DNA Vaccines Targeting Novel Cancer-Associated Antigens Frequently Expressed in Head and Neck Cancer Enhance the Efficacy of Checkpoint Inhibitor.

HPV-independent head and neck squamous cell carcinoma (HNSCC) is a common cancer globally. The overall response rate to anti-PD1 checkpoint inhibitors (CPIs) in HNSCC is ~16%. One major factor influencing the effectiveness of CPI is the level of tumor infiltrating T cells (TILs). Converting TILlow tumors to TILhigh tumors is thus critical to improve clinical outcome. Here we describe a novel DNA vaccines to facilitate the T-cell infiltration and control tumor growth. We evaluated the expression of target antigens and their respective immunogenicity in HNSCC patients. The efficacy of DNA vaccines targeting two novel antigens were evaluated with or without CPI using a syngeneic model. Most HNSCC patients (43/44) co-expressed MAGED4B and FJX1 and their respective tetramer-specific T cells were in the range of 0.06-0.12%. In a preclinical model, antigen-specific T cells were induced by DNA vaccines and increased T cell infiltration into the tumor, but not MDSC or regulatory T cells. The vaccines inhibited tumor growth and improved the outcome alone and upon combination with anti-PD1 and resulted in tumor clearance in approximately 75% of mice. Pre-existence of MAGED4B and FJX1-reactive T cells in HNSCC patients suggests that these widely expressed antigens are highly immunogenic and could be further expanded by vaccination. The DNA vaccines targeting these antigens induced robust T cell responses and with the anti-PD1 antibody conferring excellent tumor control. This opens up an opportunity for combination immunotherapy that might benefit a wider population of HNSCC patients in an antigen-specific manner.

Correction to: Characterising a human endogenous retrovirus(HERV)-derived tumour-associated antigen: enriched RNA-Seq analysis of HERV-K(HML-2) in mantle cell lymphoma cell lines.

An amendment to this paper has been published and can be accessed via the original article.

Characterising a human endogenous retrovirus(HERV)-derived tumour-associated antigen: enriched RNA-Seq analysis of HERV-K(HML-2) in mantle cell lymphoma cell lines.

BACKGROUND: The cell-surface attachment protein (Env) of the HERV-K(HML-2) lineage of endogenous retroviruses is a potentially attractive tumour-associated antigen for anti-cancer immunotherapy. The human genome contains around 100 integrated copies (called proviruses or loci) of the HERV-K(HML-2) virus and we argue that it is important for therapy development to know which and how many of these contribute to protein expression, and how this varies across tissues. We measured relative provirus expression in HERV-K(HML-2), using enriched RNA-Seq analysis with both short- and long-read sequencing, in three Mantle Cell Lymphoma cell lines (JVM2, Granta519 and REC1). We also confirmed expression of the Env protein in two of our cell lines using Western blotting, and analysed provirus expression data from all other relevant published studies. RESULTS: Firstly, in both our and other reanalysed studies, approximately 10% of the transcripts mapping to HERV-K(HML-2) came from Env-encoding proviruses. Secondly, in one cell line the majority of the protein expression appears to come from one provirus (12q14.1). Thirdly, we find a strong tissue-specific pattern of provirus expression. CONCLUSIONS: A possible dependency of Env expression on a single provirus, combined with the earlier observation that this provirus is not present in all individuals and a general pattern of tissue-specific expression among proviruses, has serious implications for future HERV-K(HML-2)-targeted immunotherapy. Further research into HERV-K(HML-2) as a possible tumour-associated antigen in blood cancers requires a more targeted, proteome-based, screening protocol that will consider these polymorphisms within HERV-K(HML-2). We include a plan (and necessary alignments) for such work.

Muscle activation and local muscular fatigue during a 12-minute rotational bridge.

Due to anecdotal reports of back pain during a 12-minute rotational bridge test by uniformed services, the level of fatigue leading to possible back pain and or injury was investigated. We hypothesised a high level of fatigue due to diminishing core muscle activation. Nineteen highly trained uniformed service members were measured by surface electromyography of the rectus abdominis, external oblique, internal oblique, lumbar erector spinae, thoracic erector spinae and latissimus dorsi. Average rectified electromyography amplitude (AEMG) and median power frequency were analysed to determine activation and fatigue. All AEMG were normalised and expressed as a percentage of maximal voluntary isometric contraction (%MVIC). Significant increases in AEMG were observed over the test duration for the rectus abdominis (+19.5%MVIC), external oblique (+18.0%MVIC) and internal oblique (+23.2%MVIC) during the prone position; and for the external oblique (+21.8%MVIC) when bracing on the measurement side (all, p < 0.05). No significant changes in median power frequency were observed (all, p > 0.05). Combining prone and side bridge positions is a reasonable measure of anterior, posterior and lateral trunk musculature. Muscular fatigue remained low throughout making this a safe assessment in trained individuals.

Targeting Head and Neck Cancer by Vaccination.

Head and neck cancer (HNC) is a heterogeneous group of squamous cell cancers that affect the oral cavity, pharynx, and larynx. Worldwide, it is the sixth most common cancer but in parts of Southern and South-East Asia, HNC is one of the most common cancers. A significant proportion of HNC is driven by human papillomavirus (HPV) infection, whereas HPV-independent HNC is associated with alcohol, smoking, and smokeless tobacco consumption. Here, we review the past and present experience of targeting HNC with vaccination focusing on HPV-derived antigens as well as non-viral antigens for HPV-negative HNC. Novel therapeutic approaches for HNC will focus not only on effective vaccine platforms but will also target the stroma-rich immunosuppressive microenvironment found in those tumours.

Electromyographic analysis of muscle activation during pull-up variations.

This study sought to identify any differences in peak muscle activation (EMGPEAK) or average rectified variable muscle activation (EMGARV) during supinated grip, pronated grip, neutral grip and rope pull-up exercises. Nineteen strength trained males (24.9±5y; 1.78±0.74m; 81.3±11.3kg; 22.7±2.5kgm-2) volunteered to participate in the study. Surface electromyography (EMG) was collected from eight shoulder-arm-forearm complex muscles. All muscle activation was expressed as a percentage of maximum voluntary isometric contraction (%MVIC). Over a full repetition, the pronated grip resulted in significantly greater EMGPEAK (60.1±22.5vs. 37.1±13.1%MVIC; P=0.004; Effect Size [ES; Cohen's d]=1.19) and EMGARV (48.0±21.2vs. 27.4±10.7%MVIC; P=0.001; ES=1.29) of the middle trapezius when compared to the neutral grip pull-up. The concentric phases of each pull-up variation resulted in significantly greater EMGARV of the brachioradialis, biceps brachii, and pectoralis major in comparison to the eccentric phases (P=<0.01). Results indicate that EMGPEAK and EMGARV of the shoulder-arm-forearm complex during complete repetitions of pull-up variants are similar despite varying hand orientations; however, differences exist between concentric and eccentric phases of each pull-up.