Therapeutic Human Papillomavirus Vaccines Research Articles

Abstract B32: Evaluation of toll-like receptor ligands as adjuvants for an epitope-based therapeutic HPV vaccine

Abstract High-risk human papillomaviruses (HPVs), such as HPV16, cause over 500.000 cervical, anogenital and oropharyngeal cancer cases annually. The oncoproteins E6 and E7 are responsible of the transforming potential of high-risk HPVs. These proteins are indispensable for the induction and maintenance of the malignant phenotype, making them ideal targets for therapeutic HPV vaccines. In order to develop an efficient therapeutic HPV vaccine, it is essential to target E6 and E7 derived epitopes that are present on the surface of cancer cells. By using MS3 mass spectrometry for direct epitope identification, we found that the HLA-A2-restricted HPV16 epitope E711-19 is naturally processed and presented in all tested HPV16+ cell lines. Moreover, E711-19 elicited strong CTL responses in vitro. Therefore, we used this epitope as model antigen to determine the optimal vaccine formulation for anti-HPV cytotoxic T cell (CTL) induction in vivo. Short peptide epitopes (like E711-19) are poorly immunogenic when administered alone without appropriate immunostimulatory signals. Potent and proper activation of antigen presenting cells, mainly dendritic cells (DCs), is crucial for efficient priming of antigen-specific CTLs. DCs activation can be achieved by including adjuvants such as toll-like receptor (TLR) ligands. In this study, we investigated the effects of TLR3 (Poly I:C), TLR4 (MPLA), TLR7/8 (R848) and TLR9 (CpG ODNs) ligands on the maturation and activation of human and murine DCs in vitro. Moreover, we analyzed the adjuvant effects of MPLA and R848 in vivo using HLA-A2.1-/HLA-DR1-transgenic H-2 class I-/class II-knockout mice. Mice were subcutaneously vaccinated with E711-19 emulsified in Montanide ISA51 in association with either MPLA alone, R848 alone, or MPLA and R848 in combination. The properties of TLR ligands as immunostimulatory components were investigated by detailed analysis of the induced immune responses 12 days after immunization. We found that TLR4 and TLR7/8 ligands (alone and in combination) were most efficient in activating DCs in vitro, demonstrated by increased expression of CD80 on human DCs and CD40 on murine DCs. In the in vivo experiments, E711-19 induced antigen-specific T cells when coinjected with the adjuvant ISA 51. Adding MPLA to ISA51 further significantly increased the percentage of antigen-specific T cells. This study validated the use of this complex humanized mouse model to evaluate the immunogenicity of HPV epitopes in vivo. Additionally, it demonstrated that adding MPLA to an emulsion-based adjuvant (ISA51) can significantly enhance immunogenicity of epitope-based therapeutic HPV vaccines. More vaccine formulations, including other TLR ligands, are currently being tested for in vivo immunogenicity. The most immunogenic formulations will be evaluated for anti-tumor efficacy. Citation Format: Hadeel Khallouf, Jasmin Mangei, Renata Blatnik, Stephanie Hoppe, Alina Steinbach, Angelika B. Riemer. Evaluation of toll-like receptor ligands as adjuvants for an epitope-based therapeutic HPV vaccine. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B32.

Abstract B33: Endoplasmic reticulum stress enhances the antigen-specific T cell immune responses and therapeutic antitumor effects generated by therapeutic HPV vaccines

