HSP-CAR30 with a high proportion of less-differentiated T cells promotes durable responses in refractory CD30⁺ lymphoma

• CART30 with high proportion of less-differentiated memory T cells favors expansion and long-term persistence of memory CART30 cells.

• CART30 was used to treat 10 patients with refractory CD30⁺ lymphoma, with 50% experiencing durable complete responses.

CD30-directed chimeric antigen receptor T-cell therapy (CART30) has limited efficacy in relapsed or refractory patients with CD30⁺ lymphoma, with a low proportion of durable responses. We have developed an academic CART30 cell product (HSP-CAR30) by combining strategies to improve performance. HSP-CAR30 targets a proximal epitope within the nonsoluble part of CD30, and the manufacturing process includes a modulation of ex vivo T-cell activation, as well as the addition of interleukin-21 (IL-21) to IL-7 and IL-15 to promote stemness of T cells. We translated HSP-CAR30 to a phase 1 clinical trial of 10 patients with relapsed/refractory classic Hodgkin lymphoma (HL) or CD30⁺ T-cell non-Hodgkin lymphoma. HSP-CAR30 was mainly composed of memory stem–like (T_SCM-like) and central memory (T_CM) CAR30⁺ T cells (87.5% ± 5%). No dose-limiting toxicities were detected. Six patients had grade 1 cytokine release syndrome, and no patient developed neurotoxicity. The overall response rate was 100%, and 5 of 8 patients with HL achieved complete remission (CR). An additional patient with HL achieved CR after a second HSP-CAR30 infusion. Remarkably, 60% of patients have ongoing CR after a mean follow-up of 34 months. CAR30⁺ T cells at expansion peak had a predominance of T_SCM and T_CM cells, and CAR30⁺ T cells remained detectable in 3 of 5 evaluable patients at least 12 months after infusion. Our study shows that selection of the epitope targeting CD30 and ex vivo preservation of less-differentiated memory T cells may enhance the efficacy of CART30 in patients with refractory HL. This trial is registered at www.clinicaltrials.gov (NCT04653649).