Soluvapaa DNA ei-pienisoluisessa keuhkosyövässä

Keuhkosyöpä aiheutti vuonna 2018 eniten syöpäkuolemia. Laaja-alaisesta tutkimuksesta huolimatta keuhkosyöpäpotilaiden ennuste on edelleen keskimäärin huono. Keuhkosyöpä jaetaan erilaisiin histologisiin alatyyppeihin. Kaksi pääalatyyppiä ovat ei-pienisoluinen keuhkosyöpä ja pienisoluinen keuhkosyöpä. Nykyään keuhkosyöpädiagnostiikan kulmakivinä ovat kuvantamistutkimukset ja kudosnäytteen ottaminen. Parantavaan eli kuratiiviseen hoitotulokseen päästään useimmiten vain kirurgisella hoitolinjalla paikallisessa varhaisen vaiheen ei-pienisoluisessa keuhkosyövässä. Vain 20–25% ei-pienisoluisista keuhkosyövistä soveltuvat kuratiiviseen kirurgiseen hoitoon. Lisäksi 30–55%:lla kuratiivisen kirurgisen hoidon saaneista potilaista syöpä uusiutuu. Soluvapaa DNA (cfDNA) on solun ulkopuolista DNA:ta, jota vapautuu kaikista kehon soluista ruumiin nesteisiin, kuten verenkiertoon. Kun cfDNA on peräisin syöpäsoluista, kutsutaan sitä kiertäväksi kasvain-DNA:ksi (ctDNA). Viime vuosina ctDNA:n käyttö syöpämarkkerina on herättänyt kiinnostusta, koska sitä voisi käyttää keuhkosyöpäpotilaan hoitoketjun eri vaiheissa, kuten tuumorin aikaisemmassa havaitsemisessa, diagnostiikassa, yksilöllisen hoitovalinnan tukena, hoitovasteen seurannassa ja syövän uusiutumisen toteamisessa. Soluvapaa DNA -näytteitä voidaan ottaa nestebiopsioiden muodossa esimerkiksi verestä tai pleuranesteestä. Yksi nestebiopsian eduista on se, että se on nykyään usein käytettyyn radiologisesti ohjattuun kudosbiopsiaan verrattuna vähemmän kajoavampi ja mahdollistaa taudin seurannan. Nestebiopsia voisi tulevaisuudessa ainakin osittain korvata kudosnäytteen ottamisen. Vaikka cfDNA:n käyttö kliinisessä työssä vaatii vielä lisää tutkimuksia, on hyvin mahdollista, että cfDNA:sta tulee tulevaisuudessa keskeinen osa onkologisia hoitoja.Lung cancer caused the most cancer related deaths world-wide in 2018 and despite extensive research the prognosis of a lung cancer patient remains generally poor. Lung cancer is divided into different histological subtypes the two main types being non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Currently lung cancer is diagnosed with radiological imaging and tissue biopsies. Generally, curative treatment can be achieved only by surgical treatment of early-stage NSCLC. Only 20–25% of NSCLC are eligible for curative intent surgery. Furthermore, 30–55% of these patients have a fatal recurrence of lung cancer. Cell-free DNA (cfDNA) has gained interest in the field of oncology. Generally, cfDNA refers to all the DNA in the body that is free from cellular confinement. Circulating tumor DNA (ctDNA) is cfDNA that originates from cancer cells. It has potential to be a minimally invasive method used in various parts of cancer management including early detection, diagnosis, treatment, monitoring the response for treatment and identification of drug resistance. While the use of cfDNA still lacks clinical trials to be widely used in a clinical setting, it is highly possible that cfDNA analysis establishes a central role in the future in the oncological field

Local delivery of interleukin 7 with an oncolytic adenovirus activates tumor-infiltrating lymphocytes and causes tumor regression

Cytokines have proven to be effective for cancer therapy, however whilst low-dose monotherapy with cytokines provides limited therapeutic benefit, high-dose treatment can lead to a number of adverse events. Interleukin 7 has shown promising results in clinical trials, but anti-cancer effect was limited, in part due to a low concentration of the cytokine within the tumor. We hypothesized that arming an oncolytic adenovirus with Interleukin 7, enabling high expression localized to the tumor microenvironment, would overcome systemic delivery issues and improve therapeutic efficacy. We evaluated the effects of Ad5/3-E2F-d24-hIL7 (TILT-517) on tumor growth, immune cell activation and cytokine profiles in the tumor microenvironment using three clinically relevant animal models and ex vivo tumor cultures. Our data showed that local treatment of tumor bearing animals with Ad5/3- E2F-d24-hIL7 significantly decreased cancer growth and increased frequency of tumor-infiltrating cells. Ad5/3-E2F-d24-hIL7 promoted notable upregulation of pro-inflammatory cytokines, and concomitant activation and migration of CD4+ and CD8 + T cells. Interleukin 7 expression within the tumor was positively correlated with increased number of cytotoxic CD4+ cells and IFNg-producing CD4+ and CD8+ cells. These findings offer an approach to overcome the current limitations of conventional IL7 therapy and could therefore be translated to the clinic.Peer reviewe

Effective intravenous delivery of adenovirus armed with TNFα and IL-2 improves anti-PD-1 checkpoint blockade in non-small cell lung cancer

Publisher Copyright: © 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.Lung cancer remains among the most difficult-to-treat malignancies and is the leading cause of cancer-related deaths worldwide. The introduction of targeted therapies and checkpoint inhibitors has improved treatment outcomes; however, most patients with advanced-stage non-small cell lung cancer (NSCLC) eventually fail these therapies. Therefore, there is a major unmet clinical need for checkpoint refractory/resistant NSCLC. Here, we tested the combination of aPD-1 and adenovirus armed with TNFα and IL-2 (Ad5-CMV-mTNFα/mIL-2) in an immunocompetent murine NSCLC model. Moreover, although local delivery has been standard for virotherapy, treatment was administered intravenously to facilitate clinical translation and putative routine use. We showed that treatment of tumor-bearing animals with aPD-1 in combination with intravenously injected armed adenovirus significantly decreased cancer growth, even in the presence of neutralizing antibodies. We observed an increased frequency of cytotoxic tumor-infiltrating lymphocytes, including tumor-specific cells. Combination treatment led to a decreased percentage of immunosuppressive tumor-associated macrophages and an improvement in dendritic cell maturation. Moreover, we observed expansion of the tumor-specific memory T cell compartment in secondary lymphoid organs in the group that received aPD-1 with the virus. However, although the non-replicative Ad5-CMV-mTNFα/mIL-2 virus allows high transgene expression in the murine model, it does not fully reflect the clinical outcome in humans. Thus, we complemented our findings using NSCLC ex vivo models fully permissive for the TNFα and IL-2- armed oncolytic adenovirus TILT-123. Overall, our data demonstrate the ability of systemically administered adenovirus armed with TNFα and IL-2 to potentiate the anti-tumor efficacy of aPD-1 and warrant further investigation in clinical trials.Peer reviewe