Abstract Endoplasmic reticulum stress has a profound effect on cancer cell proliferation and survival, and also has the capacity to activate cells of the adaptive immune system. Multimodality treatments that combine conventional cancer therapies with antigen-specific immunotherapy have emerged as promising approaches for the control of cancer. However, it is not well known whether ER stress inducing agents can influence the efficacy of tumor antigen targeted vaccines. We used previously developed therapeutic human papillomavirus (HPV) DNA vaccines encoding calreticulin (CRT) linked to HPV-16 E7 antigen (CRT/E7) vaccine and ER stress inducing agent, 3-bromopyruvate in a preclinical model for its potential to enhance E7-specific CD8+ T cell immune responses as well as antitumor effects against E7-expressing tumor (TC-1 cells). In vitro assay, luciferase-expressing TC-1 tumor cells were treated with 3-bromopyruvate. E7-specific CD8+ T cells were added to evaluate the cytotoxicity. The degree of cytotoxic T lymphocytes-mediated killing of the tumor cells was measured with the IVIS Luminescence Imaging System. We also determined the levels of ER stress markers in 3-bromopyruvate treated TC-1 cells. In vivo assay, TC-1 tumor-bearing mice were treated with 3-bromopyruvate (10mg/kg, intraperitoneal injection) and/or CRT/E7 DNA vaccine (30μg/mouse). The tumor mass size and survival were evaluated. Treatment of TC-1 cells with 3-bromopyruvate induced significant in vitro cytotoxicity. We found that treatment with 3-bromopyruvate led to upregulation of ER stress markers (CHOP, GRP78) in E7-expressing TC-1 tumor cells. More importantly, treatment with combination of 3-bromopyruvate and CRT/E7 DNA vaccine led to improved antigen-specific CD8+ T cell immune responses as well as therapeutic antitumor effects in TC-1 tumor-bearing mice. Thus, our data indicate that 3-bromopyruvate can enhance therapeutic HPV vaccine potency in generating improved antigen-specific immune responses and antitumor effects. These findings have important implications for future clinical translation. Citation Format: Sung Yong Lee, JaeJeong Shim, Kang Kyung Ho, Kye Young Lee, Chien-Fu Hung, T.-C. Wu. Endoplasmic reticulum stress enhances the antigen-specific T cell immune responses and therapeutic antitumor effects generated by therapeutic HPV vaccines. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B33.

Vulvar Intraepithelial Neoplasia (VIN) and Condylomata.

Human papillomavirus (HPV) infection of the lower genital tract is common and its effects are variable. The majority of infections are transient and the related pathology is self-resolving. Condyloma accuminatum is caused predominantly by HPV 6, 11 and can be managed with medical or surgical therapy. Vulvar intraepithelial neoplasia is a treatable precursor to vulvar cancer with 2 main forms: one related to HPV and the other to chronic vulvar inflammatory conditions. It may be treated medically, surgically, or potentially via the use of therapeutic HPV vaccines. Preventive utilization of a quadrivalent HPV vaccine has the potential to decrease HPV-related lower genital disease burden substantially.

A phase I dose-escalation clinical trial of a peptide-based human papillomavirus therapeutic vaccine with Candida skin test reagent as a novel vaccine adjuvant for treating women with biopsy-proven cervical intraepithelial neoplasia 2/3

PURPOSE: Non-surgical treatments for cervical intraepithelial neoplasia 2/3 (CIN2/3) are needed as surgical treatments have been shown to double preterm delivery rate. The goal of this study was to demonstrate safety of a human papillomavirus (HPV) therapeutic vaccine called PepCan, which consists of four current good-manufacturing production-grade peptides covering the HPV type 16 E6 protein and Candida skin test reagent as a novel adjuvant.PATIENTS AND METHODS: The study was a single-arm, single-institution, dose-escalation phase I clinical trial, and the patients (n = 24) were women with biopsy-proven CIN2/3. Four injections were administered intradermally every 3 weeks in limbs. Loop electrical excision procedure (LEEP) was performed 12 weeks after the last injection for treatment and histological analysis. Six subjects each were enrolled (50, 100, 250, and 500 μg per peptide).RESULTS: The most common adverse events (AEs) were injection site reactions, and none of the patients experienced dose-limiting toxicities. The best histological response was seen at the 50 μg dose level with a regression rate of 83% (n = 6), and the overall rate was 52% (n = 23). Vaccine-induced immune responses to E6 were detected in 65% of recipients (significantly in 43%). Systemic T-helper type 1 (Th1) cells were significantly increased after four vaccinations (P = 0.02).CONCLUSION: This study demonstrated that PepCan is safe. A significantly increased systemic level of Th1 cells suggests that Candida, which induces interleukin-12 (IL-12) in vitro, may have a Th1 promoting effect. A phase II clinical trial to assess the full effect of this vaccine is warranted.

