Altres ajuts: This work was supported in part by grants from La Marató TV3 (Exp. 20130710), Deutsche José Carreras Leukämie Stiftung (DJCSL 10R/2016), Fundación Científica Asociación Española Contra el Cáncer (AECC-AIO2017), Fundacion Bancaria 'La Caixa', TerCel (SG/11/2008)

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) to improve engraftment, persistence and antitumor activity. T 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. CD30-CAR T 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 products confer a survival advantage in vivo, in contrast to more differentiated CAR T cells, with higher tumor infiltration and enhanced antitumor effect. This study supports the use of a refined CD30-CAR T cells with highly enriched T products to improve clinical efficacy of CAR T for Hodgkin lymphoma. We have studied the efficacy of a redesigned CD30-chimeric antigen receptor (CAR) targeting a proximal epitope to enhance the antitumor efficacy. CD30-CAR T cells show potent in vivo antitumor effect in different Hodgkin lymphoma models, and overcome inhibition by soluble CD30. CD30-CAR memory stem T-cell products show long-term persistence, improved tumor homing and long-lasting immunity.