Intradermal naked DNA vaccination by DNA tattooing for mounting tumor-specific immunity in stage IV melanoma patients: a phase I clinical trial.

INTRODUCTION: Naked DNA vaccination could be a powerful and safe strategy to mount antigen-specific cellular immunity. We designed a phase I clinical trial to investigate the toxicity of naked DNA vaccines encoding CD8+ T-cell epitope from tumor-associated antigen MART-1 in patients with advanced melanoma. METHODS: This dose escalating phase Ia clinical trial investigates the toxicity and immunological response upon naked DNA vaccines encoding a CD8+ T-cell epitope from the tumor-associated antigen MART-1, genetically linked to the gene encoding domain 1 of subunit-tetanus toxin fragment C in patients with advanced melanoma (inoperable stage IIIC-IV, AJCC 7th edition). The vaccine was administrated via intradermal application using a permanent make-up or tattoo device. Safety was monitored according to CTCAE v.3.0 and skin biopsies and blood samples were obtained for immunologic monitoring. RESULTS: Nine pretreated, HLA-A*0201-positive patients with advanced melanoma expressing MART-1 and MHC class I, with a good performance status, and adequate organ function, were included. With a median follow-up of 5.9 months, DNA vaccination was safe, without treatment-related deaths. Common treatment-emergent adverse events of any grade were dermatologic reactions at the vaccination site (100%) and pain (56%). One patient experienced grade 4 toxicity, most likely related to tumor progression. One patient (11%) achieved stable disease, lasting 353 days. Immune analysis showed no increase in vaccine-induced T cell response in peripheral blood of five patients, but did show a MART-1 specific CD8+ T cell response at the tattoo administration site. The maximum dose administered was 2 mg due to lack of clinical activity. CONCLUSION: We showed that the developed DNA vaccine, applied using a novel intradermal application strategy, can be administered safely. Further research with improved vaccine formats is required to show possible clinical benefit of DNA vaccination.

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma.

BACKGROUND: Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma. METHODS: In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×109 TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival. RESULTS: A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression. CONCLUSIONS: In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. (Funded by the Dutch Cancer Society and others; ClinicalTrials.gov number, NCT02278887.).

Signatures of recent activation identify a circulating T cell compartment containing tumor-specific antigen receptors with high avidity.

T cell receptor (TCR) avidity is assumed to be a major determinant of the spatiotemporal fate and protective capacity of tumor-specific T cells. However, monitoring polyclonal T cell responses with known TCR avidities in vivo over space and time remains challenging. Here, we investigated the fate and functionality of tumor neoantigen-specific T cells with TCRs of distinct avidities in a well-established, reductionist preclinical tumor model and human patients with melanoma. To this end, we used polyclonal T cell transfers with in-depth characterized TCRs together with flow cytometric phenotyping in mice inoculated with MC38 OVA tumors. Transfer of T cells from retrogenic mice harboring TCRs with high avidity resulted in best tumor protection. Unexpectedly, we found that both high- and low-avidity T cells are similarly abundant within the tumor and adopt concordant phenotypic signs of exhaustion. Outside the tumor, high-avidity TCR T cells were not generally overrepresented but, instead, selectively enriched in T cell populations with intermediate PD-1 protein expression. Single-cell sequencing of neoantigen-specific T cells from two patients with melanoma-combined with transgenic reexpression of identified TCRs by CRISPR-Cas9-mediated orthotopic TCR replacement-revealed high-functionality TCRs to be enriched in T cells with RNA signatures of recent activation. Furthermore, of 130 surface protein candidates, PD-1 surface expression was most consistently enriched in functional TCRs. Together, our findings show that tumor-reactive TCRs with high protective capacity circulating in peripheral blood are characterized by a signature of recent activation.

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells.