Abstract LB-235: Therapeutic human papillomavirus vaccine design based on epitopes identified on the tumor cell surface by mass spectrometry

Abstract Detailed knowledge about T cell epitopes, which are bona fide presented on the surface of human papillomavirus (HPV)-transformed cells, is essential for rational design of therapeutic HPV vaccines. HPV affects the cellular antigen processing machinery, thus not every epitope derived from viral proteins is presented on human leukocyte antigen (HLA) molecules. Even the presented epitopes are displayed in low abundance. In this study, we developed a highly sensitive nano-UPLC-ESI-MS3 multiple-reaction monitoring mass spectrometry (MS) approach for direct detection of low-abundant epitopes on the cell surface. Several web-based prediction algorithms were used to predict prospective epitopes from the HPV16 E6 and E7 proteins. These candidate epitopes were tested for actual HLA binding in cellular binding assays. The presence of binding peptides on HPV16-transformed cells was analyzed by our MS technology. Immunogenicity of candidate peptides was assessed in vitro with short-term and long-term T cell line experiments, generated from peripheral blood mononuclear cells of healthy donors, and in vivo for a selected HLA-A2-restricted epitope in HLA-A2/DR-1 transgenic mice. To ensure >95% population coverage, prospective HPV epitopes were predicted for the HLA supertypes HLA-A1, A2, A3, A11, A24, B7, and B15. Close to 500 peptides were tested in competition-based binding assays and multiple novel binders were identified. MS epitope detection was first established for HLA-A2 epitopes, and is now extended to the other supertypes. In the immunogenicity assays, several peptides induced robust IFN-γ responses. In conclusion, several new HPV16 E6 and E7 epitopes were identified and validated in this study. They represent promising candidates for inclusion into a therapeutic HPV vaccine. Validated epitopes are the basis of rational therapeutic vaccine design and are also important for immunomonitoring purposes. Citation Format: Stephanie Hoppe, Renata Blatnik, Julia P. Schessner, Lisa Dressler, Alina Steinbach, Jan Winter, Martin Wuehl, Alexandra Klevenz, Hadeel Khallouf, Angelika B. Riemer. Therapeutic human papillomavirus vaccine design based on epitopes identified on the tumor cell surface by mass spectrometry. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-235. doi:10.1158/1538-7445.AM2015-LB-235

A phase I dose-escalation clinical trial of a peptide-based human papillomavirus therapeutic vaccine with candida skin test reagent as a novel vaccine adjuvant for treating women with biopsy-proven cervical intraepithelial neoplasia 2/3.

3032 Background: Non-surgical treatments for cervical intraepithelial neoplasia 2/3 (CIN2/3) are needed as surgical treatments have been shown to double preterm delivery rate. An investigational hu...

MPG-based nanoparticle: An efficient delivery system for enhancing the potency of DNA vaccine expressing HPV16E7

DNA vaccines against human papillomavirus (HPV) type 16 have not been successful in clinical trials, due to the lack of an appropriate delivery system. In this study, a peptide-based gene delivery system, MPG, which forms stable non-covalent nanoparticles with nucleic acids, was used for in vitro and in vivo delivery of HPV16 E7 DNA as a model antigen. The results demonstrated that at Nitrogen/Phosphate (N/P) ratio over 10:1, this peptide can effectively condense plasmid DNA into stable nanoparticles with an average size of 180–210nm and a positive surface charge. The transfection efficiency of MPG-based nanoparticles was shown to be comparable with Polyethyleneimine (PEI). The efficient protein expression detected by western blotting and flow cytometry supports the potential of MPG-based nanoparticles as a potent delivery system in DNA vaccine formulations. Immunization with MPG/E7DNA nanoparticles at an N/P ratio of 10:1 induced a stronger Th1 cellular immune response with a predominant interferon-γ (IFN-γ) profile than those induced by E7DNA alone in a murine tumor model. These findings suggest that MPG peptide as a novel gene delivery system could have promising applications in improving HPV therapeutic vaccines.

