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      Immunotherapy for penile cancer

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          Abstract

          Background Penile carcinoma is a rare disease, with incidence rates varying in the range of 1–10 cases per 100,000 men depending on ethnicity, geographic area, cultural background and social habits [1,2]. Tumorigenesis of penile carcinoma is governed by a complex interplay of multiple causative factors. These include initiating agents, such as tobacco toxins, UV radiation and, possibly, household contaminants from solid fuel combustion, which have been implicated in carcinoma of the cervix [3], as well as promoting agents, such as cytokines related to chronic inflammation and high-risk HPV, mainly HPV-16 and HPV-18 [2], which are well known for their major etiopathogenetic role in cervix carcinomas [4]. In patients with carcinoma of the penis, keratinizing squamous cell and verrucous lesions harbor high-risk HPV only in 30% of cases and coexist with squamous cell hyperplasia and/or lichen sclerosus, while basaloid and warty carcinomas, which are composed of small, undifferentiated basaloid cells with koilocytic changes, harbor HPV in 80–100% of cases [2]. Positivity to high-risk HPV has both prognostic and biological implications in penile cancer. In fact, HPV infection may be associated with better outcomes in penile cancer men, as reported in a retrospective study of 171 patients showing a 5-year cancer-specific survival rate of 78 and 93%, respectively, in the high-risk HPV-negative subgroup versus the high-risk HPV-positive subgroup (log rank test p = 0.03) [5]. Furthermore, while HPV-positive tumors express more frequently HER3 and cytoplasmic Akt1, HPV-negative tumors express more frequently phosphorylated EGFR [6], which is consistent with the negative prognostic effect associated with presence of phosphorylated EGFR [7]. The role of HPV as a potential target for immunotherapy The HPV proteins E6 and E7 play a key role in HPV-mediated carcinogenesis. In addition to inactivating p53, E6 can bind to transcription factors (myc), autocrine motility factors that regulate cell adhesion and polarity (paxillin), apoptosis-inducing factors (Bcl2) and replication and DNA repair factors (mcm7), while the E7 protein inactivates the retinoblastoma tumor-suppressor protein via proteasome-dependent degradation and causes p16INK4a overexpression, which can be detected on immunohistochemistry and can be employed as a reliable diagnostic marker of high-risk HPV infection [8]. Interestingly, the p16INK4a protein is overexpressed both in intraepithelial and invasive lesions [9,10], and can serve as a reliable diagnostic histologic biomarker of HPV infection in penile cancers. On the basis of the established etiopathogenetic role of HPV in a subgroup of penile cancer patients, we wish to speculate here that HPV-associated antigens have the potential to provide specific targets for an immunotherapy approach in men with penile cancer. At the present time, two vaccines based on HPV L1 virus-like particles are commercially available and approved in young women in order to prevent HPV infection, that is Gardasil ®(Merck & Co., NJ, USA) and Cervarix® (GlaxoSmithKline, England, UK). While Gardasil contains virus-like particles from HPV-16 and HPV-18, but also from low-risk carcinogenic genotypes 6 and 11, which cause benign genital warts, Cervarix contains virus-like particles from HPV-16 and HPV-18 only [11]. Spontaneous clearance of high-risk HPV occurs in approximately a third of women after 6 months and in approximately half of the women after 12 months [11]. Although available preventive anti-HPV vaccines are able to induce both antibody and cellular responses, they are not able to improve spontaneous HPV clearance rate [11], so they cannot be considered as candidates