Phase I trial of viral vector based personalized vaccination elicits robust neoantigen specific antitumor T cell responses

Purpose: Personalized vaccines targeting multiple neoantigens (nAgs) are a promising strategy for eliciting a diversified antitumor T cell response to overcome tumor heterogeneity. NOUS-PEV is a vector based personalized vaccine, expressing 60 nAgs and consists of priming with a non-human Great Ape Adenoviral vector (GAd20) followed by boosts with Modified Vaccinia Ankara (MVA). Here, we report data of a phase Ib trial of NOUS-PEV in combination with pembrolizumab in treatment naïve metastatic melanoma patients (NCT04990479). Experimental Design: The feasibility of this approach was demonstrated by producing, releasing and administering to six patients 11 out of 12 vaccines within 8 weeks from biopsy collection to GAd20 administration. Results: The regimen was safe, with no treatment-related serious adverse events observed and mild vaccine-related reactions. Vaccine immunogenicity was demonstrated in all evaluable patients receiving the prime/boost regimen, with detection of robust neoantigen specific immune responses to multiple neoantigens comprising both CD4 and CD8 T cells. Expansion and diversification of vaccine-induced TCR clonotypes was observed in the post-treatment biopsies of patients with clinical response providing evidence of tumor infiltration by vaccine-induced neoantigen-specific T cell. Conclusions: These findings indicate the ability of NOUS-PEV to amplify and broaden the repertoire of tumor reactive T cells to empower a diverse, potent and durable antitumor immune response. Finally, a gene signature indicative for reduced presence of activated T cells together with very poor expression of the antigen processing machinery (APM) genes has been identified in pre-treatment biopsies as a potential biomarker of resistance to the treatment

Deranged Dimensionality of Vestibular Re-Weighting in Multiple Chemical Sensitivity

Background: Multiple chemical sensitivity (MCS) is a chronic multisystem condition characterized by low levels of multiple chemical susceptibility inducing a spectrum of central nervous system symptoms, including dizziness. Thus, considering (i) the overlapping psychogenic and organic burdens shared in MCS development and in vestibular disorders; (ii) the number of previous studies describing central processing impairment related to inner ear inflow in this syndrome; and (iii) the lack of literature with respect to clinical evidence of the presentation of MCS dizziness, the purpose of the present study was to highlight the possible hidden aspects of vestibular impairment by applying the recent contribution of implemented otoneurological testing, inferential statistic and principal component (PC) analysis in 18 MCS and 20 healthy subjects (HC); Methods: Both groups filled in a dizziness and environment exposure inventory and underwent the Rod and Disc and Rod and Frame Test, video Head Impulse Test (vHIT) and Static Posturography Test (SPT) with fast Fourier Transform (FFT). Between-group analysis of variance and PC analysis implemented on otoneurological variables were performed; Results: Defective vestibular processing was identified in 18 MCS patients (11 female and 7 male; mean age 49.5 ± 9.3 years) by finding a significant increase in SPT and FFT parameters and in Visual Dependency (VD) behaviour and a decrease in vHIT scores. Component correlation analysis in MCS showed a positive correlation of FFT parameters in PC1 and SPT parameters in PC2 with a negative correlation of vHIT and VD values in PC2. HC subjects demonstrated a positive correlation of VD and SPT parameters in PC1 and FFT parameters in PC2. Conclusion: Inferential and PC analysis provided the opportunity to disclose such possible hidden phenomena to (i) support that MCS physiopathological cascades could lead to a vestibular decay; and (ii) suggest rearrangement of the dimension of the variables as an aspect of near-optimal re-weighting, possibly underpinning the dizzy symptoms complained of by MCS patients

Vector Aided Microenvironment programming (VAMP): reprogramming the TME with MVA virus expressing IL-12 for effective antitumor activity

Background Tumor microenvironment (TME) represents a critical hurdle in cancer immunotherapy, given its ability to suppress antitumor immunity. Several efforts are made to overcome this hostile TME with the development of new therapeutic strategies modifying TME to boost antitumor immunity. Among these, cytokine-based approaches have been pursued for their known immunomodulatory effects on different cell populations within the TME. IL-12 is a potent pro-inflammatory cytokine that demonstrates striking immune activation and tumor control but causes severe adverse effects when systemically administered. Thus, local administration is considered a potential strategy to achieve high cytokine concentrations at the tumor site while sparing systemic adverse effects.Methods Modified Vaccinia Ankara (MVA) vector is a potent inducer of pro-inflammatory response. Here, we cloned IL-12 into the genome of MVA for intratumoral immunotherapy, combining the immunomodulatory properties of both the vector and the cargo. The antitumor activity of MVA-IL-12 and its effect on TME reprogramming were investigated in preclinical tumor models. RNA sequencing (RNA-Seq) analysis was performed to assess changes in the TME in treated and distal tumors and the effect on the intratumoral T-cell receptor repertoire.Results Intratumoral injection of MVA-IL-12 resulted in strong antitumor activity with the complete remission of established tumors in multiple murine models, including those resistant to checkpoint inhibitors. The therapeutic activity of MVA-IL-12 was associated with very low levels of circulating cytokine. Effective TME reprogramming was demonstrated on treatment, with the reduction of immunosuppressive M2 macrophages while increasing pro-inflammatory M1, and recruitment of dendritic cells. TME switch from immunosuppressive into immunostimulatory environment allowed for CD8 T cells priming and expansion leading to tumor attack.Conclusions Intratumoral administration of MVA-IL-12 turns immunologically ‘cold’ tumors ‘hot’ and overcomes resistance to programmed cell death protein-1 blockade

Adipogenesis of skeletal muscle fibro/adipogenic progenitors is affected by the WNT5a/GSK3/β-catenin axis

Fibro/Adipogenic Progenitors (FAPs) are muscle-interstitial progenitors mediating pro-myogenic signals that are critical for muscle homeostasis and regeneration. In myopathies, the autocrine/paracrine constraints controlling FAP adipogenesis are released causing fat infiltrates. Here, by combining pharmacological screening, high-dimensional mass cytometry and in silico network modeling with the integration of single-cell/bulk RNA sequencing data, we highlighted the canonical WNT/GSK/beta-catenin signaling as a crucial pathway modulating FAP adipogenesis triggered by insulin signaling. Consistently, pharmacological blockade of GSK3, by the LY2090314 inhibitor, stabilizes beta-catenin and represses PPAR gamma expression abrogating FAP adipogenesis ex vivo while limiting fatty degeneration in vivo. Furthermore, GSK3 inhibition improves the FAP pro-myogenic role by efficiently stimulating, via follistatin secretion, muscle satellite cell (MuSC) differentiation into mature myotubes. Combining, publicly available single-cell RNAseq datasets, we characterize FAPs as the main source of WNT ligands inferring their potential in mediating autocrine/paracrine responses in the muscle niche. Lastly, we identify WNT5a, whose expression is impaired in dystrophic FAPs, as a crucial WNT ligand able to restrain the detrimental adipogenic differentiation drift of these cells through the positive modulation of the beta-catenin signaling

Assessment of network module identification across complex diseases

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