HPV 16 infection (88% vs. 70%; p=0.12). Women who had a previous LEEP or ablation for CIN were 2.7 times more likely to have a complete response compared to patients without previous treatment, although the difference was not statistically significant (95% CI for rate ratio: 0. 95-6.19, p=0.10). At a cellular level, there was a significant association between local inflammation and response; lower grade of lesional inflammation correlated with a response to HspE7 (p=0.04 using Wilcoxon rank sum test). Conclusions-HspE7 appeared to demonstrate activity in women with CIN III and met a priori assumptions for efficacy; however, it is unclear whether this response was due to natural regression rather than treatment effect. HspE7, which targets the HPV 16 E7 oncoprotein, had efficacy in patients infected with HPV types other than 16, suggesting cross-reactivity. A larger randomized, controlled trial is needed to better define efficacy and to identify subsets of women most likely to benefit from immunotherapy.

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Section: Response To Treatmentsupporting

confidence: 82%

“…Clinical responses to HspE7 immunotherapy have been observed in children with recurrent respiratory papillomatosis [21] and men and women with genital warts [22] and anal intraepithelial neoplasia (AIN) [23]. Since responses to HspE7 were seen in these other HPV-related diseases, we tested HspE7 in women with CIN III.…”

Section: Introductionmentioning

confidence: 99%

Heat shock fusion protein-based immunotherapy for treatment of cervical intraepithelial neoplasia III

Einstein

Kadish

Burk

et al. 2007

Gynecologic Oncology

129

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“…Live viral vectors also have been tested in the clinic, with vaccinia virus constructs coding for either bovine Papillomavirus E2 (20,21) or HPV-16 and -18 E6 and E7 (22). As for protein vaccines, a fusion protein of heat shock protein 65 with HPV-16 E7 has been tested in three phase II trials (23)(24)(25). In addition, a fusion protein of HPV-16 E6, E7, and L2 was also in a phase II trial (26), and a HPV-16 E7 fusion protein with a Haemophilus influenza protein or HPV-16 E6 and E7 were applied in phase I trials in various adjuvants (13,27).…”

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confidence: 99%

A Conserved E7-derived Cytotoxic T Lymphocyte Epitope Expressed on Human Papillomavirus 16-transformed HLA-A2+ Epithelial Cancers

Riemer

Keskin

Zhang

et al. 2010

Journal of Biological Chemistry

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Human Papillomavirus 16 (HPV-16) has been identified as the causative agent of 50% of cervical cancers and many other HPV-associated tumors. The transforming potential/tumor maintenance capacity of this high risk HPV is mediated by two viral oncoproteins, E6 and E7, making them attractive targets for therapeutic vaccines. Of 21 E6 and E7 peptides computed to bind HLA-A*0201, 10 were confirmed through TAP-deficient T2 cell HLA stabilization assay. Those scoring positive were investigated to ascertain which were naturally processed and presented by surface HLA molecules for CTL recognition. Because IFN␥ ELISpot frequencies from healthy HPV-exposed blood donors against HLA-A*0201-binding peptides were unable to identify specificities for tumor targeting, their physical presence among peptides eluted from HPV-16-transformed epithelial tumor HLA-A*0201 immunoprecipitates was analyzed by MS 3 Poisson detection mass spectrometry. Only one epitope (E7 11-19 ) highly conserved among HPV-16 strains was detected. This 9-mer serves to direct cytolysis by T cell lines, whereas a related 10-mer (E7 11-20 ), previously used as a vaccine candidate, was neither detected by MS 3 on HPV-transformed tumor cells nor effectively recognized by 9-mer specific CTL. These data underscore the importance of precisely defining CTL epitopes on tumor cells and offer a paradigm for T cellbased vaccine design.The transforming potential of human Papillomavirus (HPV), 4 first suspected in the 1970s, has now been firmly established both biologically and epidemiologically (1-3). The single most important variable linked to malignant transformation is persistent infection with one of the high-risk HPV types. The E6 and E7 proteins encoded by high-risk HPVs have transforming activities and functionally inactivate the p53 and retinoblastoma (Rb) tumor suppressor proteins, respectively (3, 4). HPV-16 is the most abundant high risk HPV and has been detected in Ͼ50% of cervical cancer cases and in most other HPV-induced tumors, such as carcinomas of the vagina, anus, vulva, penis, and oropharynx (3, 5, 6). Worldwide, high risk HPVs are thought to be responsible for Ͼ500,000 malignancies per year, representing more than 5% of human cancers (7).A major breakthrough in combating HPV-induced disease was the development of prophylactic vaccines to prevent HPV infection in previously unexposed individuals. These vaccines are based on virus-like particles consisting of the L1 capsid protein (8, 9). Virus-like particles resemble natural virions and are able to induce high titers of L1-neutralizing antibodies. Two vaccines, one against HPV-16, -18, -6, and -11 and another against HPV-16 and -18, were approved for clinical use in 2006 (10 -12). Although the impact of prophylactic HPV vaccination on the incidence of vaccine type HPV-associated disease and cancer is unquestionable over time, these vaccines have no therapeutic efficacy for established HPV infections. Antibodies neutralize virus particles only before infection. Moreover, as HPV capsid proteins are exc...

