Regular Article CLINICAL TRIALS AND OBSERVATIONS A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma

The majority of Hodgkin lymphoma (HL) patients can be cured with risk-adapted treatment, including chemotherapy and radiotherapy. Even when initially diagnosed with advanced-stage disease,.70% of these patients achieve long-term remission. However, depending on initial risk factors and treatment, 10% to 30% progress or relapse. Of these patients, only up to 50% can be cured with highdose chemotherapyandautologous stemcell transplantation (ASCT). The median overall survival after ASCT failure is ;2 years. A significantly poorer outcome was observed for patients with primary progressive HL or relapse within 12 months after initial therapy. Severe life-threatening treatment-related side effects such as organ toxicity or secondary malignancies might occur during first-line therapy or after treatment. Several new drugs are currently in clinical development for the treatment of relapsed/refractoryHL, including small molecules affecting signaling pathways and specific as well as nonspecific immunotherapeutic approaches. Brentuximab vedotin, an antibody drug conjugate targeting CD30, was the first targeted therapy approved in 2011. Today, brentuximab vedotin is an established treatment of relapsed or refractory HL. However, although the vast majority of patients respond to this treatment, the median progression-free survival is,6 months. This indicates a continuing high medical need for the respective patient population. Immunotherapies play an increasingly important role in the treatment of hematologic malignancies, including HL. Three immunologic approaches are currently the focus of clinical development in HL: (1) the so-called checkpoint inhibition (eg, nivolumab, pembrolizumab, and ipilimumab [https://clinicaltrials.gov/ct2/show/NCT01592370]), (2) the modulation of the immune status and tumor environment (eg, lenalidomide), or (3) the direct engagement of cytotoxic immune effector cells, such asT cells or natural killer (NK) cells, tomediate tumor cell lysis (eg, by engineering T cells with chimeric antigen receptors, or CAR-T cells [https://clinicaltrials.gov/ct2/show/NCT01192464]) or by recruitingNKcells usingbispecific antibodies (AFM13).Tcells andNK cells are immunologic effector cells with the potential to fight cancer via tumor cell lysis. About 15 years ago, 2 bispecific antibodies targeting CD30 tumor cells were investigated in phase 1 clinical studies in HL: an anti-CD303CD16 and an anti-CD303CD64 antibody.