Lorenzo De Marco

Scopus Publications

Mutations Targeted by Nous-209 Immunotherapy Occur Early in Lynch Syndrome Carriers’ Precancer Lesions with Microsatellite Instability
Elisa Micarelli, Lorenzo De Marco, Paola Spaggiari, Anna Morena D’Alise, Arianna Dal Buono, Maddalena Menini, Valentina Giatti, Alessandro D’Aprano, Elisa Scarselli, Cesare Hassan, Alessandro Repici
Cancer Prevention Research, 2026
This study provides a molecular characterization of precancerous colorectal lesions in Lynch syndrome (LS) carriers to assess the preventive potential of Nous-209 immunotherapy against colorectal cancer development. A total of 50 adenomas and 12 advanced adenomas (AA) were collected from 26 LS carriers with pathogenic variants in either MLH1 or MSH2. Molecular analyses included assessment of mismatch repair (MMR) status, microsatellite instability (MSI), and detection of mutations targeted by Nous-209. We found that 83% of AAs and 58% of adenomas were MMR-deficient (dMMR). Notably, although all dMMR AA were MSI-high (MSI-H), only 66% of dMMR adenomas showed MSI-H. The presence of Nous-209 mutations correlated strongly with MSI status, with mutation counts ranging from 15 to 57 in dMMR/MSI-H lesions. dMMR adenomas classified as MSI-low carried a limited number of mutations (6–19), whereas microsatellite-stable lesions harbored very few (0–2) Nous-209 mutations, regardless of MMR proficiency. These findings confirm the molecular heterogeneity of precancerous lesions and support the potential of Nous-209 immunotherapy to prevent MSI colorectal cancer in LS by targeting the adenoma–carcinoma sequence at the time of MSI acquisition. Prevention Relevance: Our study shows that MSI and neoantigen accumulation emerge during the evolution of precancerous lesions in LS. These findings support the clinical evaluation of Nous-209, a shared neoantigen vaccine, as an immunoprevention strategy for MSI-driven colorectal carcinogenesis, with important implications for cancer prevention research.
NOUS-209 Off-the-shelf Immunotherapy Has the Potential to Hit Primary and Metachronous Colorectal and Urothelial Cancers in Lynch Syndrome
Lorenzo De Marco, Elisa Micarelli, Joni Panula, Jussi Nikkola, Lauri Moilanen, Matti Annala, Jouni Härkönen, Kalle E. Hokkanen, Anna Morena D’Alise, Kirsi Pylvänäinen, Päivi T. Peltomäki, Maarit Ahtiainen, Jan Böhm, Jukka-Pekka Mecklin, Elisa Scarselli, Toni T. Seppälä
Molecular Cancer Therapeutics, 2026
Lynch syndrome is characterized by the development of microsatellite-instable cancers that share neoantigens, offering an opportunity for targeted immunotherapy. NOUS-209 is a heterologous prime-boost cancer vaccine in clinical development, employing viral vectors encoding 209 shared neoantigen peptides derived from frameshift mutations (FSM) commonly found in microsatellite-instable tumors. In this study, we investigated the presence and dynamics of NOUS-209 targeted FSMs in both primary and metachronous Lynch syndrome–associated cancers. Whole-exome sequencing was performed for 73 tumors, including 58 colorectal cancers and 15 urothelial cancers, from 58 individuals with confirmed Lynch syndrome. A median of 57 FSMs per colorectal cancer and 24 FSMs per urothelial cancer were observed, with similar FSM burdens in both primary and metachronous tumors. Analysis of nine matched primary–metachronous tumor pairs revealed evidence of immune editing: FSMs predicted to encode highly immunogenic neoepitopes were selectively lost in metachronous tumors, whereas those with lower predicted immunogenicity were retained. Importantly, all subsequent primary cancers acquired novel FSMs encoding neoantigens with strong predicted HLA-binding affinity, supporting the rationale for NOUS-209–mediated immune interception. These findings demonstrated that NOUS-209 FSMs are present in both colorectal cancers and urothelial cancers in Lynch syndrome, expanding the therapeutic potential of NOUS-209 beyond colorectal cancer. Moreover, the emergence of novel targetable FSMs in metachronous tumors suggests that NOUS-209 immunotherapy may be effective in the prevention of both primary and metachronous Lynch syndrome–associated cancers.
