Coinfections with additional oncoviruses in HPV+ individuals: Status, function and potential clinical implications.

Oncovirus infections account for an estimated 12%-20% of human cancers worldwide. High-risk human papillomavirus (HPV) infection is the etiological agent of some malignancies such as cervical, oropharyngeal, anal, penile, vaginal, and vulvar cancers. However, HPV infection is not the only cause of these cancers or may not be sufficient to initiate cancer development. Actually, certain other risk factors including additional oncoviruses coinfections have been reported to increase the risk of patients exposed to HPV for developing different HPV-related cancers. In the current review, we summarize recent findings about coinfections with different oncoviruses in HPV+ patients from both clinical and mechanistic studies. We believe such efforts may lead to an interesting direction for improving our understanding and developing new treatments for virus-induced cancers.

An Online Survey and Focus Groups for Promoting Cancer Prevention Measures.

In order to design a cancer prevention promotion program in the region, suggestions were solicited at a medical center. We hypothesized that a majority would be native to state, and would be able to articulate about the barriers that may exist. Through online survey and focus groups, suggestions were sought, and the knowledge and the compliance with cancer prevention recommendations were assessed to determine the participants' qualifications as potential educators. Sixty-five point two percent of participants (n = 1018) graduated from high school in Arkansas. The most commonly given suggestions were to provide education to increase awareness, to use social media for promotion, to improve access, and to reduce costs. Self-reported adherence rates to breast, cervical, and colorectal cancer screening were 82.6% (n = 954), 75.8% (n = 541), and 76.7% (n = 453), respectively. Having a personal history of cancer significantly increased colorectal cancer screening uptake (p = 0.04), but paradoxically decreased mammography uptake (p = 0.007). Salary of $40,000 and more and having a Bachelor's degree or higher were associated with higher compliance of Papanicolaou test only (p = 0.007 and p = 0.001, respectively). A majority (67.7%, n = 1056) of respondents expressed willingness to contribute to promoting cancer prevention measures, and 38.3% (n = 559) were willing to participate in focus groups. However, only 6.3% (n = 35) actually participated. The participants' knowledge and compliance appeared to be sufficient, but their follow through in focus group participation was poor.

Assessing the Feasibility of an Online Module for Promoting Cancer Prevention Measures.

OBJECTIVES: The aims of this pilot study were (1) to develop a cancer prevention module consisting of an animated video and a short questionnaire, (2) to assess new knowledge gained by the participants, and (3) to solicit feedback for improving the cancer prevention module. METHODS: Volunteers who previously agreed to be contacted regarding research studies were approached via email. After completing the cancer prevention module, a list of cancer prevention recommendations was provided. Newly gained knowledge was assessed, and feedback was solicited. RESULTS: Overall, 290 of 3165 individuals contacted completed the online module (9.2%), and 38.6% of the participants indicated that they learned something new about cancer prevention measures. A similar proportion, 41.4%, mentioned that they learned about measures that were recommended and due. Paradoxically, response rate was the lowest in the ≥50 year old age group although this group reported the highest rate of learning about new cancer prevention measures. Feedback was favorable in that 70.7% mentioned that the recommendations were helpful to them personally, 69.3% felt motivated to take action to reduce their risk of cancers, and 67% would recommend the online module to their friends and family. CONCLUSION: We developed an online cancer prevention module which seems to be suitable for promoting cancer prevention measures as feedback was favorable, and new knowledge was gained. Future efforts will focus on using the module to promote cancer prevention measures to the general public particularly for the ≥50 year age group.

Examining aspects of successful community-based programs promoting cancer screening uptake to reduce cancer health disparity: A systematic review.