for an immunotherapy approach in HPV-mediated tumors. In fact, while HPV L1 protein is predominantly expressed in terminally differentiated keratinocytes, expression of the E6 and E7 proteins is retained through all of the epithelial layers and through multiple stages of infection. As a result, an immune response against E6 and E7 antigens may be effective to clear E6- and E7-expressing neoplastic cells [12]. Future perspective: VGX-3100 & anti-PD1/PD-L1 agents The novel immunotherapy agent VGX-3100 (Inovio Pharmaceuticals, PA, USA), which is delivered via electroporation, is based on two property DNA synthetic plasmids that encode the E6 and E7 genes of HPV-16 and HPV-18 [12]. Electroporation uses brief electric pulses to cause transient and reversible permeabilization of the cell membrane, which optimizes transfection of nucleic acids, with a 100–1000-fold enhancement of plasmid delivery and gene expression [12]. VGX-3100 was tested in a pivotal Phase I study in 18 women with recurrent cervical intraepithelial neoplasia (CIN) grade 2 or 3, showing encouraging results in terms of HPV-specific CD8(+) and CD4+ T-cell response [12]. In a subsequent double-blind, placebo-controlled Phase IIb study [13], 167 patients with CIN2/3 associated with HPV-16 and HPV-18 were randomly assigned in a 3:1 ratio to receive 6 mg VGX-3100 (n = 125) or 1 ml placebo solution (n = 42), both given intramuscularly at 0, 4 and 12 weeks. The primary objective of the study, that was improvement of histopathological regression rate of CIN 2/3 lesions, was met in the modified intention-to-treat analysis, with 55 (48·2%) of the 114 patients receiving VGX-3100 and 12 (30·0%) of the 40 placebo recipients showing regression to CIN 1 or no disease. The safety profile of VGX-3100 was excellent, with the majority of patients showing injection-site reactions, and erythema being significantly more frequent in the VGX-3100 group (98/125, 78·4%) with respect to the placebo group (24/42, 57·1%; p = 0·007). While VGX-3100 may be useful to avoid morbidity of surgical treatment in women with CIN2/3 cancers, this agent may provide survival benefits in patients with limited therapeutic options such as those with penile carcinoma. As we reported previously, prognosis of penile cancer is excellent in patients with noninvasive disease, while in patients with invasive tumors 5-year cancer-specific survival rates vary in the ranges of 75–93%, 40–70%, 33–50% and 20–34% in men with cN0, cN1, cN2 and cN3 disease [14]. Prognosis of patients requiring systemic chemotherapy for advanced disease is poor – approximately 6–12 months [15,16]. We speculate that a potential setting of experimental use of VGX 3100 in a clinical trial may include men with p16INK4a-positive penile cancer who have undergone complete surgical resection, but are at significant risk of disease recurrence. Conversely, we speculate that in men with metastatic penile cancer that tested positive for HPV 16/18, given the high burden of the disease, combination of an active, antigen-specific immunotherapy treatment such as VGX 3100 with an anti-PD (Programmed Death)-1/PD-L1 (Programmed Death-Ligand 1) agent may be beneficial. In fact, in a recently published retrospective study, 23 (62.2%) of 37 primary tumors were positive for PD-L1 expression, with a strong positive correlation of PD-L1 expression in primary and metastatic samples [17]. Of note, anti PD-1 agent nivolumab has shown efficacy in head and neck cancers, which share histologic (squamous histology) and pathogenic (HPV infection) characteristics with penile cancer [18]. In conclusion, although the industry may show little interest in rare diseases such as penile cancer, a continued effort should be made by independent investigators to contribute to advances in the treatment of such a devastating disease, given its high morbidity and mortality.

