Browsing by Subject "oncoimmunology"

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  • Fusciello, Manlio; Fontana, Flavia; Tähtinen, Siri; Capasso, Cristian; Feola, Sara; da Silva Lopes Martins, Beatriz; Chiaro, Jacopo; Peltonen, Karita; Ylösmäki, Leena; Ylösmäki, Erkko; Hamdan Hissaoui, Firas; Kari, Otto K.; Ndika, Joseph; Alenius, Harri; Urtti, Arto; Hirvonen, Jouni T.; Santos, Hélder A.; Cerullo, Vincenzo (2019)
    Virus-based cancer vaccines are nowadays considered an interesting approach in the field of cancer immunotherapy, despite the observation that the majority of the immune responses they elicit are against the virus and not against the tumor. In contrast, targeting tumor associated antigens is effective, however the identification of these antigens remains challenging. Here, we describe ExtraCRAd, a multi-vaccination strategy focused on an oncolytic virus artificially wrapped with tumor cancer membranes carrying tumor antigens. We demonstrate that ExtraCRAd displays increased infectivity and oncolytic effect in vitro and in vivo. We show that this nanoparticle platform controls the growth of aggressive melanoma and lung tumors in vivo both in preventive and therapeutic setting, creating a highly specific anti-cancer immune response. In conclusion, ExtraCRAd might serve as the next generation of personalized cancer vaccines with enhanced features over standard vaccination regimens, representing an alternative way to target cancer.
  • Cervera-Carrascón, Víctor (Helsingin yliopisto, 2021)
    Over the last ten years, the use of immunotherapeutic treatments for cancer has exponentially increased due to the promising responses across different tumour types. One of the particularities of the approach is that patients can develop long lasting curative responses. Unfortunately, those encouraging complete responses happen only in a minority of patients (< 10%). Immune checkpoint inhibitors, like anti-PD-1 or anti-PD-L1, are embodiments of that kind of therapy, whose concept revolves around the concept of stopping inhibitory signals that limit the development of antitumour responses. Results obtained from clinical experiences showed that patients responding better to immune checkpoint inhibitors tend to have “hot tumours”, meaning that there are effector components (such as T cells) and the microenvironment supports their function. To make immune checkpoint inhibitors work in those patients with cold tumours, the use of oncolytic adenoviruses could provide the spark to warm them. Viruses are able to trigger the immune alarm and thus, make tumours hot when their replication is restricted to the tumour. To study the potential of oncolytic viruses to increase the efficacy of immune checkpoint inhibitors, an array of preclinical models that allowed to study the matter from different angles were used. While in vivo murine and hamster models provided the basis for direct antitumour effect and survival assessments, other studies including human tumour sample histocultures and other in vitro experiments were performed to understand the subjacent cellular and molecular mechanisms involved. Due to the critical role of the T-cell compartment surrounding the activity of immune checkpoint inhibitors, different virus families were studied in terms of their ability to trigger T-cell responses. The best T-cell engagement was provided by the adenovirus candidate. An adenovirus engineered to support further antitumour immune responses was used to enable anti-PD-1 and anti-PD-L1 therapies. In both cases, the proposed strategy was able to cure all the animals. Additionally, tumours that were already refractory to anti-PD-1 still respond to virotherapy and the virus resets the tumour microenvironment sensitizing those tumours respond to anti-PD-1. Overall, this work revealed the potential of using engineered adenoviruses to repolarize the tumour microenvironment in general and the T-cell compartment in particular to a point that complement the mechanism of action of PD-1 and PD-L1 inhibitory antibodies. That synergistic combination rendered an increased percentage of responses even in tumours previously resistant or refractory to immune checkpoint inhibitors.