Certain minorities in the US are disproportionately burdened with higher cancer incidence and mortality rates. Programs encouraging timely uptake of cancer screening measures serve to reduce cancer health disparities. A systematic literature review was conducted to assess the effectiveness and the qualities of these programs, and to elucidate characteristics of success programs to aid in designing of future ones. We focused on community-based programs rather than clinic-based programs as the former are more likely to reach disadvantaged populations, and on prevention programs for breast, cervical, and/or colon cancers as longstanding screening recommendations for these cancers exist. PubMed, CINAHL and EBSCO databases were searched for articles that utilized community organizations and community health workers. Fourteen programs described in 34 manuscripts were identified. While 10 of 14 programs reported statistically significant increases in cancer prevention knowledge and/or increase in screening rates, only 7 of them enrolled large numbers of participants (defined as ≥1000). Only 7 programs had control groups, only 4 programs independently verified screening uptake, and 2 programs had long-term follow-up (defined as more than one screening cycle). Only one program demonstrated elimination of cancer health disparity at a population level. While most community-based cancer prevention programs have demonstrated efficacy in terms of increased knowledge and/or screening uptake, scalability and demonstration in reduction at a population level remain a challenge.

Low Body Mass Index and Myeloablative Conditioning Regimen Prolong the Duration of Parenteral Nutrition During Hematopoietic Stem Cell Transplantation.

BACKGROUND/AIMS: Patients undergoing hematopoietic stem cell transplantation (HSCT) often receive total parenteral nutrition (TPN) due to poor oral intake. In clinical practice, it is difficult to predict adequate nutritional management, especially the duration of parenteral nutrition (PN), because of inter-individual variability in the conditions and types of treatment regimens. This study investigated the relationship between patient factors and the duration of TPN and the duration of PN. METHODS: Data on clinical features, patient characteristics, and the duration of TPN and PN were collected from medical records of 61 of 73 patients who underwent HSCT between April 2010 and December 2014 and were analyzed by multiple linear regression analysis. RESULTS: Forty-nine patients (80.3%) received TPN and 53 (86.9%) received PN. Sixty patients were affected by poor oral intake soon after pretreatment. Body mass index (BMI) was significantly correlated with the duration of TPN (ß = -2.733; 95% CI -4.679 to -0.787). BMI (ß = -2.260; 95% CI -4.304 to -0.213) and conditioning regimen (ß = 12.726; 95% CI 0.692-24.76) were significantly correlated with the duration of PN. CONCLUSIONS: BMI at admission and the type of conditioning regimen should be considered in choosing the nutritional management plan in patients with HSCT with poor oral intake.

Human papillomavirus type 16 viral load is decreased following a therapeutic vaccination.

In the dose-escalation phase of a Phase I clinical trial in which six subjects each were vaccinated with PepCan at the 50, 100, 250, and 500 µg per peptide dose, the 50 µg dose showed the best histological regression rate. Ten additional subjects were vaccinated at this dose in the final dose phase. As with the dose-escalation phase, no dose-limiting toxicities were observed. Overall, the histological regression rates were 50% at the 50 µg dose (7 of 14) and 100 µg dose (3 of 6), and 45 % overall (14 of 31). Of subjects in whom HPV type 16 (HPV 16) was detected at entry, it became undetectable in three subjects after vaccination, and the viral loads significantly decreased in nine subjects in whom HPV 16 infection was detected at entry and exit (p = 0.008). Immune profiling revealed increased T-helper type 1 cells after vaccinations (p = 0.02 and 0.0004 after 2 and 4 vaccinations, respectively). T-helper type 2 cells initially increased after two vaccinations (p = 0.01), but decreased below the baseline level after four vaccinations although not significantly. Pre-vaccination regulatory T cell levels were significantly lower in histological responders compared to non-responders (p = 0.03). Feasibility of testing plasma for multiplex cytokine/chemokine analysis and of performing proteomic analysis of PBMCs was examined for potentially identifying biomarkers in the future. While these analyses are feasible to perform, attention needs to be given to how soon the blood samples would be processed after phlebotomy. As sufficient safety of PepCan has been demonstrated, enrollment for the Phase II clinical trial has been opened.

A novel use of a statewide telecolposcopy network for recruitment of participants in a Phase I clinical trial of a human papillomavirus therapeutic vaccine.