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“…Patients with recurrent respiratory papillomatosis, which were treated with HspE7 after debulking surgery, had a significantly extended time until repeat surgery [67] .…”

Section: Examples Of Vaccines In Clinical Trialsmentioning

confidence: 99%

Therapeutic Human Papillomavirus Vaccination

Albers

Kaufmann

2009

Public Health Genomics

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Despite impressive progress in prevention and therapy of premalignant and malignant dysplasia the worldwide burden of cancer is relatively unchanged. Supplementation of the therapeutic arsenal by immunotherapeutic methods would have the potential to make a significant impact. Dysplastic lesions and cancer of the cervix show strong association with human papillomaviruses (HPV), as do tumours of other mucosal epithelia like squamous cell carcinoma of the head and neck. Such tumours are distinct from most other malignancies in that they harbour foreign antigens derived from the virus. The expression of viral oncogenes is necessary to maintain the cancerous phenotype. Therefore, these antigens are unique to the tumour and very attractive targets for ‘proof of concept’ studies in the development of therapeutic vaccinesshowing the general applicability of tumour vaccination and prove the correlation of immune response and clinical response. To date numerous clinical trials have been performed with candidate vaccines predominantly for cervical cancer and its precursors. Although a naturally induced anti-HPV T cell response in patients can be shown, the success of therapeutic vaccines has so far been limited. This can probably be attributed to immunosuppression, immunoselection and immunoediting of the tumour cells and other, mostly unknown, factors of the individual contributing to the failure of autonomous clearance of the infection. Overriding this failure, reversing immunosuppression and application in early stages of the disease are the key tasks for future development of therapeutic vaccines. This review will summarize the basis and recent developments of therapeutic vaccines and discuss obstacles that hinder their success.

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HspE7 Treatment of Pediatric Recurrent Respiratory Papillomatosis: Final Results of an Open-Label Trial

Abstract: Treatment with HspE7 appears to significantly improve the clinical course in pediatric patients with RRP insofar as it reduces the frequency of required surgeries. These results warrant a confirmatory phase III trial.

Cited by 77 publications

References 27 publications

Heat shock fusion protein-based immunotherapy for treatment of cervical intraepithelial neoplasia III

Heat shock fusion protein-based immunotherapy for treatment of cervical intraepithelial neoplasia III

A Conserved E7-derived Cytotoxic T Lymphocyte Epitope Expressed on Human Papillomavirus 16-transformed HLA-A2+ Epithelial Cancers

Therapeutic Human Papillomavirus Vaccination

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