Chimeric Antigen Receptor T-Cell Therapy Targeting Tumor Necrosis Factor Receptor Superfamily Member 8 (CD30) for Relapsed or Refractory Anaplastic Large Cell Lymphoma: Rationale, Strategies, and Emerging Clinical Evidence

Chimeric Antigen Receptor (CAR) T-cell therapy has fundamentally altered the treatment paradigm for relapsed or refractory (R/R) B-cell malignancies. However, translating this success to T-cell lymphomas has been impeded by a critical biological barrier: fratricide. This process describes the self-destruction of therapeutic T-cells caused by their shared expression of target antigens, such as Tumor Necrosis Factor Receptor Superfamily Member 8 (CD30), following activation. Anaplastic Large Cell Lymphoma (ALCL), characterized by its uniform and high-level expression of CD30, represents both an ideal candidate for this approach and a significant scientific challenge. This comprehensive review begins by outlining the established landscape of approved CD19- and BCMA-directed CAR-T therapies to provide context. It then focuses specifically on the application of anti-CD30 CAR-T therapy for ALCL, examining the molecular mechanisms that drive fratricide. We explore the innovative engineering and manufacturing strategies developed to overcome this obstacle, including ultrarapid production protocols, the selection of virus-specific T-cells, and precise genetic disruption of the TNFRSF8 gene using CRISPR/Cas9 technology. An analysis of early phase clinical trial data reveals encouraging efficacy, with high rates of durable complete responses observed even in heavily pretreated patients who have failed brentuximab vedotin therapy. Furthermore, these initial studies report a remarkably favorable safety profile, characterized by a near absence of severe cytokine release syndrome and neurotoxicity─a feature that distinctly contrasts with CD19-directed therapies. While these findings are promising, it is essential to acknowledge that the current evidence base remains preliminary, derived from small, heterogeneous patient cohorts and requiring validation in larger, more definitive trials with extended follow-up. By successfully addressing the challenge of fratricide, anti-CD30 CAR-T therapy holds the potential to become a transformative and potentially curative option for patients with R/R ALCL and may offer a valuable blueprint for developing effective immunotherapies against other T-cell malignancies.