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We previously demonstrated that patients with metastatic unresectable stage IIIb–IV melanoma receiving cetirizine (a second-generation H1 antagonist antihistamine) premedication with immunotherapy had better outcomes than those not receiving cetirizine. In this retrospective study, we searched for a gene signature potentially predictive of the response to the addition of cetirizine to checkpoint inhibition (nivolumab or pembrolizumab with or without previous ipilimumab). Transcriptomic analysis showed that inducible T cell costimulator ligand (ICOSLG) expression directly correlated with the disease control rate (DCR) when detected with a loading value > 0.3. A multivariable logistic regression model showed a positive association between the DCR and ICOSLG expression for progression-free survival and overall survival. ICOSLG expression was associated with CD64, a specific marker of M1 macrophages, at baseline in the patient samples who received cetirizine concomitantly with checkpoint inhibitors, but this association was not present in subjects who had not received cetirizine. In conclusion, our results show that the clinical advantage of concomitant treatment with cetirizine during checkpoint inhibition in patients with malignant melanoma is associated with high ICOSLG expression, which could predict the response to immune checkpoint inhibitor blockade. [ABSTRACT FROM AUTHOR]

Summary: We demonstrated that dose‐densified and dose‐intensified ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine; ABVDDD‐DI) was safe and effective. Here, we present a post hoc long‐term analysis of the 82 patients enrolled in the original study. The median observation time was 175 months (IQR 159–197). At 15 years, progression‐free and overall survival rates were 81.2% (95% CI, 69.9%–88.7%) and 92.7% (95% CI, 82.6%–97.0%), respectively. Four patients with multiple cardiovascular risk factors experienced delayed G3 cardiac events. The cumulative incidence of second malignancies at 20 years was 6.1%. Fertility and childbearing potential were unaffected. Data support an ongoing benefit for ABVDDD‐DI without uneven late toxicities. [ABSTRACT FROM AUTHOR]

Resistance biomarkers are needed to identify patients with advanced melanoma obtaining a response to ICI treatment and developing resistance later. We searched a combination of molecular signatures of response to ICIs in patients with metastatic melanoma. In a retrospective study on patients with metastatic melanoma treated with an anti-PD-1 agent carried out at Istituto Nazionale Tumori—IRCCS—Fondazione "G. Pascale", Naples, Italy. We integrated a whole proteome profiling of metastatic tissue with targeted transcriptomics. To assess the prognosis of patients according to groups of low and high risk, we used PFS and OS as outcomes. To identify the proteins and mRNAs gene signatures associated with the patient's response groups, the discriminant analysis for sparse data performed via partial least squares procedure was performed. Tissue samples from 22 patients were analyzed. A combined protein and gene signature associated with poorer response to ICI immunotherapy in terms of PFS and OS was identified. The PFS and OS Kaplan–Meier curves were significantly better for patients with high expression of the protein signature compared to patients with low expression of the protein signature and who were high-risk (Protein: HR = 0.023, 95% CI: 0.003–0.213; p < 0.0001. Gene: HR = 0.053, 95% CI: 0.011–0.260; p < 0.0001). The Kaplan–Meier curves showed that patients with low-risk gene signatures had better PFS (HR = 0 0.221, 95% CI: 0.071–0.68; p = 0.007) and OS (HR = 0.186, 95% CI: 0.05–0.695; p = 0.005). The proteomic and transcriptomic combined analysis was significantly associated with the outcomes of the anti-PD-1 treatment with a better predictive value compared to a single signature. All the patients with low expression of protein and gene signatures had progression within 6 months of treatment (median PFS = 3 months, 95% CI: 2–3), with a significant difference vs. the low-risk group (median PFS = not reached; p < 0.0001), and significantly poorer survival (OS = 9 months, 95% CI: 5–9) compared to patients with high expression of protein and gene signatures (median OS = not reached; p < 0.0001). We propose a combined proteomic and transcriptomic signature, including genes involved in pro-tumorigenic pathways, thereby identifying patients with reduced probability of response to immunotherapy with ICIs for metastatic melanoma. [ABSTRACT FROM AUTHOR]

