RESUMO
Medulloblastoma is the most common malignant brain tumor in children. Immunotherapy is yet to demonstrate dramatic results in medulloblastoma, one reason being the low rate of mutations creating new antigens in this entity. In tumors with low mutational burden, gene fusions may represent a source of tumor-specific neoantigens. Here, we reviewed the landscape of fusions in medulloblastoma and analyzed their predicted immunogenicity. Furthermore, we described a new in-frame fusion protein identified by RNA-Seq. The fusion involved two genes on chromosome 2 coding for the enhancer of polycomb homolog 2 (EPC2) and GULP PTB domain containing engulfment adaptor 1 (GULP1) respectively. By qRT-PCR analysis, the fusion was detected in 3 out of 11 medulloblastoma samples, whereby 2 samples were from the same patients obtained at 2 different time points (initial diagnosis and relapse), but not in other pediatric brain tumor entities. Cloning of the full-length sequence indicated that the fusion protein contains the N-terminal enhancer of polycomb-like domain A (EPcA) of EPC2 and the coiled-coil domain of GULP1. In silico analyses predicted binding of the neoantigen-derived peptide to HLA-A*0201. A total of 50% of the fusions described in the literature were also predicted to produce an immunogenic peptide. The EPC2-GULP1 fusion peptide was able to induce a de novo T cell response characterized by interferon gamma release of CD8+ cytotoxic T cells in vitro. While the functional relevance of this fusion in medulloblastoma biology remains to be clarified, our data support an immunotherapeutic approach for pediatric medulloblastoma patients carrying the EPC2-GULP1 fusion and other immunogenic fusions.
RESUMO
BACKGROUND: Rituximab is a well-established component of treatment regimens for B-cell non-Hodgkin lymphoma. Rituximab binds the CD20 antigen on the surface of B lymphocytes, causing an enhanced clearance of malignant and benign B cells. Thus, rituximab leads to depletion of normal B lymphocytes as well, which can cause substantial immunodeficiency. Ibrutinib inhibits the Bruton tyrosine kinase and thereby B-cell activity. It is used for the treatment of different B-lymphocyte malignancies, such as mantle cell lymphoma. Recently, the combination of both drugs has been tested in various clinical scenarios. CASE PRESENTATION: We present a case of disseminated enterovirus infection resulting from combined rituximab and ibrutinib maintenance treatment in a 57-year-old Caucasian patient. with mantle cell lymphoma. Initially presenting with myositis symptoms, further diagnostic investigation revealed myocarditis, enteritis, myeloencephalitis, and hepatitis. These organ manifestations led to potentially life-threatening complications such as rhabdomyolysis, delirium, and heart rhythm disturbances. After treatment with high-dose intravenous immunoglobulins, virus clearance was achieved and organ functions could be restored. CONCLUSIONS: This case emphasizes the risk of combined therapy with rituximab/ibrutinib for severe immune-related side effects with the necessity of continuous patient monitoring. High-dose intravenous therapy should be considered as treatment for severe enterovirus infection. In severe enterovirus infections, we recommend subtyping for the development of efficient preventive and therapeutic strategies.