HSP-CAR30, an Academic Memory-Enriched CART30, for the Treatment of Relapsed or Refractory Hodgkin Lymphoma and CD30+ T Cell Lymphoma: Clinical Results of a Phase I/II Trial

Chimeric antigen receptor T cells targeting CD30 (CART30) in patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (HL) have shown clinical responses. However, most patients eventually relapse. Presence of early-memory T cells in the CART infusion product (i.e., memory stem T cells -T_SCM-), was previously correlated with clinical efficacy and survival after CART therapy in lymphoma patients. We designed a CAR which binds to an epitope within the non-soluble region of the CD30 molecule, and generated CART30 products enriched in less-differentiated memory T cells (HSP-CAR30) to improve antitumor efficacy (Álvarez/Escribá et al. 2021). HSP-CAR30 was translated to a phase I/II trial for R/R patients with HL or CD30⁺T-cell non-Hodgkin lymphoma (T-NHL) (#NCT04653649). Here, we present data on the long-term follow-up of the phase I and report, for the first time, results from the ongoing phase II study.

Methods: Patients (age 18-70y) with HL were R/R to chemotherapy, brentuximab (BV), and anti-PD-1; T-NHL patients were R/R to at least 2 lines, including BV. In the phase I (n=10 patients), 3 doses of CAR30⁺ T cells (3, 5 and 10x10⁶/kg) were evaluated in a dose escalation fashion; the recommended phase II cell dose was 5x10⁶/kg CAR30⁺ T cells. HSP-CAR30 was infused fresh, with a vein-to-vein time (i.e., from apheresis to infusion) of 10 days. Primary endpoints were complete response (CR) rate and safety. Secondary endpoints included overall response (OR) rate, disease-free survival (DFS), and cellular kinetics.

Results: As of July 26, 2024, 31 patients (median age 42.1; min to max, 18-65) were included (29 HL and 2 T-NHL), and 28 received HSP-CAR30. Median number of previous lines was 5 (3 – 11). Most patients were primarily refractory (71%), and 76% had progressive disease (PD) at the time of receiving HSP-CAR30. Lymphodepletion with fludarabine/bendamustine was administered to 76% of patients and 24% of them received fludarabine/cyclophosphamide. HSP-CAR30 products showed a mean CAR30 expression of 94.76±0.6%, with a predominance of memory T cells, both in CD4⁺ (T_SCM33±6.8%, T_CM 54.7±6.7%) and CD8⁺ (T_SCM 49.3 ±7.7%, T_CM 36.6±9%).

Toxicity assessment revealed CRS in 39% of patients, 10 patients (91%) with grade 1, and 1 patient (9%) with grade 3. One patient had grade 3 ICANS that fully resolved with steroids and anakinra, and one had grade 1 macrophage activation syndrome. Self-limiting grade 1 skin rash was observed in 6 (21%) of patients. One patient with history of cytomegalovirus (CMV) infections developed CMV pneumonia, and one patient had pulmonary tuberculosis, both resolved. Two patients developed myeloid neoplasms; one showed a TP53 mutation with high VAF in the bone marrow performed before CART30. Eleven patients died, 9 (82%) due to PD and 2 (18%) due to second neoplasms. There were no deaths related to HSP-CAR30.

As of data cutoff, the mean follow-up was 21.7 months (9 - 37). Efficacy assessment, performed in 27 evaluable patients, showed an OR rate of 89%, including 37% CR. Overall survival at 12 months was 69.8% (CI 95% 54.3% - 89.7%). Progression-free survival at 12 months was 37% (CI 95% 22.6% - 60.6%). Mean duration of response for all patients was 10 months (0.6 – 36.6), and 21.1 months (9.3 – 36.6) for patients with CR. One HL patient treated in the phase I had PD and achieved an ongoing CR (+22 months) after a second HSP-CAR30 infusion.

Mean time to CAR30⁺ T cells peak expansion was 23.6 days (4 – 91) with a mean of 14.6±3.8% CAR30⁺ T cells in peripheral blood. Preliminary data of T cell composition at expansion peak showed a predominance of T_SCM and T_CM cells over more differentiated effector T cells.

Conclusion: HSP-CAR30, the first academic CART30 developed in Europe, results in durable complete responses in heavily-treated HL patients with a favorable safety profile. This trial, with a limited number of patients, shows the potential of memory-enriched CART30 therapy for HL patients who have failed all standard therapies, and support continued development of HSP-CAR30 in patients with refractory HL.