Psychometric Evaluation and Adaptation of the Five-Factor Sexual Satisfaction Scale (SSS-W) for Use in Men: The Sexual Satisfaction Scale (SSS).

The Sexual Satisfaction Scale for Women (SSS-W) is a psychometrically sound, widely used instrument for assessing sexual satisfaction and distress in women. Because the majority of scale items are gender nonspecific, numerous researchers have adapted this scale for use in male samples. The goal of the current study was to assess the reliability and validity of a slightly modified version of the SSS-W in a male sample (N = 268). A Confirmatory Factor Analysis of five previously established factors provided evidence for consistency of internal structure in men. The adapted scale (SSS) exhibited acceptable test-retest reliability, as well as evidence for validity based on relationships with theoretically predicted variables. Taken together, there is evidence to suggest that the SSS may be a reliable and valid psychometric tool for the measurement of sexual satisfaction and distress in both men and women.

History of Sexual Assault as a Predictor of Response to a Self-Guided Online Program for Sexual Desire and Arousal Difficulties in Women.

Sexual Interest/Arousal Disorder (distressing, long-lasting impairments in sexual desire and/or arousal) is common in women, but few have access to efficacious psychotherapies, including cognitive-behavioral therapy (CBT) and mindfulness-based therapy (MBT). eSense, an online program meant to maximize treatment access, has been shown to be a feasible, satisfactory, and potentially efficacious intervention. However, subpopulations such as sexual assault survivors may find the program less usable or efficacious. The current study compared women with and without a history of sexual assault (SA) regarding their ability to use and benefit from eSense. Forty-four women (22 with a history of SA; M age = 34.20 years) used eSense (CBT or MBT) and completed validated self-report scales of sexual function, sexual distress, treatment satisfaction, and homework compliance. A history of SA did not predict differences in attrition or changes in clinical outcomes. Exploratory analyses suggested that women with a history of SA reported slightly higher difficulty completing homework assignments, but also slightly higher treatment satisfaction. These preliminary results suggest that eSense may be usable and helpful for women with a history of SA. We discuss ways to maximize the acceptability and efficacy of online programs for women with a history of SA.

Feasibility of an Online Mindfulness-Based Intervention for Women with Sexual Interest/Arousal Disorder.

Objectives: Difficulties with sexual desire impact up to a third of women and most do not seek or receive appropriate care for these complaints, in part due to stigma, embarrassment, and limited availability of treatment. In-person mindfulness-based interventions have lasting benefits to sexual desire and sex-related distress in controlled clinical trials but are difficult to access. Online cognitive-behavioral interventions for sexual concerns have shown promising findings, but online mindfulness interventions have received little testing. The current study assessed the feasibility of an online program (called eSense-Mindfulness) adapted from an effective face-to-face intervention for women with Sexual Interest/Arousal Disorder. Methods: Thirty cisgender women (M age = 35.3) with Sexual Interest/Arousal Disorder consented and completed at least one of the eight modules of eSense-Mindfulness while providing weekly feedback regarding their experience. Feasibility was assessed via attrition rates and participant self-report regarding challenges of using the program. Limited efficacy testing was based on effect sizes for changes in sexual response and sex-related distress. Results: Participants (n = 25 who completed all testing) reported high levels of usability and ease of understanding content and reported the mindfulness exercises as well as the information on partner communication to be the most relevant. Limited efficacy testing showed large effect sizes for reductions in sex-related distress, and improvements in sexual desire, arousal, and satisfaction whereas there were smaller effect sizes for improvements in lubrication, orgasm, and vaginal pain. Conclusions: The findings suggest that efficacious face-to-face mindfulness interventions for sexual dysfunction in women show excellent evidence of feasibility when delivered online without personalized guidance.

Feasibility of a cognitive behavioral online intervention for women with Sexual Interest/Arousal Disorder.