Cross-Reactivity, Epitope Spreading, and De Novo Immune Stimulation Are Possible Mechanisms of Cross-Protection of Nonvaccine Human Papillomavirus (HPV) Types in Recipients of HPV Therapeutic Vaccines.

Numerous versions of human papillomavirus (HPV) therapeutic vaccines designed to treat individuals with established HPV infection, including those with cervical intraepithelial neoplasia (CIN), are in development because approved prophylactic vaccines are not effective once HPV infection is established. As human papillomavirus 16 (HPV-16) is the most commonly detected type worldwide, all versions of HPV therapeutic vaccines contain HPV-16, and some also contain HPV-18. While these two HPV types are responsible for approximately 70% of cervical cancer cases, there are other high-risk HPV types known to cause malignancy. Therefore, it would be of interest to assess whether these HPV therapeutic vaccines may confer cross-protection against other high-risk HPV types. Data available from a few clinical trials that enrolled subjects with CINs regardless of the HPV type(s) present demonstrated clinical responses, as measured by CIN regression, in subjects with both vaccine-matched and nonvaccine HPV types. The currently available evidence demonstrating cross-reactivity, epitope spreading, and de novo immune stimulation as possible mechanisms of cross-protection conferred by investigational HPV therapeutic vaccines is discussed.

Antigen design enhances the immunogenicity of Semliki Forest virus-based therapeutic human papillomavirus vaccines.

Cellular immunity against cancer can be achieved with viral vector- and DNA-based immunizations. In preclinical studies, cancer vaccines are very potent, but in clinical trials these potencies are not achieved yet. Thus, a rational approach to improve cancer vaccines is warranted. We previously demonstrated that the relatively low intrinsic immunogenicity of DNA vaccines could be enhanced by inclusion of endoplasmic reticulum (ER) targeting and universal helper epitopes within the vaccine. We now evaluated whether an optimal antigen format, as defined in DNA vaccines, can further enhance the effectiveness of recombinant Semliki Forest virus (rSFV) vaccines. To this purpose, we generated, characterized and evaluated the efficacy of rSFV replicon particles expressing human papillomavirus E6 and/or E7 proteins fused to several helper T-cell epitopes and an ER targeting signal. Here, we show that inclusion of a helper cassette and an ER targeting signal enhanced protein stability and markedly augmented the frequencies of human papillomavirus-specific T cells. Even at an immunization dose of as low as 10(5) replicon particles, this novel vaccine achieved tumor regression and protection. Thus, even highly effective viral vector vaccines can benefit from an improved antigen format, based on the inclusion of defined helper epitopes and ER targeting.

The LALF32-51 peptide as component of HPV therapeutic vaccine circumvents the alum-mediated inhibition of IL-12 and promotes a Th1 response

Aluminum-containing adjuvants (alum) continue to be the most widely used adjuvants. It is common knowledge that these adjuvants predominantly induce humoral immunity, but some reports also describe their role combined with IL-12 in the induction of a Th1 immune response. In this study we want to investigate if alum could be an adjuvant to be used as a component of a therapeutic vaccine that require the generation of cell-mediated immunity. To demonstrate this concept we selected the human papillomavirus (HPV) 16-transformed mouse TC-1 cells as model and the fusion protein LALF32-51-E7 as antigen. Our results suggest that LALF32-51-E7 combined with aluminum hydroxide adjuvant promotes a Th1 immune response and consequently an anti-tumor response in the TC-1 tumor model. These results could have important application in future clinical trials in women with low grade squamous intraepithelial neoplasia.

Current and Next-generation Vaccines against Human Papillomaviruses

Human papillomaviruses (HPVs) infect the squamous epithelium, and cause skin warts, genital warts and cancers, including uterine cervical cancer. Amongst the enormously diverse types of HPVs, HPV16 and HPV18 are most prevalent and responsible for approximately 70% of cervical cancer cases. Current preventive HPV vaccines contain virus-like particles which are composed of L1 major capsid proteins of HPV16 and HPV18. Although bivalent and quadrivalent vaccines exhibit excellent preventive efficacy and safety, they have several limitations. First, since the protection against HPV is type-restricted, the remaining 30% of cervical cancers and warts cannot be prevented. Second, due to the absence of therapeutic activity in the vaccines, people already infected by the HPVs cannot benefit from the current vaccines. Therefore, new preventive and therapeutic vaccines are required for better control of HPV-associated diseases. New developments include a novel nonavalent preventive vaccine that contains five additional cancer-associated HPV types, and it has been tested and approved in 2014. Recently, several groups reported promising clinical results with novel therapeutic HPV vaccines. This review provides an overview of the success of current preventive vaccines and perspectives on the next-generation HPV vaccines.

