Understanding CD30 biology and therapeutic targeting: a historical perspective providing insight into future directions

Abstract

CD30 is a member of the tumor necrosis factor receptor superfamily. It is characteristically expressed in certain hematopoietic malignancies, including anaplastic large cell lymphoma and Hodgkin lymphoma, among others. The variable expression of CD30 on both normal and malignant lymphoid cells has focused research efforts on understanding the pathogenesis of CD30 upregulation, its contribution to lymphomagenesis through anti-apoptotic mechanisms, and its effect on cell survival. Given the restriction of CD30 to certain tumor types, the logical extension of this has been to attempt to exploit it as a therapeutic target. The efficacy of naked anti-CD30 antibodies in practice was, however, modest. Moreover, combinations with bacterial toxins and radioimmunoconjugates have also had limited success. The development of the antibody-drug compound brentuximab vedotin (BV), however, has rejuvenated interest in CD30 as a tumor target. Phase I and II clinical trials in Hodgkin lymphoma, peripheral T-cell lymphoma, cutaneous T cell lymphoma, and even CD30-expressing B-cell lymphomas, have shown the compound is well tolerated, but more importantly, able to deliver meaningful disease control even in patients with multiply relapsed or refractory disease. FDA approval has been granted for its use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. A recent phase III trial of BV in cutaneous T-cell lymphoma has confirmed its superiority to standard of care therapies. In this manuscript, we explore the history of CD30 as a tumor marker and as a therapeutic target, both in the laboratory and in the clinic, with a view to understanding future avenues for further study.

Figure 1

CD30 mediates its effects through a number of diverse signaling pathways, which in concert confer a survival benefit to the cells on which CD30 is upregulated. Stimulation of the CD30 molecule results in trimerization and signal mediation through tumor necrosis factor receptor-associated proteins (TRAF), in particular TRAF2, but also TRAF1 and TRAF5, to stimulate the nuclear factor-kappa B (NFkB) pathway. In addition to this, CD30 ligation also signals through the mitogen-activated protein kinase (MAPK) pathways, including ERK1 and ERK2, which have diverse anti-apoptotic and pro-survival benefits in the neoplastic cell. There appears to be a positive feedback loop between the MAPK/ERK pathway and the nuclear transcription factor JunB, which not only contributes to cell survival, but also upregulates CD30 expression.