Autotaxin (ATX; ENPP2) produces lysophosphatidic acid (LPA) that regulates multiple biological functions via cognate G protein-coupled receptors LPAR1-6. ATX/LPA promotes tumor cell migration and metastasis via LPAR1 and T cell motility via LPAR2, yet its actions in the tumor immune microenvironment remain unclear. Here, we show that ATX secreted by melanoma cells is chemorepulsive for tumor-infiltrating lymphocytes (TILs) and circulating CD8+ T cells ex vivo, with ATX functioning as an LPA-producing chaperone. Mechanistically, T cell repulsion predominantly involves Gα12/13-coupled LPAR6. Upon anti-cancer vaccination of tumor-bearing mice, ATX does not affect the induction of systemic T cell responses but, importantly, suppresses tumor infiltration of cytotoxic CD8+ T cells and thereby impairs tumor regression. Moreover, single-cell data from melanoma tumors are consistent with intratumoral ATX acting as a T cell repellent. These findings highlight an unexpected role for the pro-metastatic ATX-LPAR axis in suppressing CD8+ T cell infiltration to impede anti-tumor immunity, suggesting new therapeutic opportunities.

Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response.

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment of melanoma patients. Based on early studies addressing the mechanism of action, it was assumed that PD-1 blockade mostly influences T cell responses at the tumor site. However, recent work has demonstrated that PD-1 blockade can influence the T cell compartment in peripheral blood. If the activation of circulating, tumor-reactive T cells would form an important mechanism of action of PD-1 blockade, it may be predicted that such blockade would alter either the frequency and/or the breadth of the tumor-reactive CD8 T cell response. To address this question, we analyzed CD8 T cell responses toward 71 melanoma-associated epitopes in peripheral blood of 24 melanoma patients. We show that both the frequency and the breadth of the circulating melanoma-reactive CD8 T cell response was unaltered upon PD-1 blockade. In contrast, a broadening of the circulating melanoma-reactive CD8 T cell response was observed upon CTLA-4 blockade, in concordance with our prior data. Based on these results, we conclude that PD-1 and CTLA-4 blockade have distinct mechanisms of action. In addition, the data provide an argument in favor of the hypothesis that anti-PD-1 therapy may primarily act at the tumor site.

HPV-16 E6/E7 DNA tattoo vaccination using genetically optimized vaccines elicit clinical and immunological responses in patients with usual vulvar intraepithelial neoplasia (uVIN): a phase I/II clinical trial.

BACKGROUND: Usual vulvar intraepithelial neoplasia (uVIN) is a premalignancy caused by persistent infection with high-risk types of human papillomavirus (HPV), mainly type 16. Even though different treatment modalities are available (eg, surgical excision, laser evaporation or topical application of imiquimod), these treatments can be mutilating, patients often have recurrences and 2%-8% of patients develop vulvar carcinoma. Therefore, immunotherapeutic strategies targeting the pivotal oncogenic HPV proteins E6 and E7 are being explored to repress carcinogenesis. METHOD: In this phase I/II clinical trial, 14 patients with HPV16+ uVIN were treated with a genetically enhanced DNA vaccine targeting E6 and E7. Safety, clinical responses and immunogenicity were assessed. Patients received four intradermal HPV-16 E6/E7 DNA tattoo vaccinations, with a 2-week interval, alternating between both upper legs. Biopsies of the uVIN lesions were taken at screening and +3 months after last vaccination. Digital photography of the vulva was performed at every check-up until 12 months of follow-up for measurement of the lesions. HPV16-specific T-cell responses were measured in blood over time in ex vivo reactivity assays. RESULTS: Vaccinations were well tolerated, although one grade 3 suspected unexpected serious adverse reaction was observed. Clinical responses were observed in 6/14 (43%) patients, with 2 complete responses and 4 partial responses (PR). 5/14 patients showed HPV-specific T-cell responses in blood, measured in ex vivo reactivity assays. Notably, all five patients with HPV-specific T-cell responses had a clinical response. CONCLUSIONS: Our results indicate that HPV-16 E6/E7 DNA tattoo vaccination is a biologically active and safe treatment strategy in patients with uVIN, and suggest that T-cell reactivity against the HPV oncogenes is associated with clinical benefit. TRIAL REGISTRATION NUMBER: NTR4607.