Toll-like receptor agonist imiquimod facilitates antigen-specific CD8+ T-cell accumulation in the genital tract leading to tumor control through IFNγ.

Imiquimod is a Toll-like receptor 7 agonist used topically to treat external genital warts and basal cell carcinoma. We examined the combination of topical imiquimod with intramuscular administration of CRT/E7, a therapeutic human papillomavirus (HPV) vaccine comprised of a naked DNA vector expressing calreticulin fused to HPV16 E7. Using an orthotopic HPV16 E6/E7(+) syngeneic tumor, TC-1, as a model of high-grade cervical/vaginal/vulvar intraepithelial neoplasia, we assessed if combining CRT/E7 vaccination with cervicovaginal deposition of imiquimod could result in synergistic activities promoting immune-mediated tumor clearance. Imiquimod induced cervicovaginal accumulation of activated E7-specific CD8(+) T cells elicited by CRT/E7 vaccination. Recruitment was not dependent upon the specificity of the activated CD8(+) T cells, but was significantly reduced in mice lacking the IFNγ receptor. Intravaginal imiquimod deposition induced upregulation of CXCL9 and CXCL10 mRNA expression in the genital tract, which are produced in response to IFNγ receptor signaling and attract cells expressing their ligand, CXCR3. The T cells attracted by imiquimod to the cervicovaginal tract expressed CXCR3 as well as CD49a, an integrin involved in homing and retention of CD8(+) T cells at mucosal sites. Our results indicate that intramuscular CRT/E7 vaccination in conjunction with intravaginal imiquimod deposition recruits antigen-specific CXCR3(+) CD8(+) T cells to the genital tract. Several therapeutic HPV vaccination clinical trials using a spectrum of DNA vaccines, including vaccination in concert with cervical imiquimod, are ongoing. Our study identifies a mechanism by which these strategies could provide therapeutic benefit. Our findings support accumulating evidence that manipulation of the tumor microenvironment can enhance the therapeutic efficacy of strategies that induce tumor-specific T cells.

HPV Infection-Associated Cancers: Next-Generation Technology for Diagnosis and Treatment.

Disease caused by human papillomavirus (HPV) remains common, despite preventive vaccines and screening strategies. Globally, HPVs cause one third of infection-associated cancers. The indolent clinical course of the precursor intraepithelial lesions provides an opportunity to understand immunologic obstacles posed by the microenvironment of incipient disease, and how they might be overcome. Results from recent therapeutic HPV vaccine clinical trials suggest that relevant immune responses may be sequestered at the lesion site and are difficult to detect in the circulation. In this Cancer Immunology at the Crossroads article, we outline the current understanding of the risk, diagnosis, and treatment of HPV infection-associated cancers and suggest that quantitative tissue-based endpoints should be included whenever possible in the evaluation of immune-based therapies.

Therapeutic Vaccine Strategies against Human Papillomavirus.

High-risk types of human papillomavirus (HPV) cause over 500,000 cervical, anogenital and oropharyngeal cancer cases per year. The transforming potential of HPVs is mediated by viral oncoproteins. These are essential for the induction and maintenance of the malignant phenotype. Thus, HPV-mediated malignancies pose the unique opportunity in cancer vaccination to target immunologically foreign epitopes. Therapeutic HPV vaccination is therefore an ideal scenario for proof-of-concept studies of cancer immunotherapy. This is reflected by the fact that a multitude of approaches has been utilized in therapeutic HPV vaccination design: protein and peptide vaccination, DNA vaccination, nanoparticle- and cell-based vaccines, and live viral and bacterial vectors. This review provides a comprehensive overview of completed and ongoing clinical trials in therapeutic HPV vaccination (summarized in tables), and also highlights selected promising preclinical studies. Special emphasis is given to adjuvant science and the potential impact of novel developments in vaccinology research, such as combination therapies to overcome tumor immune suppression, the use of novel materials and mouse models, as well as systems vaccinology and immunogenetics approaches.

