Trial in progress: Open-label dose-finding and dose-expansion study to evaluate the safety, expansion, persistence, and clinical activity of UCART20x22 in subjects with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) nathali-01 Free

Despite significant advances in the treatment of B-cell non-Hodgkin's lymphoma, new treatment approaches are needed for patients with relapsed/refractory (R/R) disease, especially for those with chemo-refractory NHL who fail to achieve a response or relapse early after the standard of care. UCART20x22 is a first-in-class allogeneic, non-alloreactive, engineered human CAR T-cell product endowed with dual CAR expression, targeting both CD20 and CD22 antigens and represents a potential new therapeutic option for patients with R/R B-NHL. TALEN ® gene editing technology is used to inactivate the TRAC and CD52 genes to minimize graft-versus-host disease (GvHD) and allow for the use of alemtuzumab (CLLS52, an anti-CD52 monoclonal antibody) in the lymphodepletion (LD) regimen. Clinical and preclinical studies suggest that exogenous low dose Interleukin-2 (IL-2) administration can enhance the expansion and persistence of CAR-T cells significantly to boost CAR-T efficacy without exacerbating toxicity. An in vivo study of UCART20x22 in combination with IL-2 demonstrated that IL-2 dosing can increase persistent circulating levels of UCART20x22 in a mouse model harboring disseminated tumors and enhance anti-tumor efficacy, without inducing treatment-associated toxicity. We hypothesize that combining UCART20x22 with low-dose IL-2 may deepen and extend anti-tumor activity in patients with R/R B-NHL.

UCART20x22 monotherapy is being evaluated in an ongoing first-in-human, open-label Phase 1/2a dose-finding and dose-expansion study (Nathali-01, NCT05607420) in patients with R/R B-NHL. The protocol is now amended to add a treatment cohort of UCART20x22 in combination with low-dose IL-2 in dose- finding and dose expansion. After Lymphodepletion with FCA3 (fludarabine 30 mg/m² × 3d, cyclophosphamide 0.5g/m² × 3d, CLLS52 in a weight-based dose x 3 or 4d), a single infusion of UCART20x22 is administered at a flat dose level ([DL1] 50 x 10⁶ cells; [DL2] and 150 x 10⁶ cells). A short course of low-dose IL-2 will be given as a subcutaneous injection after UCART20x22 infusion for patients enrolled in the combo cohort. Phase 1 with up to 42 eligible patients follows BOIN design and explores UCART20x22 dose levels with or without IL-2 in conjunction with the corresponding FCA3 to identify the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D). UCART20x22 at DL1 with IL-2 combo cohort will commence after UCART20x22 monotherapy at DL1 with the corresponding FCA is deemed safe. Once RP2D is determined, the phase 2 expansion of up to 38 patients with R/R LBCL in two dose cohorts is planned, utilizing a Simon's two-stage design to evaluate the clinical activity of UCART20x22 at the RP2D with or without IL-2 in combination with optimal LD. Nathali-01 study began enrolling patients in November 2022 and is ongoing in US, France and Spain. Dose escalation up to 3 cohorts of UCART20x22 monotherapy under FCA1 has been completed, enrollment to UCART20x22 monotherapy at dose cohort 1 with FCA3 began in May 2025. AEs are assessed according to CTCAE v5. Tumor response is determined according to Lugano 2014 criteria and safety findings reviewed by the PSRC, which will determine the RP2D and MTD. Patients must be aged 18- 80 years old, have Eastern Cooperative Oncology Group performance status ≤1, with adequate organ function, and have CD20+ and /or CD22+ B-NHL that progressed after ≥2 lines of systemic therapy including an anti-CD20 antibody and an alkylating agent or approved autologous anti-CD19 CAR T-cell therapy if available. Exclusion criteria include active CNS lymphoma, hypersensitivity to alemtuzumab or IL-2 if applicable, or history of ADA against alemtuzumab or IL-2 if applicable. Primary endpoints are incidence of dose-limiting toxicities and the incidence and severity of treatment-emergent adverse events. Secondary endpoints include alemtuzumab PK parameters, objective response rate, duration of response, progression-free survival, and overall survival.