Associations between job demands, job resources and patient-related burnout among physicians: results from a multicentre observational study.

OBJECTIVES: To investigate associations of job demands and resources with patient-related burnout among physicians. DESIGN: Multicentre observational study. SETTING: Fifty medical departments at 14 (academic and non-academic) hospitals in the Netherlands. PARTICIPANTS: Four hundred sixty-five physicians (71.6% response rate), comprising 385 (82.8%) medical specialists and 80 (17.2%) residents. MAIN OUTCOME MEASURES: Job demands (workload and bureaucratic demands), job resources (participation in decision making, development opportunities, leader's inspiration, relationships with colleagues and patients)-measured with the validated Questionnaire of Experience and Evaluation of Work and Physician Worklife Survey-and patient-related burnout, measured using the validated Copenhagen Burnout Inventory. RESULTS: Patient-related burnout was positively associated with workload (b=0.36; 95% CI, 0.25 to 0.48; p<0.001) and negatively associated with development opportunities (b=-0.18; 95% CI, -0.27 to -0.08; p<0.001) and relationships with patients (b=-0.12; 95% CI, -0.22 to -0.03; p=0.01). Relationships with patients moderated the association between bureaucratic demands and patient-related burnout (b=-0.15; 95% CI, -0.27 to -0.04; p=0.01). CONCLUSIONS: Physicians with high workloads and few development opportunities reported higher levels of patient-related burnout. Those with positive patient relationships were less likely to experience patient-related burnout, even in the presence of excessive bureaucracy. Therefore, positive physician-patient relationships may be supported to reduce the likelihood of physicians' patient-related burnout. However, the specific support needed to effectively reduce patient-related burnout may vary per healthcare context and thus requires intensified research across healthcare systems and settings.

Tumor infiltrating lymphocytes (TIL) therapy in metastatic melanoma: boosting of neoantigen-specific T cell reactivity and long-term follow-up.

Treatment of metastatic melanoma with autologous tumor infiltrating lymphocytes (TILs) is currently applied in several centers. Robust and remarkably consistent overall response rates, of around 50% of treated patients, have been observed across hospitals, including a substantial fraction of durable, complete responses. PURPOSE: Execute a phase I/II feasibility study with TIL therapy in metastatic melanoma at the Netherlands Cancer Institute, with the goal to assess feasibility and potential value of a randomized phase III trial. EXPERIMENTAL: Ten patients were treated with TIL therapy. Infusion products and peripheral blood samples were phenotypically characterized and neoantigen reactivity was assessed. Here, we present long-term clinical outcome and translational data on neoantigen reactivity of the T cell products. RESULTS: Five out of 10 patients, who were all anti-PD-1 naïve at time of treatment, showed an objective clinical response, including two patients with a complete response that are both ongoing for more than 7 years. Immune monitoring demonstrated that neoantigen-specific T cells were detectable in TIL infusion products from three out of three patients analyzed. For six out of the nine neoantigen-specific T cell responses detected in these TIL products, T cell response magnitude increased significantly in the peripheral blood compartment after therapy, and neoantigen-specific T cells were detectable for up to 3 years after TIL infusion. CONCLUSION: The clinical results from this study confirm the robustness of TIL therapy in metastatic melanoma and the potential role of neoantigen-specific T cell reactivity. In addition, the data from this study supported the rationale to initiate an ongoing multicenter phase III TIL trial.

Evaluating different adoption scenarios for TIL-therapy and the influence on its (early) cost-effectiveness.