Varan: a tool for managing mutational data and creating cancer studies in cBioPortal
Chiara Parrillo, Michele Kulesko, Federica Persiani, Lorenzo De Marco, Paolo Petescia, et al.
Nar Genomics and Bioinformatics, 2025
cBioPortal has established itself as a widely used platform for exploring and visualizing multidimensional cancer data. Additionally, users have the option to upload their own cancer study for a comprehensive experience. However, the uploading step can be challenging due to the numerous files required by the platform, as well as the meticulous review of genomic alterations that need to be included in the study. Therefore, there is an increasing need for efficient data management solutions to facilitate the creation of studies in cBioPortal and optimize user experience by streamlining research workflows. In this application note, we present Varan, an innovative data management tool developed to help users at the initial stage of cancer genomic studies' upload, enhancing the data preparation process. Varan addresses challenges related to data formatting, filtering variants based on annotation, metadata file creation, quality checks, and study versioning, thereby enabling researchers to shorten the preparation process time and have control over the type of data to be uploaded to cBioPortal. In conclusion, Varan significantly improves the efficiency and accuracy of preparing cancer genomic studies for cBioPortal, ultimately enhancing the user experience and advancing cancer research through streamlined data management.
Primary and Recall Immune Responses to SARS-CoV-2 in Breakthrough Infection
Silvia D’Orso, Marta Pirronello, Alice Verdiani, Angelo Rossini, Gisella Guerrera, Mario Picozza, Manolo Sambucci, Andrea Misiti, Lorenzo De Marco, Antonino Salvia, Carlo Caltagirone, Emiliano Giardina, Luca Battistini, Giovanna Borsellino
Vaccines, 2023
Breakthrough infections in SARS-CoV-2 vaccinated individuals are an ideal circumstance for the simultaneous exploration of both the vaccine-induced memory reaction to the spike (S) protein and the primary response to the membrane (M) and nucleocapsid (N) proteins generated by natural infection. We monitored 15 healthcare workers who had been vaccinated with two doses of Pfizer BioNTech BNT162b2 and were then later infected with the SARS-CoV-2 B.1.617.2. (Delta) variant, analysing the antiviral humoral and cellular immune responses. Natural infection determined an immediate and sharp rise in anti-RBD antibody titres and in the frequency of both S-specific antibody secreting cells (ASCs) and memory B lymphocytes. T cells responded promptly to infection by activating and expanding already at 2–5 days. S-specific memory and emerging M- and N-specific T cells both expressed high levels of activation markers and showed effector capacity with similar kinetics but with different magnitude. The results show that natural infection with SARS-CoV-2 in vaccinated individuals induces fully functional and rapidly expanding T and B lymphocytes in concert with the emergence of novel virus-specific T cells. This swift and punctual response also covers viral variants and captures a paradigmatic case of a healthy adaptive immune reaction to infection with a mutating virus.
Assessment of T-cell Reactivity to the SARS-CoV-2 Omicron Variant by Immunized Individuals
Lorenzo De Marco, Silvia D’Orso, Marta Pirronello, Alice Verdiani, Andrea Termine, Carlo Fabrizio, Alessia Capone, Andrea Sabatini, Gisella Guerrera, Roberta Placido, Manolo Sambucci, Daniela F. Angelini, Flavia Giannessi, Mario Picozza, Carlo Caltagirone, Antonino Salvia, Elisabetta Volpe, Maria Pia Balice, Angelo Rossini, Olaf Rötzschke, Emiliano Giardina, Luca Battistini, Giovanna Borsellino
JAMA Network Open, 2022
Key Points Question What is the cellular immunity associated with the Omicron variant of SARS-CoV-2 among immunized individuals? Findings In this cohort study among 61 individuals who had been vaccinated against COVID-19, cellular responses to the mutated regions of the Omicron spike protein were detected in 80% of participants. The mutations were associated with significantly reduced T-cell recognition compared with the vaccine strain, while reactivity to the whole spike protein was present in 100% of participants, and the proportion of remaining immunity to SARS-CoV-2 was estimated to be 87%. Meaning These findings suggest that cellular immunity to the Omicron variant was maintained despite the mutations in its spike protein; thus, immunization may confer protection from severe COVID-19 from the Omicron variant.