Dendritic cell (DC) cancer vaccines are a promising therapeutic approach, leveraging the immune system to fight tumors. These vaccines utilize DCs' ability to present tumor-associated antigens to T cells, triggering a robust immune response. DC vaccine development has progressed through three generations. The first generation involved priming DCs with tumor-associated antigens or messenger RNA outside the body, showing limited clinical success. The second generation improved efficacy by using cytokine mixtures and specialized DC subsets to enhance immunogenicity. The third generation used blood-derived DCs to elicit a stronger immune response. Clinical trials indicate that cancer vaccines have lower toxicity than traditional cytotoxic treatments. However, achieving significant clinical responses with DC immunotherapy remains challenging. Combining DC vaccines with immune checkpoint inhibitors (ICIs), such as anticytotoxic T-lymphocyte Antigen 4 and antiprogrammed death-1 antibodies, has shown promise by enhancing T-cell responses and improving clinical outcomes. These combinations can transform non-inflamed tumors into inflamed ones, boosting ICIs' efficacy. Current research is exploring new checkpoint targets like LAG-3, TIM-3, and TIGIT, considering their potential with DC vaccines. Additionally, engineering T cells with chimeric antigen receptors or T-cell receptors could further augment the antitumor response. This comprehensive strategy aims to enhance cancer immunotherapy, focusing on increased efficacy and improved patient survival rates. [ABSTRACT FROM AUTHOR]

Background: Nivolumab is an anti-PD1 antibody that has dramatically improved metastatic melanoma patients' outcomes. Nevertheless, many patients are resistant to PD-1 inhibition, occasionally experiencing severe off-target immune toxicity. In addition, no robust and reproducible biomarkers have yet been validated to identify the correct selection of patients who will benefit from anti-PD-1 treatment avoiding unwanted side effects. However, the strength of CD26 expression on CD4+ T lymphocytes permits the characterization of three subtypes with variable degrees of responsiveness to tumors, suggesting that the presence of CD26-expressing T cells in patients might be a marker of responsiveness to PD-1-based therapies. Methods: The frequency distribution of peripheral blood CD26-expressing cells was investigated employing multi-parametric flow cytometry in 69 metastatic melanoma patients along with clinical characteristics and blood count parameters at baseline (W0) and compared to 20 age- and sex-matched healthy controls. Percentages of baseline CD4+CD26high T cells were correlated with the outcome after nivolumab treatment. In addition, the frequency of CD4+CD26high T cells at W0 was compared with those obtained after 12 weeks (W1) of therapy in a sub-cohort of 33 patients. Results: Circulating CD4+CD26high T cells were significantly reduced in melanoma patients compared to healthy subjects (p = 0.001). In addition, a significant association was observed between a low baseline percentage of CD4+CD26high T cells (< 7.3%) and clinical outcomes, measured as overall survival (p = 0.010) and progression-free survival (p = 0.014). Moreover, patients with clinical benefit from nivolumab therapy had significantly higher frequencies of circulating CD4+CD26high T cells than patients with non-clinical benefit (p = 0.004) at 12 months. Also, a higher pre-treatment proportion of circulating CD4+CD26high T cells was correlated with Disease Control Rate (p = 0.014) and best Overall Response Rate (p = 0.009) at 12 months. Interestingly, after 12 weeks (W1) of nivolumab treatment, percentages of CD4+CD26high T cells were significantly higher in comparison with the frequencies measured at W0 (p < 0.0001), aligning the cell counts with the ranges seen in the blood of healthy subjects. Conclusions: Our study firstly demonstrates that peripheral blood circulating CD4+CD26high T lymphocytes represent potential biomarkers whose perturbations are associated with reduced survival and worse clinical outcomes in melanoma patients. [ABSTRACT FROM AUTHOR]

Research was conducted to demonstrate that the alpha-v-beta-3 integrin is expressed by normal cells in a latent state characterized by its inability to form cytoskeletal connections and to promote cell adhesion to extracellular matrix ligands. A cellular system of human thyroid clones was used to investigate the influence of cytokines on nonfunctional epithelial integrins. Results indicate the importance of cytokine-based autocrine loops for the physiological regulation of integrin activation.