OBJECTIVES: Difficulties with sexual desire and arousal are common in women, but most lack access to effective treatment such as cognitive-behavioral therapy (CBT). eSense is a recently created online CBT intervention for sexual difficulties with promising evidence of usability. The current study assessed the feasibility of women completing the full eSense CBT program without guidance. METHODS: Eleven women with Sexual Interest/Arousal Disorder completed eSense and provided feedback via semi-structured interviews. RESULTS: Participants reported high satisfaction with eSense's functionality, improved knowledge about sexuality, greater awareness of their thought patterns, and better perspective around their sexual difficulties. Despite some difficulty completing homework, participants exhibited statistically significant pre-post improvements in sexual desire (d = 1.04), sexual arousal (d = 1.83), sexual satisfaction (d = 1.35), and sexual distress (d = 1.79). CONCLUSION: The findings add to the growing evidence that self-guided online interventions are feasible and potentially efficacious in treating female sexual dysfunction.

Stop, Drop, and Roll! An Arthroscopic Technique for Anterior Glenoid Labrum Repair in the Lateral Decubitus Position.

This article describes a simple and reproducible arthroscopic technique for passing sutures in the shoulder glenoid labrum in the lateral decubitus position for orthopaedic surgeons. Communicating and teaching surgeons how to perform certain maneuvers with precision can be challenging at times. This technique will simplify and more efficiently communicate the advanced arthroscopic motor skill of passing sutures in the shoulder. It will facilitate skill acquisition while teaching surgeons in training how to perform the procedure.

Feasibility of a Brief Online Psychoeducational Intervention for Women With Sexual Interest/Arousal Disorder.

BACKGROUND: Low sexual desire and arousal are the most common sexual concerns in women, but most women lack access to effective treatment such as cognitive behavioral therapy. Web-based psychological interventions, which are economical, private, easily accessible, and potentially effective, may increase the reach of evidence-based treatment. AIM: To determine the feasibility of translating cognitive behavioral therapy for the most common female sexual dysfunction, Female Sexual Interest/Arousal Disorder, into an online format. The present study examined the feasibility of an introductory psychoeducational module of eSense, an online program currently being developed that is based on existing empirically supported in-person treatments, which delivers content to the user in a visually appealing and interactive manner. METHODS: Sixteen cisgender women (M age = 31.9) with female sexual arousal/interest disorder worked through a pilot module of eSense inperson at a sexual health laboratory. OUTCOMES: Qualitative semistructured interviews and online questionnaires were used to assess participants' experiences of usability of the platform, clarity/relevance of the content, satisfaction with the experience, and any changes in clinical outcomes of sexual function and distress. RESULTS: Participants reported a high level of satisfaction with the website's functionality and presentation. They reported greater knowledge, felt validated and more hopeful, and were eager to continue the remaining modules. Participants also reported notable prepost improvements in sexual desire, arousal, and satisfaction. CLINICAL IMPLICATIONS: Initial user-experience assessment may represent a method of simultaneously improving online interventions and providing therapeutic education to participants. STRENGTHS & LIMITATIONS: This is one of the first studies, to our knowledge, to test a graphics-rich, interactive online intervention for sexual difficulties that does not require direct contact with expert providers or support groups. Limitations include the high level of education, motivation, and technical fluency of the sample and the potentially confounding effect of the researcher's presence during interviews. Because this was a feasibility study, the sample size was small, and no control group was included, limiting conclusions about efficacy and generalizability. CONCLUSION: The format of eSense appears to be feasible and usable, lending support to the growing evidence that it is possible to take in-person therapeutic interventions online. Zippan N, Stephenson KR, Brotto LA, Feasibility of a Brief Online Psychoeducational Intervention for Women With Sexual Interest/Arousal Disorder. J Sex Med 2020;17:2208-2219.

Enhanced immunotherapeutic profile of oncolytic virus-based cancer vaccination using cyclophosphamide preconditioning.