Identification of promiscuous HPV16-derived T helper cell epitopes for therapeutic HPV vaccine design.

Cervical carcinoma and several other human papillomavirus (HPV)-induced malignancies are a global public health problem, thus novel treatment modalities are urgently needed. Immunotherapy is an attractive option for treatment of HPV infection and HPV-mediated premalignant and malignant lesions. However, previous approaches--focusing on the induction of cytotoxic CD8+ T cells (CTLs)--have as yet not yielded clinical successes. Since CD4+ T cells have been shown to be crucial for the induction and maintenance of CTL responses, and more recently to be also important for direct anti-tumor immunity, human leukocyte antigen (HLA) class II-restricted epitopes are intensively investigated to improve the efficacy of peptide-based HPV immunotherapy. We here present an approach to identify promiscuous HPV16-derived CD4+ T helper epitopes, which are capable of inducing T cell immunity in a large proportion of the population. To this end, we combined HLA class II epitope prediction servers with in vitro immunological evaluation to identify HPV16 E2-, E5-, E6-, and E7-derived CD4+ T cell epitopes. Candidate selected HPV16-derived epitopes were found to be restricted by up to nine HLA-DR molecules. Furthermore, they were found to induce frequent and robust HPV16 peptide-specific Th1 responses in healthy donors, as monitored by interferon (IFN)-γ ELISPOT and cytokine secretion assays. Moreover, these selected peptides also induced specific IFN-γ T cell responses in blood from HPV16+ CIN2/3 and cervical carcinoma patients. We thus conclude that the identified T helper epitopes are valuable candidates for the development of a comprehensive therapeutic HPV vaccine.

Cytotoxic T lymphocytes elicited by dendritic cell-targeted delivery of human papillomavirus type-16 E6/E7 fusion gene exert lethal effects on CaSki cells.

Human papillomavirus (HPV) is the primary etiologic agent of cervical cancer. Consideration of safety and non human leukocyte antigen restriction, protein vaccine has become the most likely form of HPV therapeutic vaccine, although none have so far been reported as effective. Since tumor cells consistently express the two proteins E6 and E7, most therapeutic vaccines target one or both of them. In this study, we fabricated DC vaccines by transducing replication-defective recombinant adenoviruses expressing E6/E7 fusion gene of HPV-16, to investigate the lethal effects of specific cytotoxic T lymphocytes (CTL) against CaSki cells in vitro. Mouse immature dendritic cells (DC) were generated from bone marrow, and transfected with pAd-E6/E7 to prepare a DC vaccine and to induce specific CTL. The surface expression of CD40, CD68, MHC II and CD11c was assessed by flow cytometry (FCM), and the lethal effects of CTL against CaSki cells were determined by DAPI, FCM and CCK-8 methods. Immature mouse DC was successfully transfected by pAd-E6/E7 in vitro, and the transfecting efficiency was 40%-50%. A DC vaccine was successfully prepared and was used to induce specific CTL. Experimental results showed that the percentage of apoptosis and killing rate of CaSki cells were significantly increased by coculturing with the specific CTL (p <0.05). These results illustrated that a DC vaccine modified by HPV-16 E6/E7 gene can induce apoptosis of CaSki cells by inducing CTL, which may be used as a new strategy for biological treatment of cervical cancer.