BACKGROUND: Historically, recruitment and retention of young women in intervention-based clinical trials have been challenging. In August 2012, enrollment for a clinical trial testing of an investigational human papillomavirus therapeutic vaccine called PepCan was opened at our institution. This study was an open-label, single-arm, single-institution, dose-escalation Phase I clinical trial. Women with recent Papanicolaou smear results showing high-grade squamous intraepithelial lesions or results that could not rule out high-grade squamous intraepithelial lesion were eligible to enroll. Patients with biopsy-confirmed high-grade squamous intraepithelial lesion were also eligible. Colposcopy was performed at the screening visit, and participants became eligible for vaccination when the diagnosis of high-grade squamous intraepithelial lesion was confirmed with biopsy and other inclusion criteria were met. The aim of this study was to identify strategies and factors effective in recruitment and retention of study participants. METHODS: Potential vaccine candidates were recruited through direct advertisement as well as referrals, including referrals through the Arkansas telecolposcopy network. The network is a federally funded program, administered by physicians and advanced practice nurses. The network telemedically links rural health sites and allows physician-guided colposcopy and biopsies to be conducted by advanced practice nurses. A variety of strategies were employed to assure good retention, including face-to-face contact with the study coordinator at the time of consent and most of study visits; frequent contact using text messaging, phone calls, and e-mails; and creation of a private Facebook page to improve communication among research staff and study participants. A questionnaire, inquiring about motivation for joining the study, occupation, education, household income, number of children, and number of sexual partners, was administered at the screening visit with the intent of identifying factor(s) associated with recruitment and retention. RESULTS: A total of 37 participants were enrolled between September 2012 and March 2014. The largest proportion of participants (46%) was enrolled from the telecolposcopy network. Others were enrolled through outside institutions (43%), in-house referrals (8%), or direct advertisement (3%). Most participants were motivated to join the study to take care of their health issues. Only two participants joined the Facebook private page. Of the 24 participants who qualified for vaccination, only 1 terminated early due to an unanticipated move. CONCLUSION: The availability of a large number of potential participants from the telecolposcopy network increased recruitment to this clinical trial by 85% over other traditional means of recruitment. The telecolposcopy network is not only a means of providing a gynecological service to women who otherwise would forego care but also a novel and valuable resource in recruiting participants for a clinical trial.

Rituximab and intermediate-purity plasma-derived factor VIII concentrate (Koate®) as adjuncts to therapeutic plasma exchange for thrombotic thrombocytopenic purpura in patients with an ADAMTS13 inhibitor.

Thrombotic thrombocytopenic purpura (TTP) results from a congenital or acquired deficiency of the von Willebrand factor (vWF)-cleaving protease ADAMTS13. The disease can be fatal and hence treatment should be initiated promptly. Therapeutic plasma exchange (TPE) remains the standard treatment along with adjunct therapies including steroids and immunosuppressive drugs. Addition of rituximab to TPE has been shown to be beneficial in refractory/relapsing TTP; however, TPE results in removal of rituximab from the circulation requiring more frequent dosing of rituximab to achieve a favorable outcome. The intermediate-purity plasma-derived Factor VIII concentrate (FVIII) Koate® contains the highest amount of ADAMTS13 activity yet reported and has been used successfully in treating congenital TTP. Here we report our experience with addition of this FVIII concentrate to rituximab, corticosteroids and TPE in three TTP patients with an ADAMTS13 inhibitor to permit withholding TPE for 48 h after rituximab infusion.

IL-12 secretion by Langerhans cells stimulated with Candida skin test reagent is mediated by dectin-1 in some healthy individuals.

