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Monica Valente,1 Maura Colucci,2 Virginia Vegni,3 Valentina Croce,2 Cristiana Bellan,4 Giulia Rossi,1 Giulia Gibilisco,2 Francesco Frongia,2 Raffaella Guazzo,4 Claudia Ghiribelli,5 Elena Bargagli,6 Vinno Savelli,7 Matteo Ravara,2 Tommaso Sani,2 Elena Simonetti,2 Michele Maio,1– 3 Luana Calabrò,8,9 Anna Maria Di Giacomo1– 3 1Department of Oncology, Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy; 2Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; 3NIBIT Foundation Onlus, Siena, Italy; 4Department of Medical Biotechnology, Pathology Unit, University Hospital of Siena, Siena, Italy; 5Cardio-Thoracic-Vascular Department, Interventional and Diagnostic Bronchoscopy Unit, University Hospital of Siena, Siena, Italy; 6Department of Medicine, Surgery and Neurosciences, Respiratory Diseases Unit, University of Siena, Siena, Italy; 7Department of Medicine, Surgery and Neurosciences, Surgical Oncology Unit, University Hospital of Siena, Siena, Italy; 8Department of Translational Medicine, University of Ferrara, Ferrara, Italy; 9Department of Medical Oncology, University Hospital of Ferrara, Ferrara, ItalyCorrespondence: Anna Maria Di Giacomo, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy, Tel +39-0577-586336, Fax +39-0577-586303, Email annamaria.digiacomo@unisi.itPurpose: Treatment with immune-checkpoint inhibitors (ICIs) can be associated with a wide spectrum of immune-related adverse events (irAEs). Among irAEs, immune-mediated pneumonitis (im-PN) is a rare but potentially life-threatening side effect. TPrompt multidisciplinary diagnosis and effective management of im-PN may be essential to avoid severe complications and allowing resumation of therapy.Patients and Methods: We collected a case series of skin (melanoma, cutaneous squamous cell carcinoma-CSCC), lung, and mesothelioma cancer patients (pts), treated with ICI at the Center for Immuno-Oncology University Hospital of Siena, Italy, and diagnosed with im-PN. Clinical and radiologic data were thoroughly collected, as well as bronchoalveolar lavage (BAL) samples; im-PN was graded using CTCAE v. 5.0. Radiological patterns were reported according to the Fleischner Society classification.Results: From January 2014 to February 2023, 1004 patients with melanoma (522), CSCC (42), lung (342) or mesothelioma (98) were treated with ICI (619 monotherapy; 385 combination). Among treated patients, 24 (2%) developed an im-PN and 58% were symptomatic. Im-PN were classified as grades G1 (10) and G2 (14). Prompt steroid treatment led to complete resolution of im-PN in 21 patients, with a median time to resolution of 14 weeks (range: 0.4– 51). Twelve patients resumed ICI therapy once fully-recovered and 2 experienced a recurrence that completely resolved with steroids after resumption of treatment. Three radiologic patterns were identified: organizational pneumonia-like (67%), pulmonary eosinophilia (29%), and hypersensitivity pneumonitis (4%). Furthermore, BAL analysis performed in 8 (33%) patients showed an inflammatory lymphocytic infiltrate, predominantly consisting of foam cell-like macrophage infiltrates in 6 cases. Notably, transmission electron microscopy evaluation performed in 2 patients revealed a scenario suggestive of a drug-mediated toxicity.Conclusion: Im-PN is a rare but challenging side effect of ICI therapy, with variable time of onset and with heterogeneous clinical and radiological presentations. A multidisciplinary assessment is mandatory to optimize the clinical management of im-PN. Keywords: immunotherapy, immune-checkpoint inhibitors, immune-mediated pneumonitis, cancer

Elena Simonetti,1 Serena Cutarella,1 Monica Valente,2 Tommaso Sani,1 Matteo Ravara,1 Michele Maio,1– 3 Anna Maria Di Giacomo1– 3 1University of Siena, Siena, Italy; 2Center for Immuno-Oncology, Medical Oncology and Immunotherapy, Department of Oncology, University Hospital, Siena, Italy; 3NIBIT Foundation Onlus, Genoa, ItalyCorrespondence: Anna Maria Di Giacomo, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Viale Bracci, 14, Siena, 53100, Italy, Email annamaria.digiacomo@unisi.itAbstract: Harnessing the immune system with immune-checkpoint(s) blockade (ICB) has dramatically changed the treatment landscape of advanced melanoma patients in the last decade. Indeed, durable clinical responses and long-term survival can be achieved with anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) and anti-Programmed cell Death-1 (PD-1) monoclonal antibodies (mAb) either alone or in combination. Despite these unprecedented results, due to intrinsic or acquired resistance to ICB-based immunotherapy, about half of metastatic melanoma (MM) patients neither respond to therapy nor experience durable clinical benefit or long-term survival. To improve the efficacy of ICB therapy among a larger proportion of MM patients, in addition to the targeting of immune-checkpoint(s) inhibitors (ICI) such as CTLA-4 or PD-1, several co-stimulatory molecules, such as Inducible T-cell COStimulator (ICOS), CD137 and OX40, have been investigated in MM, with initial signs of activity. Thus, a number of MM patients have been exposed to co-inhibitory and co-stimulatory mAb in the course of their disease. Being aware of the clinical outcome of such patients may pave the way to novel and more effective clinical approaches and therapeutic sequences for MM patients. Here we report a paradigmatic clinical case of a cutaneous MM patient who achieved multiple and durable complete responses, leading to an extraordinary long-term survival with sequential ICB therapies, suggesting the possibility to build a highly effective continuum of care with co-inhibitory and co-stimulatory therapeutic mAb.Keywords: immunotherapy, combinations, anti-PD1, anti-CTLA-4, CD137 agonist, ICOS agonist