Memory stem T cells modified with a redesigned CD30‐chimeric antigen receptor show an enhanced antitumor effect in Hodgkin lymphoma

Abstract

Abstract 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 (TSCM) to improve engraftment, persistence and antitumor activity. Methods TSCM‐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 TSCM‐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 TSCM‐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 TSCM‐like products to improve clinical efficacy of CAR T for Hodgkin lymphoma.

Keywords

• chimeric antigen receptor
• immunotherapy
• memory stem T cells