Integration of Translational Research in the European Organization for Research and Treatment of Cancer Research (EORTC) Clinical Trial Cooperative Group Mechanisms

The landscape for cancer research is profoundly different today from that only one decade ago. Basic science is moving rapidly and biotechnological revolutions in molecular targeting and immunology have completely modified the opportunities and concepts for cancer treatment. In contrast to the recent past where cytotoxic molecules were screened in the laboratory and then tested in early clinical studies with toxicity as endpoint instead of the often poorly defined mechanism for its potential anti-tumor effect, we now have entered the age of molecular therapeutics, rationally designed to target "strategic" checkpoints that underlie the malignant phenotype. Translational research in early clinical trials (Phase I and II) is an integral aspect of the development of the new generation of cancer drugs as it is necessary to implement radically different early phase clinical trial design and to validate new biological end-points if the full potential of these new agents is to be realized. The "proof of principle with mechanistic analysis" strategy will allow optimisation of therapy from the beginning, and provide important feedback to pre-clinical drug developers. Translational research is also essential in late (phase III) clinical trials in defining different patient populations that may benefit to differing degrees from new treatments, and thus provide further insight and refine clinical practice in a more and more patient-tailored approach. In this editorial we will discuss the integration of Translational Research in the Organization for Research and Treatment of Cancer (EORTC)

Giant solitary fibrous tumour of the liver

BACKGROUND: Solitary fibrous tumour (SFT) is an uncommon mesenchymal neoplasm that most frequently affects the pleura, although it has been reported with increasing frequency in various other sites such as in the peritoneum, pericardium and in non-serosal sites such as lung parenchyma, upper respiratory tract, orbit, thyroid, parotid gland, or thymus. Liver parenchyma is rarely affected. Clinically, SFTs cause symptoms after having reached a certain size or when vital structures are involved. In recent years, SFTs are more often identified and distinguished from other tumours with a similar appearance due to the availability of characteristic immunohistochemical markers. CASE PRESENTATION: In this manuscript we report the case of a large tumour of the liver, which was histologically diagnosed as a SFT, and showed involvement of a single hepatic segment. Because of the patient's presentation and clinical course, it may represent a radiation-induced lesion. CONCLUSION: When a SFT has been diagnosed, surgery is the treatment of choice. The small number of patients with a SFT of the liver and its unknown natural behaviour creates the need to a careful registration and follow-up of all identified case

The future of targeting cytotoxic T-lymphocyte-associated protein-4: Is there a role?

The 2022 yearly Think Tank Meeting in Siena, Tuscany (Italy), organized by the Italian Network for Tumor Biotherapy (NIBIT) Foundation, the Parker Institute for Cancer Immunotherapy and the World Immunotherapy Council, included a focus on the future of integrating and expanding the use of targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The conference members exchanged their views on the lessons from targeting CTLA-4 and compared the effect to the impact of blocking Programmed cell death protein 1 (PD1) or its ligand (PDL1). The increasing experience with both therapeutic approaches and their combination suggests that targeting CTLA-4 may lead to more durable responses for a sizeable proportion of patients, though the specific mechanism is not entirely understood. Overcoming toxicity of blocking CTLA-4 is currently being addressed with different doses and dose regimens, especially when combined with PD1/PDL1 blocking antibodies. Novel therapeutics targeting CTLA-4 hold the promise to reduce toxicities and thus allow different combination strategies in the future. On the whole, the consent was that targeting CTLA-4 remains an important strategy to improve the efficacy of cancer immunotherapies

Cancer Core Europe: A translational research infrastructure for a European mission on cancer.

Cancer Core Europe is a European legal alliance consisting of seven leading cancer centres - most of them Comprehensive Cancer Centres (CCCs) - with a single portal system to engage in various research projects with partners. Cancer Core Europe was established to create a sustainable, high-level, shared research infrastructure platform hosting research collaborations and task forces (data sharing, clinical trials, genomics, immunotherapy, imaging, education and training, and legal and ethical issues), with a controlled expansion agenda. Translational cancer research covers the cancer research continuum from basic to preclinical to early clinical, late clinical, and outcomes research. Basic-preclinical research serves as the 'engine' for early clinical research by bridging the early translational research gap and is the primary and current focus of the consortium as exemplified by the launching of the Basket of Baskets trial, Europe's largest precision cancer medicine trial. Inspired by the creation of Cancer Core Europe, the prevention community established Cancer Prevention Europe, a consortium of ten cancer prevention centres aimed at supporting the complete prevention research continuum. Presently, Cancer Core Europe and Cancer Prevention Europe are integrating therapeutics and prevention strategies to address in partnership the widening cancer problem. By providing innovative approaches for cancer research, links to healthcare systems, development of quality-assured multidisciplinary cancer care, and assessment of long-term outcomes, the virtual infrastructure will serve as a hub to connect and interact with other centres across Europe and beyond. Together, Cancer Core Europe and Cancer Prevention Europe are prepared to function as a central engine to tackle, in collaboration with various partners, a potential 'mission on cancer' addressing the cancer burden

Prerequisites for effective adenovirus mediated gene therapy of colorectal liver metastases in the rat using an intracellular neutralizing antibody fragment to p21-Ras

Ras mutations are present in 40–50% of colorectal cancers. Inactivating this oncogene may therefore reduce proliferation capacity. In order to target ras we studied the transduction efficacy and anti tumour activity of an adenoviral vector expressing an intracellular, neutralizing single chain antibody to p21-ras (Y28). In in vitro studies transfection levels of the K-ras mutated rat colon carcinoma cell line CC531 were studied using the LacZ marker gene. In our in vivo liver metastases model different routes of administration were evaluated to determine which regimen resulted in the best transfection levels and tumour responses: intravenous injection, intratumoural injection, isolated liver perfusion, or hepatic artery infusion. CC531 cells are readily transfected in vitro, resulting in significant inhibition of tumour cell proliferation by the Y28 construct. Intravenous injection did not result in any measurable transfection. Intratumoural injection resulted only in the transfection of tumour cells along the needle track. IHP as well as single HAI achieved low transfection levels of tumour tissue. Expression of Y28 was demonstrated in tumours after IT injection, HAI and IHP. Whereas, repeated HAI's clearly achieved expression in and around tumour associated vessels. Only five times repeated HAI's with Y28 resulted in a tumour response: in all animals tumour growth was inhibited, and in three rats out of eight a complete regression of the liver tumours was observed

Combined treatment of colon adenocarcinoma in rats with tumor necrosis factor and the interferon inducer ABPP

It is well documented that the antitumor capacity of tumor necrosis factor (TNF) can be enhanced by interferons (IFNs), notably IFN-γ. The aim of this study was to investigate the efficacy of a combined treatment with TNF and the IFN-inducer 2-amino-5-bromo-6-phenyl-4-pyrimidinone (ABPP) on a transplantable colon carcinoma (CC531) in rats. The tumor was implanted under the kidney capsule of syngeneic rats; the tumors were removed a week after implantation and growth was assessed by weighing. The animals were treated with 1 μg of TNF, given i.v. on days 0, 2, and 4; and with 250 mg/kg of ABPP, administered i.p. on days 0 and 1. The results of two separate experiments indicated that both TNF and ABPP had a significant inhibitory effect on tumor growth. Combined, the two agents were found to act additively. In the dosage used, TNF toxicity was mild, transient, and not influenced by ABPP