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Objectives: Adoptive cell therapy (ACT) with mature T cells modified with a chimeric antigen receptor has demonstrated improved outcome for B-cell malignancies. However, its application for others such as Hodgkin lymphoma remains a clinical challenge. CD30 antigen, expressed in Hodgkin lymphoma cells, is absent in most healthy tissues, representing an ideal target of ACT for this disease. Despite that, efficacy of CD30-chimeric antigen receptor (CAR) T cells for Hodgkin lymphoma remains modest. Here, we have developed and tested a novel CD30-CAR T to improve efficacy of CD30-CAR therapy, using a targeting epitope within the non-cleavable part of CD30 receptor, and memory stem T cells (T SCM ) to improve engraftment, persistence and antitumor activity., Methods: T SCM-like cultures were generated and expanded ex vivo and transduced at day 1 or 2 with a lentiviral vector encoding the CD30-CAR. Therapeutic in vivo experiments were performed using NSG mice injected with L540 (sc) or L428 (iv) and treated with CD30-CAR T cells when the tumor was established., Results: CD30-CAR T SCM-like cells generated and expanded ex vivo , despite CD30 expression and fratricide killing of CD30 + CAR T cells, were not impaired by soluble CD30 and completely eradicated Hodgkin lymphoma in vivo , showing high persistence and long-lasting immunity. In addition, highly enriched CD30-CAR T SCM-like products confer a survival advantage in vivo , in contrast to more differentiated CAR T cells, with higher tumor infiltration and enhanced antitumor effect., Conclusion: This study supports the use of a refined CD30-CAR T cells with highly enriched T SCM-like products to improve clinical efficacy of CAR T for Hodgkin lymphoma., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)