Browsing by Subject "cancer immunotherapy"

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  • Cervera-Carrascon, Victor; Quixabeira, Dafne C. A.; Santos, Joao M.; Havunen, Riikka; Milenova, Ioanna; Verhoeff, Jan; Heinio, Camilla; Zafar, Sadia; Garcia-Vallejo, Juan J.; van Beusechem, Victor W.; de Gruijl, Tanja D.; Kalervo, Aino; Sorsa, Suvi; Kanerva, Anna; Hemminki, Akseli (2021)
    Immune checkpoint inhibitors such as anti-PD-1 have revolutionized the field of oncology over the past decade. Nevertheless, the majority of patients do not benefit from them. Virotherapy is a flexible tool that can be used to stimulate and/or recruit different immune populations. T-cell enabling virotherapy could enhance the efficacy of immune checkpoint inhibitors, even in tumors resistant to these inhibitors. The T-cell potentiating virotherapy used here consisted of adenoviruses engineered to express tumor necrosis factor alpha and interleukin-2 in the tumor microenvironment. To study virus efficacy in checkpoint-inhibitor resistant tumors, we developed an anti-PD-1 resistant melanoma model in vivo. In resistant tumors, adding virotherapy to an anti-PD-1 regimen resulted in increased survival (p=0.0009), when compared to anti-PD-1 monotherapy. Some of the animals receiving virotherapy displayed complete responses, which did not occur in the immune checkpoint-inhibitor monotherapy group. When adenoviruses were delivered into resistant tumors, there were signs of increased CD8 T-cell infiltration and activation, which - together with a reduced presence of M2 macrophages and myeloid-derived suppressor cells - could explain those results. T-cell enabling virotherapy appeared as a valuable tool to counter resistance to immune checkpoint inhibitors. The clinical translation of this approach could increase the number of cancer patients benefiting from immunotherapies.
  • Taipale, Kristian; Tähtinen, Siri; Havunen, Riikka; Koski, Anniina; Liikanen, Ilkka; Pakarinen, Päivi; Koivisto-Korander, Riitta; Kankainen, Matti; Joensuu, Timo; Kanerva, Anna; Hemminki, Akseli (2018)
    After the landmark approval of T-VEC, oncolytic viruses are finding their way to the clinics. However, response rates have still room for improvement, and unfortunately there are currently no available markers to predict responses for oncolytic immunotherapy. Interleukin 8 (IL-8) production is upregulated in many cancers and it also connects to several pathways that have been shown to impair the efficacy of adenoviral immunotherapy. We studied the role of IL-8 in 103 cancer patients treated with oncolytic adenoviruses. We found high baseline serum IL-8 concentration to be independently associated with poor prognosis (p <0.001). Further, normal baseline IL-8 was associated with improved prognostic potential of calculation of the neutrophil-to-lymphocyte ratio (p <0.001). Interestingly, a decrease in IL-8 concentration after treatment with oncolytic adenovirus predicted better overall survival (p <0.001) and higher response rate, although this difference was not significant (p=0.066). We studied the combination of adenovirus and IL-8 neutralizing antibody ex vivo in single cell suspensions and in co-cultures of tumor-associated CD15+ neutrophils and CD3+ tumor-infiltrating lymphocytes derived from fresh patient tumor samples. These results indicate a role for IL-8 as a biomarker in oncolytic virotherapy, but additionally provide a rationale for targeting IL-8 to improve treatment efficacy. In conclusion, curtailing the activity of IL-8 systemically or locally in the tumor microenvironment could improve anti-tumor immune responses resulting in enhanced efficacy of adenoviral immunotherapy of cancer. © Taipale et al.