OBJECTIVE: Our group and others have shown that serial intra-lesional injections of common warts with skin testing reagents such as Candida, mumps and Trichophyton are effective in regressing injected and non-injected warts. Anti-HPV T-cell responses appear to be induced. The goal of this study was to understand the mechanisms of how Candida skin testing reagent enhances immune responses. METHODS: The following immunological features were studied to understand how Candida induces immune responses in healthy subjects: (1) proliferative capacity of T-cells upon exposure to Candida through monocyte-derived human Langerhans cells (LCs) measured using alamarBlue, (2) cytokine (IL-1ß, IL-6, IL-8, IL-10, IL-12p40, IL-23Ap19, IFN-γ, and TNF- expression upon Candida stimulation of LCs by quantitative reverse transcription (qRT)-PCR and cytokine secretion by ELISA, (3) expression of pattern recognition receptors (PRRs) known to associate with Candida albicans (DC-SIGN, dectin-1, dectin-2, galectin-3, mincle, mannose receptor, Toll-like receptors 1, 2, 4, 6, and 9) on LCs by qRT-PCR, (4) role of dectin-1 in IL-12 production by antibody blocking, and (5) induction of Th1, Th2, and/or Th17 responses by intracellular cytokine staining of CD4 cells exposed to Candida pulsed LCs for IFN-γ, IL-4, and IL-17A. RESULTS: T-cell proliferation upon stimulation with Candida-pulsed LCs was significantly higher compared to proliferation in the absence of Candida (p=0.004). The most frequently expressed cytokine in stimulated LCs was IL-12p40 mRNA, and IL-12p40 and IL-12p70 were also detected at protein levels. All other cytokine mRNAs examined were detected in the following order of decreasing frequency: IL23Ap19, IFN-γ, IL-1ß, IL-6, IL-8, and IL-10. LCs expressed all PRRs examined. Anti-dectin-1 inhibited IL-12p40 mRNA production upon Candida stimulation of LCs from some healthy subjects. IFN-γ secretion was increased and IL-4 secretion was decreased in CD4 cells of a few healthy subjects, but IL-17A was essentially unchanged upon Candida treatment. CONCLUSIONS: Proliferation of T-cells in a substantial majority of healthy subjects can be demonstrated with Candida stimulation. We show Th1 promotion and dectin-1 stimulation of LCs as potential mechanisms in some healthy subjects.

A case of acquired dysfibrinogenemia in multiple myeloma treated with therapeutic plasma exchange.

A 70 year old Caucasian woman with IgG lamda multiple myeloma presented with uncontrollable bleeding from a bone marrow biopsy site which started days after the procedure. The patient was hyperviscous, and coagulation tests showed elevated activated partial thromboplastin time (aPTT) which was not corrected with a mixing study, elevated thrombin time and reptilase time, and possible inhibitors to Factors VIII and IX. Therapeutic plasma exchange was performed using plasma with corrections of plasma viscosity (1.6 to 1.1 centipoise) and aPTT (50 to 42.1s) observed. The bleeding was controlled, and purified IgG demonstrated dysfibrinogenemic effects of the patient's paraprotein.

Distribution of human papillomavirus (HPV) types and anti-HPV T-cell immune responses among different racial/ethnic groups in Central Arkansas.

The distribution of human papillomavirus (HPV) types and T-cell immune responses were compared among European American, African American, and Hispanic American populations being followed for abnormal Papanicolaou smear results who were attending the same university medical center clinic in Central Arkansas. Statistically significant differences were found for HPV types 55, 58, and 83 among the 37 HPV types tested. However, there were no differences in T-cell immune responses among these racial/ethnic groups. These results are unlikely to have an impact on therapeutic HPV vaccine development since the most prevalent HPV type among all racial/ethnic groups was HPV type 16.

CD4+ T-cell response against human papillomavirus type 16 E6 protein is associated with a favorable clinical trend.

The association between the CD8+ T-cell responses to human papillomavirus type 16 (HPV-16) E6 protein and a favorable clinical trend has been demonstrated previously. The roles of human papillomavirus (HPV)-specific CD4+ T-cell responses and of regulatory T-cells (Tregs) were examined. Subjects with a recent history of abnormal Papanicolaou smear were eligible, and colposcopy-guided biopsy was performed at enrollment. Interferon-γ enzyme-linked immunospot assay and fluorescent-activated cell sorter analysis to measure the frequencies of Tregs were performed. Subjects with histological diagnoses of cervical intraepithelial neoplasia 1, 2, or 3 were considered to have short-term persistence of cervical abnormality and were called "persistors" (n = 51) while those of normal histology were designated to be "regressors" (n = 33). A significantly higher percentage CD4+ T-cell response was detected in the regressors (15/33 or 45.5%) compared with the persistors (10/51 or 19.6%) (P = .015) for the E6 peptides but not for the E7 peptides. The CD4+ responses to certain E6 regions [E6(16-40), E6(91-115), E6(106-130), and E6(136-158)] were also significantly higher in the regressors. Although there was no difference in the frequencies of Tregs between the two groups, low frequencies of Tregs were significantly associated with positive CD4+ T-cell responses within certain E6 regions [E6(16-40), E6(31-55), E6(76-100), E6(91-115), and E6(106-130)]. The CD4+ and CD8+ T-cell responses to the HPV-16 E6 protein are associated with a favorable clinical trend. The HPV-16 E6 protein should be incorporated in the design of an HPV therapeutic vaccine.