Enhanced Cancer Radiotherapy through Immunosuppressive Stromal Cell Destruction in Tumors

Radiotherapy kills cancer cells by causing DNA damage, and stimulates a systemic antitumor immune response by releasing tumor antigen and endogenous adjuvant within the tumor microenvironment. However, radiotherapy also induces the recruitment of immunosuppressive myeloid cells, which can interfere with the antitumor immune responses elicited by apoptotic tumor cells. We hypothesized that local delivery of vaccine following radiotherapy will lead to the priming of antigen-specific CTL immune responses and render immunosuppressive myeloid cells susceptible to killing by the activated CTLs. Using several antigenic systems, we tested whether intratumoral injection of antigenic peptide/protein in irradiated tumors would be able to prime CTLs as well as load myeloid cells with antigen, rendering them susceptible to antigen-specific CTL killing. We show that by combining radiotherapy and targeted antigenic peptide delivery to the tumor, the adjuvant effect generated by radiotherapy itself was sufficient to elicit the priming and expansion of antigen-specific CTLs, through the type I IFN-dependent pathway, leading to synergistic therapeutic antitumor effects compared with either treatment alone. In addition, using two different types of transgenic mice, we demonstrated that CTL-mediated killing of stromal cells in tumors by our approach is important for tumor control. Finally, we confirmed the efficacy of this approach in our preclinical model using two clinically tested therapeutic human papilloma virus (HPV) vaccines. These data serve as an important foundation for the future clinical translation of radiotherapy combined with a clinically tested therapeutic HPV vaccine for the control of HPV-associated cancers.

Updates in Systemic Treatment for Metastatic Cervical Cancer

Cervical cancer has been a leading cause of morbidity and gynecologic cancer deaths throughout the world in this generation despite the implementation of Pap smears. The American Joint Committee on Cancer classifies metastatic cervical cancer as any tumor (T) stage and M1 (distant metastasis of peritoneal spread and involvement of supraclavicular, mediastinal, or para-aortic lymph nodes; lung; liver; or bone) at primary presentation or persistent/recurrent disease outside the pelvis. Radiation with platinum-based chemotherapy is the standard treatment for locally advanced and potentially curable disease at limited metastatic site(s). For patients with recurrent cervical cancer after definitive surgery who have not received prior radiotherapy, salvage chemoradiation is an option. Meanwhile, surgery may be offered to patients with resectable disease if they have received primary radiotherapy. Patients with distant relapse at sole/limited metastatic site(s) could undergo salvage treatment by chemoradiation, surgery plus radiotherapy/chemoradiation, or surgery alone to achieve prolonged survival; hence, they should not be treated with systemic therapy alone. For previously irradiated unresectable lesions or disseminated disease, no effective control of the disease is available; therefore, such patients are candidates for systemic treatment. The primary goal of chemotherapy for those who are not amenable to curative intent is to extend life while offering quality of life. Results of clinical trials using platinum/nonplatinum doublets, molecularly targeted therapies, and immunotherapy, including therapeutic human papillomavirus vaccines, are reviewed.

Cervical cancer: Can it be prevented?

Cervical cancer prevention requires a multipronged approach involving primary, secondary and tertiary prevention. The key element under primary prevention is human papilloma virus (HPV) vaccination. So far, only prophylactic HPV vaccines which prevent HPV infection by one or more subtypes are commercially available. Therapeutic HPV vaccines which aid in clearing established infection are still under trial. Secondary prevention entails early detection of precancerous lesions and its success is determined by the population coverage and the efficacy of the screening technique. A number of techniques are in use, including cytology, visual inspection (using the naked eye, magnivisualizer, acetic acid and Lugol's iodine), HPV testing and a combination of these methods. Updated screening guidelines have been advocated by the American Cancer Society in light of the role of HPV on cervical carcinogenesis. Recent research has also focussed on novel biomarkers that can predict progression to cancer in screen positive women and help to differentiate those who need treatment from those who can be left for follow-up. Last but not the least, effective treatment of precancerous lesions can help to reduce the incidence of invasive cervical cancer and this constitutes tertiary prevention. A combination of these approaches can help to prevent the burden of cervical cancer and its antecedent morbidity and mortality, but all of these are not feasible in all settings due to resource and allocation constraints. Thus, all countries, especially low and middle income ones, have to determine their own cocktail of approaches that work before we can say with certainty that yes, cervical cancer can be prevented.

New frontiers in cancer therapy: the 11th International Meeting of the Asian Clinical Oncology Society (ACOS)

New frontiers in cancer therapy: the 11th International Meeting of the Asian Clinical Oncology Society (ACOS)