Despite a sizeable body of research, the efficacy of therapeutic cancer vaccines remains limited when applied as sole agents. By using a prime:boost approach involving two viral cancer vaccines, we were able to generate large tumor-specific CD8+ T-cell responses in a murine model of disseminated pulmonary melanoma. Significant increases in the number and quality of circulating effector T-cells were documented when low-dose cyclophosphamide (CTX) was administered pre-vaccination to tumor-bearing but not tumor-free hosts. Interestingly, tumor-bearing mice receiving CTX and co-primed with a melanoma differentiation antigen together with an irrelevant control antigen exhibited significantly enhanced immunity against the tumor, but not the control antigen, in secondary lymphoid organs. This result highlighted an increased cancer-specific reactivity of vaccine-induced T-cell responses following CTX preconditioning. Additionally, an acute reduction of the frequency of peripheral regulatory T-cells (Tregs) was noticeable, particularly in the proliferating, presumably tumour-reactive, subset. Enhanced infiltration of lungs with multifunctional T-cells resulted in overt reduction in metastatic burden in mice pretreated with CTX. Despite doubling the median survival in comparison to untreated controls, most vaccinated mice ultimately succumbed to cancer progression. However, preconditioning of the virus-based vaccination with CTX resulted in a remarkable improvement of the therapeutic activity leading to complete remission in the majority of the animals. Collectively, these data reveal how CTX can potentiate specific cellular immunity in an antigen-restricted manner that is only observed in vaccinated tumor-bearing hosts while depleting replicating Tregs. A single low dose of CTX enhances antitumor immunity and the efficacy of this potent prime:boost platform by modulating the kinetics of the vaccine-specific responses. Clinical assessment of CTX combined with next-generation cancer vaccines is indicated.

Measles Vaccines Designed for Enhanced CD8+ T Cell Activation.

Priming and activation of CD8+ T cell responses is crucial to achieve anti-viral and anti-tumor immunity. Live attenuated measles vaccine strains have been used successfully for immunization for decades and are currently investigated in trials of oncolytic virotherapy. The available reverse genetics systems allow for insertion of additional genes, including heterologous antigens. Here, we designed recombinant measles vaccine vectors for priming and activation of antigen-specific CD8+ T cells. For proof-of-concept, we used cytotoxic T lymphocyte (CTL) lines specific for the melanoma-associated differentiation antigen tyrosinase-related protein-2 (TRP-2), or the model antigen chicken ovalbumin (OVA), respectively. We generated recombinant measles vaccine vectors with TRP-2 and OVA epitope cassette variants for expression of the full-length antigen or the respective immunodominant CD8+ epitope, with additional variants mediating secretion or proteasomal degradation of the epitope. We show that these recombinant measles virus vectors mediate varying levels of MHC class I (MHC-I)-restricted epitope presentation, leading to activation of cognate CTLs, as indicated by secretion of interferon-gamma (IFNγ) in vitro. Importantly, the recombinant OVA vaccines also mediate priming of naïve OT-I CD8+ T cells by dendritic cells. While all vaccine variants can prime and activate cognate T cells, IFNγ release was enhanced using a secreted epitope variant and a variant with epitope strings targeted to the proteasome. The principles presented in this study will facilitate the design of recombinant vaccines to elicit CD8+ responses against pathogens and tumor antigens.

Exploring the Role of Sexual Avoidance in Male Sexual Dysfunction.

Theoretical models of male sexual dysfunction highlight the role of sexual avoidance as a maintaining factor. However, little empirical research has directly tested the role of sexual avoidance in samples of men with sexual problems. The goals of the current study were to A) assess the association between sexual avoidance, sexual function, and subjective sexual well-being, and B) explore possible predictors of sexual avoidance, including insecure attachment, activation of negative sexual schemas, and trait experiential avoidance. One hundred and fifty eight men with self-identified impairments in sexual function (low desire, erectile function, and/or premature/delayed ejaculation) completed validated self-report measures in a secure online survey. Sexual avoidance was uniquely predicted by most aspects of sexual function, and was correlated with poorer subjective sexual well-being. Higher levels of attachment avoidance and activation of negative schemas uniquely predicted more frequent sexual avoidance. Alternatively, interaction models suggested that impaired erectile function was less likely to be associated with sexual avoidance for those with high levels of attachment anxiety and for those with high levels of trait experiential avoidance. Theoretical and practical implications are discussed.