A comparison of washed and volume-reduced platelets with respect to platelet activation, aggregation, and plasma protein removal.

BACKGROUND: Washed or volume-reduced platelets (PLTs) are occasionally requested for patients with a history of allergic or anaphylactic transfusion reactions. However, conclusive data are not available as to which method is more suitable. STUDY DESIGN AND METHODS: A direct comparison of saline-washed and volume-reduced PLTs was performed by splitting 11 units of 6-day-old apheresis PLT units. PLT activation, aggregation, plasma protein, and PLT count were determined before and after each procedure. To assess whether washing using neutral, calcium-free Ringer's acetate (NRA) would better preserve PLT function, 8 additional units of apheresis PLTs were split and were washed in saline or NRA. RESULTS: Saline washing resulted in significantly increased number of activated, P-selectin-expressing PLTs compared to volume reduction (24.2% vs. 10.3%, p = 0.001). Aggregation was also significantly reduced (-40.6% vs. -0.8%, p = 0.004). Plasma protein removal was significantly better for saline-washed than volume-reduced PLTs (96% vs. 51.1%, p < 0.001). PLT recovery was not significantly different for saline-washed versus volume-reduced PLTs (70.5% vs. 80.7%, p = 0.079). There was no difference between washing in saline or NRA with regard to PLT activation and loss of aggregation. CONCLUSIONS: PLT washing with saline or NRA significantly increases PLT activation and decreases PLT aggregability. On the other hand, volume reduction does not adequately remove plasma proteins. Therefore, PLT washing should be reserved for patients with a history of severe allergic or anaphylactic transfusion reactions. We suggest that fresher PLTs be selected to improve the functionality of washed PLTs.

Evaluation of DNA extraction protocols from liquid-based cytology specimens for studying cervical microbiota.

Cervical microbiota (CM) are considered an important factor affecting the progression of cervical intraepithelial neoplasia (CIN) and are implicated in the persistence of human papillomavirus (HPV). Collection of liquid-based cytology (LBC) samples is routine for cervical cancer screening and HPV genotyping and can be used for long-term cytological biobanking. We sought to determine whether it is possible to access microbial DNA from LBC specimens, and compared the performance of four different extraction protocols: (ZymoBIOMICS DNA Miniprep Kit; QIAamp PowerFecal Pro DNA Kit; QIAamp DNA Mini Kit; and IndiSpin Pathogen Kit) and their ability to capture the diversity of CM from LBC specimens. LBC specimens from 20 patients (stored for 716 ± 105 days) with CIN values of 2 or 3 were each aliquoted for each of the four kits. Loss of microbial diversity due to long-term LBC storage could not be assessed due to lack of fresh LBC samples. Comparisons with other types of cervical sampling were not performed. We observed that all DNA extraction kits provided equivalent accessibility to the cervical microbial DNA within stored LBC samples. Approximately 80% microbial genera were shared among all DNA extraction protocols. Potential kit contaminants were observed as well. Variation between individuals was a significantly greater influence on the observed microbial composition than was the method of DNA extraction. We also observed that HPV16 was significantly associated with community types that were not dominated by Lactobacillus iners.

Expansion of Human Papillomavirus-Specific T Cells in Periphery and Cervix in a Therapeutic Vaccine Recipient Whose Cervical High-Grade Squamous Intraepithelial Lesion Regressed.

