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