          Most cited references16

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          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.

          Despite preventive vaccines for oncogenic human papillomaviruses (HPVs), cervical intraepithelial neoplasia (CIN) is common, and current treatments are ablative and can lead to long-term reproductive morbidity. We assessed whether VGX-3100, synthetic plasmids targeting HPV-16 and HPV-18 E6 and E7 proteins, delivered by electroporation, would cause histopathological regression in women with CIN2/3.
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            Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial.

            Viruslike particle human papillomavirus (HPV) vaccines were designed to prevent HPV infection and development of cervical precancers and cancer. Women with oncogenic HPV infections might consider vaccination as therapy. To determine whether vaccination against HPV types 16 and 18 increases the rate of viral clearance in women already infected with HPV. Phase 3, masked, community-based randomized trial conducted in 2 provinces of Costa Rica. A total of 2189 women aged 18 to 25 years who were recruited between June 2004 and December 2005. Participants were positive for HPV DNA at enrollment, had at least 6 months of follow-up, and had follow-up HPV DNA results. Participants were randomly assigned to receive 3 doses of a bivalent HPV-16/18 L1 protein viruslike particle AS04 candidate vaccine (n = 1088) or a control hepatitis A vaccine (n = 1101) over 6 months. Presence of HPV DNA was determined in cervical specimins by a molecular hybridization assay using chemiluminescence with HPV RNA probes and by polymerase chain reaction using SPF10 primers and a line probe assay detection system before vaccination and by polymerase chain reaction after vaccination. We compared rates of type-specific viral clearance using generalized estimating equations methods at the 6-month visit (after 2 doses) and 12-month visit (after 3 doses) in the 2 study groups. There was no evidence of increased viral clearance at 6 or 12 months in the group who received HPV vaccine compared with the control group. Clearance rates for HPV-16/18 infections at 6 months were 33.4% (82/248) in the HPV vaccine group and 31.6% (95/298) in the control group (vaccine efficacy for viral clearance, 2.5%; 95% confidence interval, -9.8% to 13.5%). Human papillomavirus 16/18 clearance rates at 12 months were 48.8% (86/177) in the HPV vaccine group and 49.8% (110/220) in the control group (vaccine efficacy for viral clearance, -2.0%; 95% confidence interval, -24.3% to 16.3%). There was no evidence of a therapeutic effect for other oncogenic or nononcogenic HPV categories, among women receiving all vaccine doses, among women with single infections, or among women stratified by the following entry variables: HPV-16/18 serology, cytologic results, HPV DNA viral load, time since sexual debut, Chlamydia trachomatis or Neisseria gonorrhoeae infection, hormonal contraceptive use, or smoking. In women positive for HPV DNA, HPV-16/18 vaccination does not accelerate clearance of the virus and should not be used to treat prevalent infections. clinicaltrials.gov Identifier: NCT00128661.
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              Immunotherapy against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses.

              Despite the development of highly effective prophylactic vaccines against human papillomavirus (HPV) serotypes 16 and 18, prevention of cervical dysplasia and cancer in women infected with high-risk HPV serotypes remains an unmet medical need. We report encouraging phase 1 safety, tolerability, and immunogenicity results for a therapeutic HPV16/18 candidate vaccine, VGX-3100, delivered by in vivo electroporation (EP). Eighteen women previously treated for cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) received a three-dose (intramuscular) regimen of highly engineered plasmid DNA encoding HPV16 and HPV18 E6/E7 antigens followed by EP in a dose escalation study (0.3, 1, and 3 mg per plasmid). Immunization was well tolerated with reports of mild injection site reactions and no study-related serious or grade 3 and 4 adverse events. No dose-limiting toxicity was noted, and pain was assessed by visual analog scale, with average scores decreasing from 6.2/10 to 1.4 within 10 min. Average peak interferon-γ enzyme-linked immunospot magnitudes were highest in the 3 mg cohort in comparison to the 0.3 and 1 mg cohorts, suggesting a trend toward a dose effect. Flow cytometric analysis revealed the induction of HPV-specific CD8(+) T cells that efficiently loaded granzyme B and perforin and exhibited full cytolytic functionality in all cohorts. These data indicate that VGX-3100 is capable of driving robust immune responses to antigens from high-risk HPV serotypes and could contribute to elimination of HPV-infected cells and subsequent regression of the dysplastic process.
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                Author and article information

                Journal
                Future Sci OA
                Future Sci OA
                FSO
                Future Science OA
                Future Science Ltd (London, UK )
                2056-5623
                August 2017
                02 May 2017
                : 3
                : 3
                : FSO195
                Affiliations
                [1 ]Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Naples, Italy
                [2 ]Istituto Zooprofilattico Sperimentale del Mezzogiorno, Portici, Italy
                Author notes
                *Author for correspondence: carbuone@ 123456hotmail.com
                Article
                10.4155/fsoa-2017-0031
                5583688
                cc2709ae-05c3-4fb3-9bb2-dd61f0e5c23c
                © Carlo Buonerba

                This work is licensed under a Creative Commons Attribution 4.0 License

                History
                : 10 March 2017
                : 10 March 2017
                Categories
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                environment,hpv,immunotherapy,nivolumab,penile cancer
                environment, hpv, immunotherapy, nivolumab, penile cancer

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