Advances in high-throughput sequencing have revolutionized the manner with which we can study T cell responses. We describe a woman who received a human papillomavirus (HPV) therapeutic vaccine called PepCan, and experienced complete resolution of her cervical high-grade squamous intraepithelial lesion. By performing bulk T cell receptor (TCR) ß deep sequencing of peripheral blood mononuclear cells before and after 4 vaccinations, 70 putatively vaccine-specific clonotypes were identified for being significantly increased using a beta-binomial model. In order to verify the vaccine-specificity of these clonotypes, T cells with specificity to a region, HPV 16 E6 91-115, previously identified to be vaccine-induced using an interferon-γ enzyme-linked immunospot assay, were sorted and analyzed using single-cell RNA-seq and TCR sequencing. HPV specificity in 60 of the 70 clonotypes identified to be vaccine-specific was demonstrated. TCR ß bulk sequencing of the cervical liquid-based cytology samples and cervical formalin-fixed paraffin-embedded samples before and after 4 vaccinations demonstrated the presence of these HPV-specific T cells in the cervix. Combining traditional and cutting-edge immunomonitoring techniques enabled us to demonstrate expansion of HPV-antigen specific T cells not only in the periphery but also in the cervix. Such an approach should be useful as a novel approach to assess vaccine-specific responses in various anatomical areas.

A favorable clinical trend is associated with CD8 T-cell immune responses to the human papillomavirus type 16 e6 antigens in women being studied for abnormal pap smear results.

OBJECTIVE: The goal of this study was to examine the role of CD8 T-cell responses to human papillomavirus type 16 (HPV-16) in a favorable clinical trend in women being studied for abnormal Pap smear results. MATERIALS AND METHODS: Human papillomavirus-deoxyribonucleic acid testing and enzyme-linked immunospot assay using the HPV-16 E6 and E7 antigens were performed. The subjects with subsequent normal histologic diagnoses were considered to be "regressors" (n = 28), whereas those with histologic diagnoses of cervical intraepithelial neoplasia 1, 2, or 3 were considered to have short-term persistence of cervical abnormality and were designated to be "persistors" (n = 37). RESULTS: There was a higher percentage of CD8 T-cell responses to the E6 antigen in the regressors (15/28 or 53.6%) when compared with the persistors (10/37 or 27.0%; p = .04), but there was no recorded response difference for the E7 antigen. Results were the same when the analyses for E6 included only subjects who were high-risk HPV-positive (p = .01). CONCLUSIONS: The CD8 T-cell immune responses to the HPV-16 E6 antigens but not to E7 antigens are associated with a favorable clinical trend regardless of HPV types currently detected.

A novel CD4 T-cell epitope described from one of the cervical cancer patients vaccinated with HPV 16 or 18 E7-pulsed dendritic cells.

Previously, safety and immunogenicity of human papillomavirus type 16 (HPV16) or 18 E7-pulsed dendritic cells (DC) vaccinations were demonstrated in a dose-escalation Phase I clinical trial which enrolled ten patients diagnosed with stage IB or IIA cervical cancer (nine HPV 16-positive, one HPV 18-positive). The goal of the study was to define the T-cell epitopes of HPV 16 or 18 E7 protein in these patients in order to develop new strategies for treating HPV-associated malignancies. This was accomplished through establishing T-cell lines by stimulating peripheral blood mononuclear cells with autologous mature DC pulsed with the HPV 16 or 18 E7 protein, examining the T-cell responses using ELISPOT assays, and isolating E7-specific T-cell clones based on IFN-gamma secretion. Then, the epitope was characterized in terms of its core sequence and the restriction element. Twelve T-cell lines from eight subjects (seven HPV 16-positive, one HPV 18-positive) were evaluated. Positive T-cell responses were demonstrated in four subjects (all HPV 16-positive). All four were positive for the HPV 16 E7 46-70 (EPDRAHYNIVTFCCKCDSTLRLCVQ) region. T-cell clones specific for the E7 47-70 region were isolated from one of the subjects. Further analyses revealed a novel, naturally processed, CD4 T-cell epitope, E7 58-68 (CCKCDSTLRLC), restricted by the HLA-DR17 molecule.

Cell-mediated immune responses to human papillomavirus 16 E6 and E7 antigens as measured by interferon gamma enzyme-linked immunospot in women with cleared or persistent human papillomavirus infection.