  • Heiniö, Camilla (Helsingin yliopisto, 2023)
    The effects of cancer immunotherapy are based on activating and utilizing the immune system to fight cancer cells. In this thesis, a form of immunotherapy, specifically oncolytic adenoviruses, were studied. Immunotherapies are costly to produce and different oncolytic viruses are used in relatively high concentrations and amounts when cancer patients are treated. Thus we wanted to optimize adenovirus vector design, enhance the delivery of adenoviruses to the tumor as well as define and show the immunological response to the adenovirus vector we have developed. It was shown, the physical and functional titers of the produced vectors were relatively stable. However, production was negatively affected if very large constructs (such as antibodies) were inserted or more than five mutations were made to the virus genome. Adenoviruses are attractive vectors for example due to their good safety profile and high production concentrations. When oncolytic virotherapy was originally conceptualized, it was believed that the lytic effect of the virus was driving the benefits for patients. Later, it was shown that other signaling events, such as danger- and pathogen-associated molecular pattern signaling, also play important roles, maybe even more so than virus-induced lysis of cancer cells. Therefore, pattern recognition receptor (PRR) signaling during an oncolytic adnovirus called TILT-123 infection was studied. TILT-123 induced alarmin release through PRRs (such as AIM2) that trigged the activation of immunostimulating signaling cascades, leading to immune-cell activation and tumor clearance. The knowledge of which signaling cascades are activated during infection can be used to further enhance effects of TILT-123 and be extended to enhance the efficacy of other virotherapeutics as well. Most humans have naturally encountered adenovirus and thus many have immune memory towards it. Therefore, when adenovirus vectors are administered intravenously, the pre-existing immunity among other virus clearing reactions, leads to unwanted clearance of the virions from the blood, before the vectors can reach their target. Consequently, we hypothesized that if a mixture of both TILT-123 and tumor infiltrating lymphocytes also known as TILs are administered intravenously a higher efficacymay be achieved. Indeed, TILT-123 did bind to the surface of T cells. When administered simultaneously, the treatment led to a positive tumor-clearing effect in vivo. Unfortunately, some cancer types are still hard to treat. For example, ovarian cancers are often diagnosed at late stages when the tumor size and metastases may hinder effective treatment of the disease. Furthermore, the tumor microenvironment in ovarian cancers is often immunosuppressive. To solve these issues, the effects of TILT-123 on ovarian cancer was studied. It was shown that TILT-123 can be employed to treat ovarian cancer. TILT-123 treatment modified the immunosuppressive microenvironment and enabled a more successful combinatorial treatment with T cell therapy.
  • Garg, Abhishek D.; Galluzzi, Lorenzo; Apetoh, Lionel; Baert, Thais; Birge, Raymond B.; Bravo-San Pedro, Jose Manuel; Breckpot, Karine; Brough, David; Chaurio, Ricardo; Cirone, Mara; Coosemans, An; Coulie, Pierre G.; De Ruysscher, Dirk; Dini, Luciana; de Witte, Peter; Dudek-Peric, Aleksandra M.; Faggioni, Alberto; Fucikova, Jitka; Gaipl, Udo S.; Golab, Jakub; Gougeon, Marie-Lise; Hamblin, Michael R.; Hemminki, Akseli; Herrmann, Martin; Hodge, James W.; Kepp, Oliver; Kroemer, Guido; Krysko, Dmitri V.; Land, Walter G.; Madeo, Frank; Manfredi, Angelo A.; Mattarollo, Stephen R.; Maueroder, Christian; Merendino, Nicolo; Multhoff, Gabriele; Pabst, Thomas; Ricci, Jean-Ehrland; Riganti, Chiara; Romano, Erminia; Rufo, Nicole; Smyth, Mark J.; Sonnemann, Juergen; Spisek, Radek; Stagg, John; Vacchelli, Erika; Vandenabeele, Peter; Vandenberk, Lien; Van den Eynde, Benoit J.; Van Gool, Stefaan; Velotti, Francesca; Zitvogel, Laurence; Agostinis, Patrizia (2015)
    The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall mmunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs). The emission of DAMPs and other mmunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.