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The original HTML version of this Article was updated shortly after publication because the previous HTML version linked to an incorrect Transparent Peer Review file.

Background Therapeutic cancer vaccines represent an intriguing approach to cancer immunotherapy and they have been widely explored for the last decade. As opposed to standard modalities, such as surgery and chemotherapy, an effective vaccine-based immune response may provide protection against metastatic disease. Peptide based vaccines can elicit a highly targeted immune response and include a simple, fast and cost-effective production due to recent developments in solid phase peptide synthesis. Recent development within the field of COVID-19 vaccines has highlighted the use of lipid nanoparticles as an effective drug delivery system for vaccination. Incorporation of peptide antigens into engineered micro- and nanoparticles enables induction of a potent T cell response, partly attributed to prolonged and improved antigen presentation by dendritic cells after particle internalization. Peptide-based vaccines are often based on delivery of high-affinity T cell model epitopes. However, the therapeutic relevance of vaccination with low-affinity epitopes is gaining increasing support following the observation that high-affinity epitopes can promote T cell exhaustion resulting from excessive T cell receptor stimulation. Here, we characterize and evaluate a novel lipid nanoparticle (LNP) vaccine platform that is suited for delivery of both high- and low-affinity epitopes in the setting of therapeutic cancer vaccination.Methods LNPs were formulated to carry high- or low-affinity peptide epitopes from Ovalbumin (OVA) in conjunction with the TLR7 agonist 1V270. The peptides were anchored to the surface of the LNPs via a reducible DSPE-PEG2000 linker system. The therapeutic vaccine platform was evaluated in vivo both as a monotherapy and in combination with adoptive transfer of OT-I T cells in the syngeneic B16-OVA murine melanoma model.Results The LNP vaccine promotes efficient antigen-release and ensures high, continuous antigen-presentation by antigen-presenting cells. While the LNPs can be administered via multiple routes, intratumoral vaccination favors enhanced particle uptake in dendritic cells in the tumor. Formulated with either high- or low-affinity epitopes, intratumorally delivered vaccine particles promote superior tumor-infiltration of adoptively transferred T cells, which translates into potent anti-tumor efficacy in vivo. Finally, we show that vaccination with both CD8+ and CD4+ epitopes can delay tumor growth and prolong survival in an antigen-dependent manner.Conclusions This study presents a versatile and multi-purpose LNP vaccine platform that ensures effective delivery of high- and low-affinity epitopes. Intratumoral administration promotes vaccine particle uptake by intratumoral dendritic cells, which is followed by T cell infiltration and anti-tumor efficacy in vivo.

Jakob H Viuff,1 Ilse Vejborg,2 Walter Schwartz,3 Martin Bak,4 Ellen M Mikkelsen1 1Department of Clinical Epidemiology, Aarhus University Hospital,Aarhus N 8200, Denmark; 2Department of Radiology, University Hospital of Copenhagen Rigshospitalet, Copenhagen 2100, Denmark; 3Department of Radiology, Odense University Hospital, Odense C 5000, Denmark; 4Department of Pathology, Sydvestjysk Sygehus, Esbjerg 6700, DenmarkCorrespondence: Jakob H ViuffVirus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen 2100, DenmarkEmail jviuff@cancer.dkPurpose: In this cross-sectional study, we evaluated the association between morbidity and participation in the prevalence round of the Danish national mammography screening program.Patients and Methods: Morbidity was assessed by the Charlson Comorbidity Index (CCI) score (0, 1– 2, and ≥ 3) and by 19 individual diagnoses. We retrieved data on participation from The Danish Quality Database of Mammography Screening and on diagnoses from The Danish National Patient Registry. We estimated prevalence proportion ratios (PR) with 95% confidence intervals (CI).Results: In total, 519,009 (79.8%) women participated in the first national breast cancer screening round. Relative to women with a CCI score of 0, the adjusted PRs were 0.96 (95% CI: 0.95– 0.96) for a CCI score of 1– 2 and 0.80 (95% CI: 0.79– 0.81) for a CCI score of ≥ 3. Compared with no disease, the PRs for a diagnosis of the most prevalent, but less severe diseases, chronic pulmonary disease, cerebrovascular disease, diabetes I and II were 0.93 (95% CI: 0.93– 0.94), 0.96 (95% CI: 0.94– 0.96), and 0.96 (95% CI: 0.95– 0.97), respectively. Among women with low prevalent, but most severe diseases, the PRs were 0.69 (95% CI: 0.60– 0.81) for AIDS and 0.73 (95% CI: 0.70– 0.76) for metastatic solid tumor.Conclusion: Women with a high CCI score or one severe chronic condition are less likely to participate in breast cancer screening compared to women without disease. However, these women account for a small proportion of all non-participating women. Thus, it might be most beneficial to maximize breast cancer screening participation in women with less severe although more common morbidities.Keywords: mass screening, mammography, breast cancer, patient compliance, morbidity and comorbidity

Table S1. Patient and tumor characteristics for the different patient materials in the derivation set. (PDF 78 kb)

Table S2. Categorized predictors in three or four groups. (PDF 66 kb)

