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

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) to improve engraftment, persistence and antitumor activity.

METHODS

T cultures were generated and expanded and transduced at day 1 or 2 with a lentiviral vector encoding the CD30-CAR. Therapeutic 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 cells generated and expanded , despite CD30 expression and fratricide killing of CD30 CAR T cells, were not impaired by soluble CD30 and completely eradicated Hodgkin lymphoma , showing high persistence and long-lasting immunity. In addition, highly enriched CD30-CAR T products confer a survival advantage , 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 products to improve clinical efficacy of CAR T for Hodgkin lymphoma.