Statistical Mediators of the Association Between Mindfulness and Sexual Experiences in Men with Impaired Sexual Function.

Mindfulness-based therapy has shown promise as a treatment for female sexual dysfunction and has the potential to be an efficacious treatment for male sexual dysfunction. However, there has been little empirical evidence regarding the mechanisms through which mindfulness may improve sexual experiences, especially for men. Recent theoretical reviews have suggested potential mediators that may explain the beneficial effects of mindfulness on symptoms of male sexual dysfunction, including reduced avoidance of sex, reduced distraction during sex, and/or reduced activation of negative sexual schemas. We attempted an initial statistical test of these factors as potential mediators of the association between trait mindfulness and multiple sexual outcomes (sexual function, sexual satisfaction, and sexual distress) using a cross-sectional correlational design. A total of 163 men with self-reported current impairments in one or more aspects of sexual function completed self-report scales using a secure online survey. Bivariate correlations indicated that mindfulness was significantly associated with sexual satisfaction, sexual distress, and premature ejaculation, but not other aspects of sexual function. Sexual avoidance statistically mediated the link between mindfulness and sexual satisfaction, both distraction and activation of negative schemas statistically mediated the link between mindfulness and premature ejaculation, and all three factors statistically mediated the link between mindfulness and sexual distress. These results generally supported previous theoretical work and have implications for future treatment outcome research.

Endogenous T cells prevent tumor immune escape following adoptive T cell therapy.

While the outcome of adoptive T cell therapy (ACT) is typically correlated with the functionality of the inoculated T cells, the role of the endogenous T cells is unknown. The success of checkpoint blockade therapy has demonstrated the potentially curative value of preexisting tumor-primed T cells in cancer treatment. Given the results from checkpoint blockade therapy, we hypothesized that endogenous T cells contribute to long-term survival following ACT. Here, we describe a therapeutic approach combining ACT with an oncolytic vaccine that allows simultaneous analysis of antitumor immunity mediated by transferred and endogenous T cells. We found that, in addition to promoting the expansion and tumor infiltration of the transferred T cells, oncolytic vaccines boosted tumor-primed host T cells. We determined that transferred T cells contributed to rapid destruction of large tumor masses while endogenous T cells concurrently prevented the emergence of antigen-loss variants. Moreover, while transferred T cells disappeared shortly after tumor regression, endogenous T cells secured long-term memory with a broad repertoire of antigen specificity. Our findings suggest that this combination strategy may exploit the full potential of ACT and tumor-primed host T cells to eliminate the primary tumor, prevent immune escape, and provide long-term protective memory.

Oncolytic Maraba virus armed with tumor antigen boosts vaccine priming and reveals diverse therapeutic response patterns when combined with checkpoint blockade in ovarian cancer.

BACKGROUND: Cancer immunotherapies are emerging as promising treatment strategies for ovarian cancer patients that experience disease relapse following first line therapy. As such, identifying strategies to bolster anti-tumor immunity and limit immune suppression, while recognizing diverse patterns of tumor response to immunotherapy is critical to selecting treatment combinations that lead to durable therapeutic benefit. METHODS: Using a pre-clinical mouse model, we evaluated a heterologous prime/boost vaccine in combination with checkpoint blockade to treat metastatic intraperitoneal ovarian cancer. Vaccine-elicited CD8+ T cell responses and changes in the tumor microenvironment following treatment were analyzed and compared to treatment outcome. Kinetics of intraperitoneal tumor growth were assessed using non-invasive magnetic resonance imaging (MRI). RESULTS: Vaccine priming followed by antigen-armed oncolytic Maraba virus boosting elicited robust tumor-specific CD8+ T cell responses that improved tumor control and led to unique immunological changes in the tumor, including a signature that correlated with improved clinical outcome of ovarian cancer patients. However, this treatment was not curative and T cells in the tumor microenvironment (TME) were functionally suppressed. Combination PD-1 blockade partially overcame the adaptive resistance in the tumor observed in response to prime/boost vaccination, restoring CD8+ T cell function in the TME and enhancing the therapeutic response. Non-invasive MRI of tumors during the course of combination treatment revealed heterogeneous radiologic response patterns following treatment, including pseudo-progression, which was associated with improved tumor control prior to relapse. CONCLUSIONS: Our findings point to a key hierarchical role for PD-1 signaling and adaptive immune resistance in the ovarian TME in determining the functional fate of tumor-specific CD8+ T cells, even in the context of robust therapy mediated anti-tumor immunity, as well as the ability of multiple unique patterns of therapeutic response to result in durable tumor control.

Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic Maraba virus currently in first-in-human trials.

Multiple immunotherapeutics have been approved for cancer patients, however advanced solid tumors are frequently refractory to treatment. We evaluated the safety and immunogenicity of a vaccination approach with multimodal oncolytic potential in non-human primates (NHP) (Macaca fascicularis). Primates received a replication-deficient adenoviral prime, boosted by the oncolytic Maraba MG1 rhabdovirus. Both vectors expressed the human MAGE-A3. No severe adverse events were observed. Boosting with MG1-MAGEA3 induced an expansion of hMAGE-A3-specific CD4+ and CD8+ T-cells with the latter peaking at remarkable levels and persisting for several months. T-cells reacting against epitopes fully conserved between simian and human MAGE-A3 were identified. Humoral immunity was demonstrated by the detection of circulating MAGE-A3 antibodies. These preclinical data establish the capacity for the Ad:MG1 vaccination to engage multiple effector immune cell populations without causing significant toxicity in outbred NHPs. Clinical investigations utilizing this program for the treatment of MAGE-A3-positive solid malignancies are underway (NCT02285816, NCT02879760).

Development and applications of oncolytic Maraba virus vaccines.

Oncolytic activity of the MG1 strain of the Maraba vesiculovirus has proven efficacy in numerous preclinical cancer models, and relied not only on a direct cytotoxicity but also on the induction of both innate and adaptive antitumor immunity. To further expand tumor-specific T-cell effector and long-lasting memory compartments, we introduced the MG1 virus in a prime-boost cancer vaccine strategy. To this aim, a replication-incompetent adenoviral [Ad] vector together with the oncolytic MG1 have each been armed with a transgene expressing a same tumor antigen. Immune priming with the Ad vaccine subsequently boosted with the MG1 vaccine mounted tumor-specific responses of remarkable magnitude, which significantly prolonged survival in various murine cancer models. Based on these promising results, we validated the safety profile of the Ad:MG1 oncolytic vaccination strategy in nonhuman primates and initiated clinical investigations in cancer patients. Two clinical trials are currently under way (NCT02285816; NCT02879760). The present review will recapitulate the discoveries that led to the development of MG1 oncolytic vaccines from bench to bedside.

Why Is Impaired Sexual Function Distressing to Men? Consequences of Impaired Male Sexual Function and Their Associations With Sexual Well-Being.

