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 CART 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 non-soluble part of CD30, and the manufacturing process includes a modulation of ex vivo T cell activation, as well as the addition of interleukin-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 classical Hodgkin lymphoma (HL) or CD30+ T cell lymphoma (T-NHL). HSP-CAR30 was mainly composed of memory stem-like (TSCM-LIKE) and central memory (TCM) 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 out of 8 patients with HL achieved complete remission (CR). An additional HL patient achieved CR after a second HSP-CAR30 infusion. Remarkably, 60% of patients have ongoing CR after a mean follow-up of 34 months. Of note, CAR30+ T cells at expansion peak had a predominance of TSCM and TCM 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).