Cell-mediated immune responses have been thought to be important in the control of human papillomavirus (HPV) infections. We examined cell-mediated immune responses to HPV-16 E6 and E7 in the peripheral blood using interferon gamma (IFN-gamma) enzyme-linked immunospot assay (Cellular Technology Ltd, Cleveland, Ohio) in women with HPV-16 infection who showed clearance and compared these women to women with HPV-16 persistence. Women participating in a longitudinal study of cervical HPV were recruited once cervical HPV-16 infection was detected by polymerase chain reaction. Four groups of women were examined: (1) persistent, (2) intermittent, (3) transient, and (4) cleared. Ninety-six samples from 55 women were compared. Comparing IFN-gamma enzyme-linked immunospot to the HPV-16 clearance of 10 women with recent persistence, none had response to either E6 or E7; of 24 women with recent clearance, 14 had E6 and 8 had E7 response. Women with intermittent persistence behaved similarly to the clearance group than recent persistors: 50% were positive to E6 and 20% to E7. In summary, anti-E6 responses seem critical in the immediate control of HPV, and in some women, an immune tolerance eventually develops if HPV is not eliminated soon after infection.

The promise of combining cancer vaccine and checkpoint blockade for treating HPV-related cancer.

Human papillomavirus (HPV)-associated intraepithelial neoplasia or cancers are ideal candidates for cancer immunotherapy since HPV oncoproteins, such as E6 and E7 proteins of high-risk HPVs, could be utilized as foreign antigens. In HPV-associated cancers as well as nonviral cancers, the cancer cells may evade host immunity through the expression of immune checkpoint molecules, downregulation of human leukocyte antigen, and activation of immune regulatory cells. Because of these immune suppressive mechanisms, HPV therapeutic vaccines have shown little efficacy against HPV-associated cancers, although they have shown efficacy in treating HPV-associated intraepithelial neoplasias. Recently, checkpoint blockade emerged as a promising new treatment for solid cancers; however, these therapies have shown only modest efficacy against HPV-associated cancers. Here we reviewed literature analyzing a combinatory therapy using an immune checkpoint inhibitor and an HPV therapeutic vaccine for treating HPV-associated cancers to compensate for shortfalls of each monotherapy. Complimentary modes of T cell activation would be deployed; as vaccines would directly stimulate the T cells, while checkpoint inhibitors would do so by releasing inhibition. Some promising studies using animal models and early human clinical trials raised a possibility that such combinations may be efficacious in regressing HPV-associated cancers. Epitope spreading (the phenomenon in which non-targeted antigens become new targets of immune response) may play a critical role mechanistically. Currently ongoing studies will shed light as to whether such combination therapy would indeed be a promising new treatment paradigm. Current and future studies must also determine the adverse effect profile of such a combination treatment.

Natural history of human papillomavirus and vaccinations in men: A literature review.

BACKGROUND AND AIMS: Infection with high-risk (HR) genotypes of the human papillomavirus (HPV) is necessary for and causative of almost all cervical cancers and their precursor condition, cervical intraepithelial neoplasia. These conditions have been sharply reduced by cervical cytology screening, and a further decrease is expected because of the recent introduction of prophylactic HPV vaccinations. While significant attention has been given to gynecologic HPV disease, men can be affected by HPV-related cancers of the anus, penis, and oropharynx. This literature review aims to address disparities in HPV-related disease in men, and certain HR male subpopulations, compared with women. DISCUSSION: Overall, immunocompetent men are far less likely than women to develop anogenital HPV-related cancers, despite harboring HR HPV infections at anogenital sites. On the other hand, men who have sex with men and men living with human immunodeficiency virus infection are at considerably higher risk of HPV-related disease. Historic rates of prophylactic HPV vaccination in males have trailed those of females due to numerous multilevel factors, although, in recent years, this sex gap in vaccination coverage has been closing. In the absence of routine HPV screening in males, therapeutic vaccinations have emerged as a potential treatment modality for preinvasive neoplasia and are in various phases of clinical testing. CONCLUSION: Successful reductions in HPV disease morbidity at the population level must acknowledge and target HPV infections in men.