Immunogenicity as a predictive tool for the response to therapy of high mutation load tumors
Cancers with high mutational load, like non-small cell lung cancers (NSCLC) and malignant melanoma (MM), escape from the immune system surveillance, explaining their poor prognostic. Immunotherapy (IT) is trying to overcome the limits of standard therapy and is likely to become a key part of the clinical management of these cancers. But IT doesn’t help everyone and only a subset of patients benefits of it. Immune checkpoint inhibitors are very promising in this setting and specific monoclonal antibodies were approved for clinical use in the treatment of these tumors. However, the clinical results of checkpoint inhibitors blockade have only 15-30% response rate demonstrating that, taken alone, are far from being perfect predictive biomarkers. Available data point towards a strong synergy between radiotherapy (RT) and IT. A crucial and still unsolved issue is the validation of reliable predictive biomarkers. Our aim is to find predictive biomarkers in MM and NSCLC to identify patients who are likely to benefit from IT alone and in combination with other therapies such as RT. We propose a comprehensive, translational and prospective study with 2 arms: experimental and clinical. In the experimental arm, multiple immune molecules at different levels will be evaluated by modern assays and technologies. In the clinical arm, patients with MM and NSCLC treated with standard therapies will be tested for the same markers and their treatment response and outcome will be assessed. This design will allow to correlate the evaluated immune markers with the clinical evolution. The original and innovative aspects of the proposal are: the evaluation and correlation of a large number of potential biomarkers, located in different sites; a comprehensive approach, from the molecular level to the cellular and clinical one, for identification of biomarkers with predictive value for the response to single or combined IT in advanced, poor prognostic cancers.
The aim of the present project is to identify predictive biomarkers in malignant melanoma and non small cell lung cancers that could help to identify patients who are likely to benefit from immunotherapy alone and in combination with other therapies
a). To evaluate molecules from each of the seven steps of the Cancer-Immunity Cycle for which there is some evidence pointing towards a potential predictive role
b). To evaluate the expression of the most important checkpoint molecules (PD-1/PD-L1) and their dynamics during therapy
c). To identify the potential of standard treatment modalities, such as RT, to activate an immune response
d) To evaluate some clinico-pathologic biomarkers which were showed to be important for the clinical outcome in these cancers and correlate them with the patient immune status and clinical response
The results of the present project may allow to create an integrated model for determining which malignant melanoma and non-small cell lung cancer patients may benefit from which therapy, either alone or in combination. The introduction of some predictive algorithms will facilitate the rational development of further clinical trials for application of personalized therapies in patients with poor prognostic cancers such as malignant melanoma and non-small cell lung cancers.
Prof. Dr. Tudor-Eliade Ciuleanu - project director
Biol. Dr. Piroska Virag
Chim. Dr. Eva Fischer-Fodor
Chim. Dr. Ovidiu Balacescu
Dr. Ioana-Carmen Brie
Dr. Olga Soritau
Dr. Maria Perde-Schrepler
Dr. Rares Buiga
Dr. Mihai Cenariu
Dr. Zsolt Fekete
Mat. Dr. Nicolae Todor
Drd. Ioana Iurca, PhD student
Drd Oana Baldasici, PhD student
Presentations at the 8th International Conference on Oxidative Stress in Skin Medicine and Biology, Andros, Greece:
- Immunotherapy in malignant melanoma: where do we stand?. Ioana-Carmen Brie, Maria Perde-Schrepler, Piroska Virag, Eva Fischer-Fodor, Ovidiu Balacescu, Olga Soritau, Ioana Iurca, Oana Baldasici, Tudor Eliade Ciuleanu
- The in vitro modulation of the angiogenic pathways by chemotherapy in vascular endothelial vein cells - an experimental model of infantile hemangioma. M. Bota, S. Chira, B. Tigu, C. Moldovan, O. Bochis, P. Virag, R. Stiufiuc, E. Fischer-Fodor, I. Berindan-Neagoe, Al. Tataru
- Best of Astro 2018, Cluj-Napoca, Romania, 18-19.05.2018; Best of Astro 2017: Biology. Ioana-Carmen Brie
Anticancer applications of nanostructured silica-based materials functionalized with titanocene derivatives: induction of cell death mechanism through TNFR1 modulation. S. Gomez-Ruiz, A. Garcia-Penas, S. Prashar, A. Rodriguez-Dieguez, E. Fischer-Fodor, Materials, 2018, 11(2), pii: E224. doi: 10.3390/ma11020224.
Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden
Matthew D. Hellmann, M.D., Tudor-Eliade Ciuleanu, M.D., Adam Pluzanski, M.D., Jong Seok Lee et al. N Engl J Med 2018; 378:2093-2104; DOI: 10.1056/NEJMoa1801946
Al 14-lea Curs Postuniversitar „Strategii terapeutice actuale și de viitor în oncologie; 28-29 Iunie 2019, Cluj-Napoca, Romania :
- Clinical Trials in The Oncology Institute Cluj-Napoca. Ioana Iurca, Tudor Eliade Ciuleanu.
- Biomarkeri ai raspunsului la inhibitia receptorilor PD1/PDL1. Maria Perde-Schrepler
- Tratamentul combinat imuno-radioterapie in mamagementul tumorilor cu prognostic nefavorabil. Ioana-Carmen Brie
- Functiile efectoare ale diferitelor subseturi de limfocite T si implicatiile acestora in imunoterapie. Piroska Virag
Al 29-lea Congres Anual al RSRMO "Cancer - multidisciplinary and complex disease: a continuous challenge": In vitro study of the checkpoint molecules as predictive biomarkers for the outcome of immune therapy and chemotherapy of NSCLC. Ioana -Carmen Brie
PostCongress Course: Progress in the Biological Treatments in Solid Tumors (Immunotherapy and Target Treatment) - 19.10.2019, Cluj-Napoca, Romania : Expanding the role of immunotherapy in lung cancer. Tudor Eliade Ciuleanu.
Palladium(II) complexes with curcuminoid ligands induce apoptosis in tumors with high mutational burden. Eva Fischer-Fodor, Piroska Virag, Ioana-Carmen Brie, Maria Perde-Schrepler, Olga Soritau, Corina Bianca Tatomir, Natalia Miklasova, Tudor Eliade Ciuleanu. Studia UBB Chemia - submis, in evaluare