Number of screened women, screen-detected cancers (invasive + DCIS) interval cancers and women with false positive screens by invitations round and region in screening mammography in Denmark 2008–2015. (DOCX 15 kb)

Number of screen-detected cancers (Invasive + DCIS), screen-detected cancers (invasive only) and interval cancers (invasive only) by invitation round and region in screening mammography in Denmark 2008â 2015. (DOCX 15Â kb)

Number of screened women, recalled women, screen-detected breast cancers (incl. DCIS) and women with false positive screen by invitation round and region in screening mammography in Denmark, 2008â 2015. (DOCX 15Â kb)

Date of start and foreseen date of end of invitations rounds by region and length (in months) of invitation round. (DOCX 12Â kb)

Number of women in target population, invited women and screened women by invitation round and region in screening mammography, Denmark 2008â 2015. (DOCX 15Â kb)

Triple-negative breast cancer (TNBC) represents a heterogeneous subgroup with generally poor outcome and lack of an effective targeted therapy. Prognostic or predictive biomarkers to guide treatment decisions for this group of patients are needed. To evaluate the potential of S100A14 protein as a novel biomarker in TNBC, the protein expression of S100A14 was correlated with clinical outcomes in a Pilot Sample set and a Danish cohort of predominantly TNBC patients. Kaplan-Meier analysis identified a prognostic impact of S100A14 on disease-free survival and overall survival, showing that tumors with high S100A14 protein expression levels were significantly correlated with poor outcome in TNBC patients (p = 0.017; p = 0.038), particularly those in the basal-like subgroup (p = 0.006; p = 0.037). Importantly, TNBC patients with high S100A14 expression, but tumor-negative axillary lymph nodes (N-), had equally poor outcomes as those with tumor-positive axillary lymph nodes (N+), while TNBC/N- patients with low S100A14 expression had a significantly better disease free survival (p = 0.013). Multivariate analysis revealed that S100A14 is an independent prognostic factor for TNBC patients (p = 0.024; p = 0.05). At the cellular level, S100A14 was found to be expressed in epithelial-like, but not in mesenchymal-like, TNBC cells in vitro. S100A14 is an independent prognostic factor in TNBC and a novel potential therapeutic target in TNBC. What's new? Patients with triple-negative breast cancer (TNBC) may respond very differently to therapy, despite their apparent similarities. Thus, prognostic and predictive biomarkers are needed in order to identify subgroups that will allow treatment to be individualized. In this study, the authors found that patients with lower expression of a calcium-binding protein called S100A14 had significantly better disease-free survival. In addition to its prognostic value, S100A14 may therefore also be a potential therapeutic target.

Accumulating evidence suggests that tumor-infiltrating lymphocytes (TILs)1, particularly CD8+T cells2 , are associated with improved disease-free and overall survival in triple-negative breast cancer (TNBC3). To evaluate the functions of TILs in breast cancer, we performed gene expression analysis of TILs isolated from frozen tumor sections of TNBC patients who experienced no recurrence or progression for at least 5 years (good prognosis) for comparison with those who had progression in the first 2 years post-surgery (bad prognosis). The results showed that 398 genes showed significantly altered expression (FDR of 0.05 and fold change of 2). 319 of these genes showed higher expression in TILs from TNBC patients with good prognosis, while only 79 showed lower expression compared to those from bad prognosis patients. Among the genes exhibiting altered expression was a strong representation of those related to lymphocyte activation, pro- and anti-inflammatory responses, cell stress and apoptotic cell clearance, including IP-10, CCL5, FCRL5, PINX1 and PSR. Co-culture experiments showed that TNBC cell lines stimulated high level expression of IP-10 (258 vs 189 pg/ml p= 0.043), IFNg (170 vs 98 pg/ml, p=0.001) and IL-10 (20 vs 8 pg/ml, p=0.01) in PBMCs from healthy volunteers compared to the ER+ breast cancer cell line (MCF7). The expression of IP-10, IP-10 receptor (CXCR3) and IFNγ was evaluated in tumor tissues from patients with TNBC (N=332) and correlated to progression-free survival (PFS). IP-10 was strongly associated with PFS independently of CXCR3 expression, while neither IFNγ (p=0.43) nor CXCR3 (p=0.72) correlated to PFS. Evaluation of CD8+ T cell infiltration levels in the same patient population showed that the level of CD8+ T cell infiltration was also significantly associated with PFS (HR 0.7, 95% CI 0.5-0.98, p=0.04). Multivariate analysis of the correlation of IP-10 expression with PFS showed that IP-10 correlated with PFS (HR 0.6, 95% CI 0.38-0.94, P=0.028) independent of the level of CD8+ T cell infiltration, tumor size, lymph node status, malignancy grade or age at diagnosis. Our data, for the first time, showed that IP-10 expression is an important and robust prognostic factor in TNBC.

Udgivelsesdato: Mar-17

Udgivelsesdato: 2007-Mar-19

Udgivelsesdato: 2005-Mar-21

This paper focuses on path following algorithms for mobile robots with velocity constraints on the wheels. The path considered consists of straight lines intersected with given angles. We present a fast real-time receding horizon controller which anticipates the intersections and smoothly controls the robot through the turnings while fulfilling the velocity constraints.