BACKGROUND: Treatment with tumor-Infiltrating Lymphocytes (TIL) is an innovative therapy for advanced melanoma with promising clinical phase I/II study results and likely beneficial cost-effectiveness. As a randomized controlled trial on the effectiveness of TIL therapy in advanced melanoma compared to ipilimumab is still ongoing, adoption of TIL therapy by the field is confronted with uncertainty. To deal with this, scenario drafting can be used to identify potential barriers and enables the subsequent anticipation on these barriers. This study aims to inform adoption decisions of TIL by evaluating various scenarios and evaluate their effect on the cost-effectiveness. METHODS: First, 14 adoption scenarios for TIL-therapy were drafted using a Delphi approach with a group of involved experts. Second, the likelihood of the scenarios taking place within 5 years was surveyed among international experts using a web-based questionnaire. Third, based on the questionnaire results and recent literature, scenarios were labeled as being either "likely" or "-unlikely". Finally, the cost-effectiveness of TIL treatment involving the "likely" scored scenarios was calculated. RESULTS: Twenty-nine experts from 12 countries completed the questionnaire. The scenarios showed an average likelihood ranging from 29 to 58%, indicating that future developments of TIL-therapy were surrounded with quite some uncertainty. Eight of the 14 scenarios were labeled as "likely". The net monetary benefit per patient is presented as a measure of cost-effectiveness, where a positive value means that a scenario is cost-effective. For six of these scenarios the cost-effectiveness was calculated: "Commercialization of TIL production" (the price was assumed to be 3 times the manufacturing costs in the academic setting) (-€51,550), "Pharmaceutical companies lowering the prices of ipilimumab" (€11,420), "Using TIL-therapy combined with ipilimumab" (-€10,840), "Automatic TIL production" (€22,670), "TIL more effective" (€23,270), "Less Interleukin-2" (€20,370). CONCLUSIONS: Incorporating possible future developments, TIL-therapy was calculated to be cost-effective compared to ipilimumab in the majority of "likely" scenarios. These scenarios could function as facilitators for adoption. Contrary, TIL therapy was expected to not be cost-effective when sold at commercial prices, or when combined with ipilimumab. These scenarios should be considered in the adoption decision as these may act as crucial barriers.

The Outcome of Ex Vivo TIL Expansion Is Highly Influenced by Spatial Heterogeneity of the Tumor T-Cell Repertoire and Differences in Intrinsic In Vitro Growth Capacity between T-Cell Clones.

PURPOSE: During our efforts to develop tumor-infiltrating lymphocyte (TIL) therapy to counter the devastating recurrence rate in patients with primary resectable pancreatic ductal adenocarcinoma (PDA), we found that PDA TILs can readily be expanded in vitro and that the majority of resulting TIL cultures show reactivity against the autologous tumor. However, the fraction of tumor-reactive T cells is low. We investigated to which extent this was related to the in vitro expansion. EXPERIMENTAL DESIGN: We compared the clonal composition of TIL preparations before and after in vitro expansion using T-cell receptor (TCR) deep sequencing. Our findings for PDA were benchmarked to experiments with melanoma TILs. RESULTS: We found that the TIL TCR repertoire changes dramatically during in vitro expansion, leading to loss of tumor- dominant T-cell clones and overgrowth by newly emerging T-cell clones that are barely detectable in the tumor. These changes are primarily driven by differences in the intrinsic in vitro expansion capacity of T-cell clones. Single-cell experiments showed an association between poor proliferative capacity and expression of markers related to antigen experience and dysfunction. Furthermore, we found that spatial heterogeneity of the TIL repertoire resulted in TCR repertoires that are greatly divergent between TIL cultures derived from distant tumor samples of the same patient. CONCLUSIONS: Culture-induced changes in clonal composition are likely to affect tumor reactivity of TIL preparations. TCR deep sequencing provides important insights into the factors that govern the outcome of in vitro TIL expansion and thereby a path toward optimization of the production of TIL preparations with high therapeutic efficacy.See related commentary by Lozano-Rabella and Gros, p. 4177.

