Schematic presentation of phenotypic features targetable by novel therapeutic agents. The HRS cell characteristic cell-surface antigen CD30 represents an attractive target for antibody-drug conjugates, such as brentuximab vedotin (BV), or for cellular-based therapies, such as CAR T cells. In Epstein-Barr virus (EBV)–positive cases, latent membrane protein 2 (LMP-2) is recognized by patient-derived cytotoxic T lymphocytes (CTLs), which are isolated and expanded ex vivo before reinfusion into the patient. Novel concepts aim at restoration of the B-cell phenotype by epigenetic modification of silenced B cell–related genes and/or transcription factors. For example, reexpressed CD19 and CD20 can then be targeted by monoclonal antibodies (mAbs) or CAR T cells, similar to B-cell non-HLs. ATO, arsenic trioxide.