Put the CAR-T before the HRS: Advances in Anti-CD30 Immunotherapy Targeting Hodgkin/Reed-Sternberg Cells in Classical Hodgkin Lymphoma

Classical Hodgkin lymphoma (cHL) is characterized by rare Hodgkin/Reed-Sternberg (HRS) tumor cells that uniformly express cluster of differentiation (CD)30 molecules and orchestrate an immunosuppressive tumor microenvironment, making CD30 an attractive and selective therapeutic target. We summarize the biological rationale for CD30 as a therapeutic target and the preclinical and clinical evidence across major platforms: antibody-drug conjugates (brentuximab vedotin), monoclonal antibodies (including acimtamig and its combinations with Natural Killer cells), second- and third-generation chimeric antigen receptor (CAR)-T cells, and alternative modalities. Particular attention is given to standardized response assessment (IWG, Lugano, RECIL criteria), which enables appropriate cross-trial comparisons. Taken together, the data indicate that beyond the established role of brentuximab vedotin, CD30-directed CAR-T cells and bispecific antibodies demonstrate high activity in refractory cHL, especially when used with fludarabine-containing lymphodepletion, combined with programmed cell death 1 (PD-1) receptor blockade as a strategy to eradicate minimal residual disease. Key challenges include durable effector-cell persistence and optimization of sequencing and combinations; notably, loss of CD30 as an escape mechanism appears uncommon. Integrating mechanistic insights into HRS biology with clinical trial data highlights strategies to enhance the efficacy, safety, and accessibility of CD30-directed immunotherapy. This review aims to provide a concise overview of CD30-targeted approaches in cHL, emphasizing therapeutic outcomes and the evolution of CAR-T technologies.