Transgenerational transfer of gene-modified T cells.

Tumor immunotherapy using gene-modified T cells has already met with considerable success in the treatment of metastatic melanoma and B cell lymphoma. With improving patient prognoses, new questions arise. In particular, the long-term consequences of treatment among individuals of childbearing age could now be considered. Former patients can carry a cohort of transgenic memory T cells long after treatment has ceased and the effector T cell population has contracted. When patients become parents well after treatment is completed, expectant mothers may still pass transgenic T cells to their unborn children. Consequences should be more measurable if the mother also breastfeeds the baby. Maternal T cells may shape immune responses in the child, can tolerize the child to maternal antigens, and might cause either beneficial or adverse effects in the offspring. The hypothesis put forth is that transgenic T cells transferred from mother to child during and after pregnancy might have consequences that have not been adequately considered to date. Depending on the targeted antigen and the MHC eventually required to present it, such transfer may be beneficial, uneventful or even damaging. Such potential consequences are addressed in this paper. The transgenic T cells might form a pocket of memory T cells in secondary lymphoid organs of the child, expand upon antigen stimulation, and react. However, simple measures might be devised to avoid any reason for concern. These considerations provide ample incentive to probe transgenerational transfer of transgenic T cells.

Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and a target for cancer immunotherapy.

Cancer cells can evade immune surveillance through the expression of inhibitory ligands that bind their cognate receptors on immune effector cells. Expression of programmed death ligand 1 in tumor microenvironments is a major immune checkpoint for tumor-specific T cell responses as it binds to programmed cell death protein-1 on activated and dysfunctional T cells1. The activity of myeloid cells such as macrophages and neutrophils is likewise regulated by a balance between stimulatory and inhibitory signals. In particular, cell surface expression of the CD47 protein creates a 'don't eat me' signal on tumor cells by binding to SIRPα expressed on myeloid cells2-5. Using a haploid genetic screen, we here identify glutaminyl-peptide cyclotransferase-like protein (QPCTL) as a major component of the CD47-SIRPα checkpoint. Biochemical analysis demonstrates that QPCTL is critical for pyroglutamate formation on CD47 at the SIRPα binding site shortly after biosynthesis. Genetic and pharmacological interference with QPCTL activity enhances antibody-dependent cellular phagocytosis and cellular cytotoxicity of tumor cells. Furthermore, interference with QPCTL expression leads to a major increase in neutrophil-mediated killing of tumor cells in vivo. These data identify QPCTL as a novel target to interfere with the CD47 pathway and thereby augment antibody therapy of cancer.

Small-scale GMP production of plasmid DNA using a simplified and fully disposable production method.

In the past years, the demand for small batches of clinical grade plasmid DNA has been growing. For that purpose, we designed and qualified a scaled-down Good Manufacturing Practices (GMP) production method, able to produce small batches (1-4 mg) of plasmid. The developed method does not require any complex production equipment and utilizes only disposable production materials, which makes it easy to implement and simplifies line-clearance. We have successfully used this method to produce several small batches of two different plasmids. The produced plasmids, both formulated in an Electroporation Buffer, are mixed and filled into small, single-use, aliquots. Quality control confirmed the robustness of the developed method and a stability study showed that the final formulation is stable for at least two years. The final patient formulation will be subsequently used in a phase I/II clinical trial in which retina cells of patients with Age Related Macular Degeneration, are transfected. The presented production method can be generically used for other plasmid constructs and final formulation designs.

Faculty's work engagement in patient care: impact on job crafting of the teacher tasks.

