NUT carcinoma (NC) is a rare and extremely aggressive form of cancer, usually presenting with intrathoracic or neck manifestations in adolescents and young adults. With no established standard therapy regimen and a median overall survival of only 6.5 months, there is a huge need for innovative treatment options. As NC is genetically driven by a single aberrant fusion oncoprotein, it is generally characterized by a low tumor mutational burden, thus making it immunologically cold and insusceptible to conventional immunotherapy. Recently, we have demonstrated that oncolytic viruses (OVs) are able to specifically infect and lyse NC cells, thereby turning an immunologically cold tumor microenvironment into a hot one. Here, we report an intensive multimodal treatment approach employing for the first time an OV (talimogene laherparepvec (T-VEC); IMLYGIC®) together with the immune checkpoint inhibitor pembrolizumab as an add-on to a basic NC therapy (cytostatic chemotherapy, radiation therapy, epigenetic therapy) in a patient suffering from a large thoracic NC tumor which exhibits an aberrant, unique BRD3:NUTM1 fusion. This case demonstrates for the first time the feasibility of this innovative add-on immunovirotherapy regimen with a profound, repetitive and durable replication of T-VEC that is instrumental in achieving tumor stabilization and improvement in the patient´s quality of life. Further, a previously unknown BRD3:NUTM1 fusion gene was discovered that lacks the extraterminal domain of BRD3.

No abstract

Sarcomas compromise a heterogenous group of tumors of a mesenchymal origin. Although treatment options in many solid tumors have evolved over the past decades, the treatment of advanced sarcoma is still based on conventional chemotherapeutic agents. Beside anthracyclines, alkylating agents such as ifosfamide are frequently used in sarcoma treatment. However, treatment with ifosfamide can cause severe dose- and treatment-limiting side effects, such as ifosfamide-induced neurotoxicity (IIN). Especially in sarcoma, consecutive risk assessment analyses investigating the individual factors associated with the increased incidence in IIN, remain insufficient so far. In this retrospective analysis, we investigated 172 sarcoma patients treated with ifosfamide. Out of 172 patients, 49 patients (28.5%) developed IIN. While gender, age, histologic origin, and tumor stage were not associated with the occurrence of IIN, infusion times, simultaneous radiotherapy, and concomitant use of opioids or anticonvulsants affected the risk of developing IIN. Sarcoma patients with IIN showed an alteration in several inflammatory markers, including a lower lymphocyte count, hemoglobin levels, and calcium levels, as well as elevated GGT, sodium, and CRP levels. Remarkably, the occurrence of IIN was associated with a worse prognosis regarding progression free and overall survival. In addition, high CTCAE grades were negatively associated with overall survival in sarcoma. The observation that an inflammatory state is associated with an increased risk of IIN in sarcoma patients can be used prospectively to further investigate the relationship of inflammation and IIN. In addition, the easily accessible blood markers used in our study to predict IIN can be incorporated into clinical decision making.