  • Almahmoudi, Rabeia; Salem, Abdelhakim; Murshid, Sakhr; Dourado, Mauricio Rocha; Apu, Ehsanul Hoque; Salo, Tuula; Al-Samadi, Ahmed (2019)
    We recently showed that extracellular interleukin-17F (IL-17F) correlates with better disease-specific survival in oral tongue squamous cell carcinoma (OTSCC) patients. However, the underlying mechanisms of such effect remain obscure. Here, we used qRT-PCR to assess the expression of IL-17F and its receptors (IL-17RA and IL-17RC) in two OTSCC cell lines (HSC-3 and SCC-25) and in normal human oral keratinocytes (HOKs). IL-17F effects on cancer cell proliferation, migration, and invasion were studied using a live-imaging IncuCyte system, and a Caspase-3/7 reagent was used for testing apoptosis. 3D tumor spheroids were utilized to assess the impact of IL-17F on invasion with or without cancer-associated fibroblasts (CAFs). Tube-formation assays were used to examine the effects of IL-17F on angiogenesis using human umbilical vein endothelial cells (HUVEC). OTSCC cells express low levels of IL-17F, IL-17RA, and IL-17RC mRNA compared with HOKs. IL-17F inhibited cell proliferation and random migration of highly invasive HSC-3 cells. CAFs promoted OTSCC invasion in tumor spheroids, whereas IL-17F eliminated such effect. IL-17F suppressed HUVEC tube formation in a dose-dependent manner. Collectively, we suggest that IL-17F counteracts the pro-tumorigenic activity in OTSCC. Due to its downregulation in tumor cells and inhibitory activity in in vitro cancer models, targeting IL-17F or its regulatory pathways could lead to promising immunotherapeutic strategies against OTSCC.
  • Cheng, Ruoyu; Fontana, Flavia; Xiao, Junyuan; Liu, Zehua; Figueiredo, Patricia; Shahbazi, Mohammad-Ali; Wang, Shiqi; Jin, Jing; Torrieri, Giulia; Hirvonen, Jouni T.; Zhang, Hongbo; Chen, Tongtong; Cui, Wenguo; Lu, Yong; Santos, Helder A. (2020)
    Recently, there has been an increasing interest for utilizing the host immune system to fight against cancer. Moreover, cancer vaccines, which can stimulate the host immune system to respond to cancer in the long term, are being investigated as a promising approach to induce tumor-specific immunity. In this work, we prepared an effective cancer vaccine (denoted as vacosome) by reconstructing the cancer cell membrane, monophosphoryl lipid A as a toll-like receptor 4 agonist, and egg phosphatidylcholine. The vacosome triggered and enhanced bone marrow dendritic cell maturation as well as stimulated the antitumor response against breast cancer 4T1 cells in vitro. Furthermore, an immune memory was established in BALB/c mice after three-time preimmunization with the vacosome. After that, the immunized mice showed inhibited tumor growth and prolonged survival period (longer than 50 days). Overall, our results demonstrate that the vacosome can be a potential candidate for clinical translation as a cancer vaccine.
  • Feola, Sara; Chiaro, Jacopo; Martins, Beatriz; Cerullo, Vincenzo (2020)
    According to the latest available data, cancer is the second leading cause of death, highlighting the need for novel cancer therapeutic approaches. In this context, immunotherapy is emerging as a reliable first-line treatment for many cancers, particularly metastatic melanoma. Indeed, cancer immunotherapy has attracted great interest following the recent clinical approval of antibodies targeting immune checkpoint molecules, such as PD-1, PD-L1, and CTLA-4, that release the brakes of the immune system, thus reviving a field otherwise poorly explored. Cancer immunotherapy mainly relies on the generation and stimulation of cytotoxic CD8 T lymphocytes (CTLs) within the tumor microenvironment (TME), priming T cells and establishing efficient and durable anti-tumor immunity. Therefore, there is a clear need to define and identify immunogenic T cell epitopes to use in therapeutic cancer vaccines. Naturally presented antigens in the human leucocyte antigen-1 (HLA-I) complex on the tumor surface are the main protagonists in evocating a specific anti-tumor CD8+ T cell response. However, the methodologies for their identification have been a major bottleneck for their reliable characterization. Consequently, the field of antigen discovery has yet to improve. The current review is intended to define what are today known as tumor antigens, with a main focus on CTL antigenic peptides. We also review the techniques developed and employed to date for antigen discovery, exploring both the direct elution of HLA-I peptides and the in silico prediction of epitopes. Finally, the last part of the review analyses the future challenges and direction of the antigen discovery field.