BACKGROUND: High levels of work engagement protect against burnout. This can be supported through the work environment and by faculty themselves when they try to improve their work environment. As a result, they can become more engaged and better performers. We studied the relationship between adaptations by physicians to improve their teaching work environment, known as job crafting, and their energy levels, or work engagement, in their work as care provider and teacher. Job crafting encompasses seeking social (i) and structural (ii) resources and challenges (iii) and avoiding hindrances (iv). METHODS: We established a cross-sectional questionnaire survey in a cohort of physicians participating in classroom and clinical teaching. Job crafting and work engagement were measured separately for physicians' clinical and teaching activities. We analyzed our data using structural equation modelling controlling for age, gender, perceived levels of autonomy and participation in decision making. RESULTS: 383 physicians were included. Physicians' work engagement for patient care was negatively associated with two job crafting behaviors in the teaching roles: seeking structural resources (classroom teaching: ß = - 0.220 [95% CI: -0.319 to - 0.129]; clinical teaching: ß = - 0.148 [95% CI: -0.255 to - 0.042]); seeking challenges (classroom teaching: ß = - 0.215 [95% CI: -0.317 to - 0.113]; clinical teaching:, ß = - 0.190 [95% CI: -0.319 to - 0.061]). Seeking social resources and avoiding hindrances were unaffected by physicians' work engagement for patient care. CONCLUSIONS: High engagement for teaching leads to job crafting in teaching. High engagement for patient care does not lead to job crafting in teaching.

Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option.

The treatment of metastatic melanoma patients with autologous tumor-infiltrating lymphocytes (TIL) shows robust, reproducible, clinical responses in clinical trials executed in several specialized centers over the world. Even in the era of targeted therapy and immune checkpoint inhibition, TIL therapy can be an additional and clinically relevant treatment line. This review provides an overview of the clinical experiences with TIL therapy thus far, including lymphodepleting regimens, the use of interleukin-2 (IL-2) and the associated toxicity. Characteristics of the TIL products and the antigen recognition pattern will be discussed, as well as the current and upcoming production strategies, including the selective expansion of specific fractions from the cell product. In addition, the future potential of TIL therapy in melanoma and other tumor types will be covered.

Treatment With Tumor-infiltrating Lymphocytes in Advanced Melanoma: Evaluation of Early Clinical Implementation of an Advanced Therapy Medicinal Product.

Tumor-infiltrating lymphocytes (TIL)-therapy in advanced melanoma is an advanced therapy medicinal product (ATMP) which, despite promising results, has not been implemented widely. In a European setting, TIL-therapy has been in use since 2011 and is currently being evaluated in a randomized controlled trial. As clinical implementation of ATMPs is challenging, this study aims to evaluate early application of TIL-therapy, through the application of a constructive technology assessment (CTA). First the literature on ATMP barriers and facilitators in clinical translation was summarized. Subsequently, application of TIL-therapy was evaluated through semistructured interviews with 26 stakeholders according to 6 CTA domains: clinical, economic, patient-related, organizational, technical, and future. In addition, treatment costs were estimated. A number of barriers to clinical translation were identified in the literature, including: inadequate financial support, lack of regulatory knowledge, risks in using live tissues, and the complex path to market approval. Innovative reimbursement procedures could particularly facilitate translation. The CTA survey of TIL-therapy acknowledged these barriers, and revealed the following facilitators: the expected effectiveness resulting in institutional support for an internal pilot, the results of which led to the inclusion of TIL-therapy in a national coverage with evidence development program, the availability of an in-house pharmacist, quality assurance expertise and a TIL-skilled technician. Institutional and national implementation of TIL-therapy remains complex. The promising clinical effectiveness is expected to facilitate the adoption of TIL-therapy, especially when validated through a randomized controlled trial. Innovative and conditional reimbursement procedures, together with the organization of knowledge transfer, could support and improve clinical translation of TIL and ATMPs.

Work engagement in health professions education.