INTRODUCTION: According to theoretical models of sexual dysfunction, the complex association between male sexual function and subjective sexual well-being (ie, sexual satisfaction and distress) may be partially mediated by specific "consequences" of impaired function, but little research has assessed the frequency of specific consequences or their association with well-being. AIM: To pilot a scale assessing consequences of impaired male sexual function, and test whether specific consequences (eg, disruption of sexual activity, negative partner responses) mediated the association between sexual function and well-being. METHODS: 166 men in sexually active heterosexual relationships completed self-report measures. A majority of men self-identified as experiencing impaired sexual function in the past month. MAIN OUTCOME MEASURE: Sexual Satisfaction Scale, International Index of Erectile Function, and Measure of Sexual Consequences. RESULTS: 17 specific consequences were reported with at least moderate frequency and were rated at least somewhat distressing. A factor analysis suggested 3 distinct categories of consequences: barrier to sex and pleasure, negative partner emotional responses, and impaired partner sexual function. These factors and the overall scale exhibited acceptable internal and test-retest reliability and each was significantly associated with multiple facets of sexual function and well-being. Frequency of sexual consequences significantly mediated the association between sexual function and well-being, with the strongest and most consistent indirect effects being found for the barrier to sex and pleasure factor. CLINICAL IMPLICATIONS: Consequences of impaired sexual function on one's sexual experiences may be an important maintaining factor of sexual dysfunction and reduction in these consequences may represent a mechanism of action for psychological treatments. STRENGTH AND LIMITATIONS: Strengths included a relatively large sample with a diverse range of sexual function and well-being, as well as modern statistical analyses to assess factor structure and mediation effects. Limitations included the use of self-report scales with limited independent evidence of validity and reliability for use with male samples, as well as the cross-sectional methods that preclude strong conclusions regarding causal relationships. CONCLUSION: Sexual consequences represent potential maintaining factors of male sexual dysfunction and may represent key targets of cognitive behavioral treatments. Stephenson KR, Truong L, Shimazu L. Why is impaired sexual function distressing to men? Consequences of impaired male sexual function and their associations with sexual well-being. J Sex Med 2018;15:1336-1349.

Transforming the prostatic tumor microenvironment with oncolytic virotherapy.

Prostate cancer (PCa) was estimated to have the second highest global incidence rate for male non-skin tumors and is the fifth most deadly in men thus mandating the need for novel treatment options. MG1-Maraba is a potent and versatile oncolytic virus capable of lethally infecting a variety of prostatic tumor cell lines alongside primary PCa biopsies and exerts direct oncolytic effects against large TRAMP-C2 tumors in vivo. An oncolytic immunotherapeutic strategy utilizing a priming vaccine and intravenously administered MG1-Maraba both expressing the human six-transmembrane antigen of the prostate (STEAP) protein generated specific CD8+ T-cell responses against multiple STEAP epitopes and resulted in functional breach of tolerance. Treatment of mice with bulky TRAMP-C2 tumors using oncolytic STEAP immunotherapy induced an overt delay in tumor progression, marked intratumoral lymphocytic infiltration with an active transcriptional profile and up-regulation of MHC class I. The preclinical data generated here offers clear rationale for clinically evaluating this approach for men with advanced PCa.

Preclinical development of peptide vaccination combined with oncolytic MG1-E6E7 for HPV-associated cancer.

Human papilloma virus (HPV)-associated cancer is a significant global health burden and despite the presence of viral transforming antigens within neoplastic cells, therapeutic vaccinations are ineffective for advanced disease. HPV positive TC1 cells are susceptible to viral oncolysis by MG1-E6E7, a custom designed oncolytic Maraba virus. Epitope mapping of mice vaccinated with MG1-E6E7 enabled the rational design of synthetic long peptide (SLP) vaccines against HPV16 and HPV18 antigens. SLPs were able to induce specific CD8+ immune responses and the magnitude of these responses significantly increased when boosted by MG1-E6E7. Logically designed vaccination induced multi-functional CD8+ T cells and provided complete sterilising immunity of mice challenged with TC1 cells. In mice bearing large HPV-positive tumours, SLP vaccination combined with MG1-E6E7 was able to clear tumours in 60% of mice and these mice were completely protected against a long term aggressive re-challenge with the TC1 tumour model. Combining conventional SLPs with the multi-functional oncolytic MG1-E6E7 represents a promising approach against advanced HPV positive neoplasia.

Separate roles of IL-6 and oncostatin M in mouse macrophage polarization in vitro and in vivo.