Work engagement deserves more attention in health professions education because of its positive relations with personal well-being and performance at work. For health professions education, these outcomes have been studied on various levels. Consider engaged clinical teachers, who are seen as better clinical teachers; consider engaged residents, who report committing fewer medical errors than less engaged peers. Many topics in health professions education can benefit from explicitly including work engagement as an intended outcome such as faculty development programs, feedback provision and teacher recognition. In addition, interventions aimed at strengthening resources could provide teachers with a solid foundation for well-being and performance in all their work roles. Work engagement is conceptually linked to burnout. An important model that underlies both burnout and work engagement literature is the job demands-resources (JD-R) model. This model can be used to describe relationships between work characteristics, personal characteristics and well-being and performance at work. We explain how using this model helps identifying aspects of teaching that foster well-being and how it paves the way for interventions which aim to increase teacher's well-being and performance.

HPV16 E7 DNA tattooing: safety, immunogenicity, and clinical response in patients with HPV-positive vulvar intraepithelial neoplasia.

BACKGROUND: Usual type vulvar intraepithelial neoplasia (uVIN) is caused by HPV, predominantly type 16. Several forms of HPV immunotherapy have been studied, however, clinical results could be improved. A novel intradermal administration route, termed DNA tattooing, is superior in animal models, and was tested for the first time in humans with a HPV16 E7 DNA vaccine (TTFC-E7SH). METHODS: The trial was designed to test safety, immunogenicity, and clinical response of TTFC-E7SH in twelve HPV16+ uVIN patients. Patients received six vaccinations via DNA tattooing. The first six patients received 0.2 mg TTFC-E7SH and the next six 2 mg TTFC-E7SH. Vaccine-specific T-cell immunity was evaluated by IFNγ-ELISPOT and multiparametric flow cytometry. RESULTS: Only grade I-II adverse events were observed upon TTFC-E7SH vaccination. The ELISPOT analysis showed in 4/12 patients a response to the peptide pool containing shuffled E7 peptides. Multiparametric flow cytometry showed low CD4+ and/or CD8+ T-cell responses as measured by increased expression of PD-1 (4/12 in both), CTLA-4 (2/12 and 3/12), CD107a (5/12 and 4/12), or the production of IFNγ (2/12 and 1/12), IL-2 (3/12 and 4/12), TNFα (2/12 and 1/12), and MIP1ß (3/12 and 6/12). At 3 months follow-up, no clinical response was observed in any of the twelve vaccinated patients. CONCLUSION: DNA tattoo vaccination was shown to be safe. A low vaccine-induced immune response and no clinical response were observed in uVIN patients after TTFC-E7SH DNA tattoo vaccination. Therefore, a new phase I/II trial with an improved DNA vaccine format is currently in development for patients with uVIN.

Is being a medical educator a lonely business? The essence of social support.

CONTEXT: Social support helps prevent burnout and promotes its positive opposite, work engagement. With higher work engagement performance increases. The context-specific aspects of social support for medical educators, in their educator role, are unknown. To help facilitate social support our study describes the essential elements of social support and their meaning for medical educators. METHODS: We held interviews with medical educators purposefully sampled for diverse backgrounds and working circumstances and who spent a considerable amount of time on education. Both clinicians and basic scientists participated. The Pictor technique guided the interviews. Participants were invited to talk about the breadth of social support and elaborate on meaningful experiences. Template analysis was used for a descriptive phenomenological approach. RESULTS: Thirteen medical educators were interviewed. We identified four themes: (i) sources of support and their intent (e.g. a superior with the intent to stimulate personal growth); (ii) the materialisation of support (e.g. sought or offered); (iii) its manifestation (e.g. the act of providing protected time); and (iv) the overarching effect of social support, both in terms of practical effects and the meaning of support. We identified three sorts of meanings of social support for educators. Receiving support could lead to (i) feeling reassured and confident; (ii) feeling encouraged and determined and (iii) a sense of relatedness and acknowledgement of the educator role. CONCLUSION: Support for education comes from a wide range of sources because it is both sought and offered beyond the boundaries of the educational role. The resulting differences in support provided necessitate that educational leaders and policymakers consider the sources available to each educator, connecting educators where necessary. When facilitating or designing social support it is important that the need to feel reassured, encouraged or related is met.