Arginase-1 (Arg-1)-expressing M2-like macrophages are associated with Th2-skewed immune responses, allergic airway pathology, ectopic B16 melanoma cancer growth in murine models, and can be induced by Oncostatin M (OSM) transient overexpression in vivo. Here, we compare OSM to the gp130-cytokine IL-6 in mediating macrophage polarization, and find that IL-6 overexpression alone (Ad vector, AdIL-6) did not induce Arg-1 protein in mouse lungs at day 7, nor ectopic melanoma tumor growth at day 14, in contrast to overexpression of OSM (AdOSM). AdOSM elevated levels of IL-4, IL-5 and IL-13 in bronchoalveolar lavage fluid, whereas AdIL-6 did not. Bone marrow-derived macrophages respond with Arg-1 enzymatic activity to M2 stimuli (IL-4/IL-13), which was further elevated in combination with IL-6 stimulation; however, OSM or LIF had no detectable activity in vitro. Arg-1 mRNA expression induced by AdOSM was attenuated in IL-6-/- and STAT6-/- mice, suggesting requirements for both IL-6 and IL-4/IL-13 signaling in vivo. Ectopic B16 tumor burden was also reduced in IL-6-/- mice. Thus, OSM induces Arg-1+ macrophage accumulation indirectly through elevation of Th2 cytokines and IL-6 in vivo, whereas IL-6 acts directly on macrophages but requires a Th2 microenvironment, demonstrating distinct roles for OSM and IL-6 in M2 macrophage polarization.

Maraba virus-vectored cancer vaccines represent a safe and novel therapeutic option for cats.

Direct killing of malignant cells combined with induction of tumour-specific immune responses makes oncolytic vaccines attractive for cancer therapy. We previously developed a heterologous cancer immunization strategy that utilized a replication-defective adenovirus-vectored primary vaccine encoding a tumour antigen followed by boosting with a replication-competent Maraba virus expressing the same antigen. To assess the safety of oncolytic Maraba virus-based booster vaccines and inform the design of clinical trials, we conducted translational studies in cats, which have immune systems that are similar to people and spontaneously develop cancers of comparable types and etiologies. A dose of Maraba virus up to 2.5 × 1011 pfu per cat was well-tolerated, with adverse effects limited to mild, transient pyrexia, weight loss, neutropenia, lymphopenia and thrombocytopenia. Maraba viral genomes were present in some urine, stool and most plasma samples up to one week post-infection, but no infectious viruses were recovered. Post-mortem analysis showed one heart, one lung and all spleen samples contained Maraba virus genomes. No replication-competent viruses were recovered from any tissues. Post-mortem histopathological analyses revealed hyperplasia of lymphoid tissues, but no abnormal lesions were attributed to vaccination. This study demonstrated that Maraba virus-vectored cancer vaccines were well-tolerated and supports their use in treating cats.

Customized Viral Immunotherapy for HPV-Associated Cancer.

The viral-transforming proteins E6 and E7 make human papillomavirus-positive (HPV+) malignancies an attractive target for cancer immunotherapy. However, therapeutic vaccination exerts limited efficacy in the setting of advanced disease. We designed a strategy to induce substantial specific immune responses against multiple epitopes of E6 and E7 proteins based on an attenuated transgene from HPV serotypes 16 and 18 that is incorporated into MG1-Maraba virotherapy (MG1-E6E7). Mutations introduced to the transgene abrogate the ability of E6 and E7 to perturb p53 and retinoblastoma, respectively, while maintaining the ability to invoke tumor-specific, multifunctional CD8+ T-cell responses. Boosting with MG1-E6E7 significantly increased the magnitude of T-cell responses compared with mice treated with a priming vaccine alone (greater than 50 × 106 E7-specific CD8+ T cells per mouse was observed, representing a 39-fold mean increase in boosted animals). MG1-E6E7 vaccination in the HPV+ murine model TC1 clears large tumors in a CD8+-dependent manner and results in durable immunologic memory. MG1-Maraba can acutely alter the tumor microenvironment in vivo and exploit molecular hallmarks of HPV+ cancer, as demonstrated by marked infection of HPV+ patient tumor biopsies and is, therefore, ideally suited as an oncolytic treatment against clinical HPV+ cancer. This approach has the potential to be directly translatable to human clinical oncology to tackle a variety of HPV-associated neoplasms that cause significant morbidity and mortality globally. Cancer Immunol Res; 5(10); 847-59. ©2017 AACR.