Initial results of a CRUK phase I/II, first in human trial of the CAR t-cell engager protein aleta-001 in patients who have received anti-CD19 CAR t-cell therapy for the treatment of b-cell malignancies

Abstract Background Anti-CD19 CAR T-cell therapies have been practice-changing in the management of refractory and relapsed (r/r) B-cell malignancies with encouraging long-term outcomes. However, 40-60% of patients relapse within 6 months of CAR T-cell infusion. Low or absent CD19 expression on tumour cells is a common cause of treatment failure following CD19-targeting CAR T-cell therapy. ALETA-001 is a first-in-class CAR T-cell engager protein developed as an off-the-shelf solution to address this issue. It contains a CD19 extracellular domain for engaging CD19-targeting CAR T-cells, an anti-CD20 VHH for binding to CD20 antigen on the B-cell surface and an anti-albumin VHH for half-life extension. ALETA-001 is designed to promote anti-tumour efficacy through enhanced antigen availability resulting in reactivation of anti-CD19 CAR T cells, redirecting them to the CD20 antigen on the tumour cell, thus circumventing low or absent CD19 expression and potentially allowing for dual targeting of both CD19 and CD20. Methods ALETA-001 is being evaluated in a multi-centre, open-label Phase I/II trial in patients with B-cell non-Hodgkin lymphoma (NHL) who have received standard of care anti-CD19 CAR T-cell therapy. A safety lead-in will determine safety and tolerability along with a recommended dose, timing and schedule of administration for a subsequent expansion phase (RP2D). The pharmacokinetic (PK) profile, clinical and pharmacodynamic (PD) activity of ALETA-001 are also being evaluated. Two time points are being investigated in the safety lead-in phase for commencement of ALETA-001:Delayed dosing cohort (cohort 1): For patients who are at least 4 weeks post CAR T-cell therapy and are either in less than a complete remission (CR) on PET scan at 4 weeks or have achieved an initial response but subsequently relapse with biopsy proven disease within 9 months.Early dosing cohort (cohort 2): In this cohort, ALETA-001 is administered to patients between 10 to 18 days post CAR T-cell therapy. In both cohorts, ALETA-001 is administered intravenously as a 2-hour infusion fortnightly (doses from 0.4mg/kg to 6mg/kg) until unacceptable toxicity, disease progression or for a total duration varying between 3-12 months depending on the cohort and response. Here we report initial results from our ongoing study in B-cell NHL. Results As of 9th July 2025, 10 patients with r/r large B-cell lymphoma (LBCL) have been enrolled into cohort 1 and received fortnightly infusions of ALETA-001. The interval between CAR T-cell therapy and first dose of ALETA-001 ranged from 46 to 158 days. Median number of infusions given was 3. In total, 57 treatment emergent adverse events have been recorded, 4 of which were considered serious including back pain, jejunal perforation (both CTCAE Grade 2) and clostridium difficile infection (CTCAE Grade 3), all not related to ALETA-001. The only serious adverse event (SAE) considered possibly related to ALETA-001 was cytokine release syndrome (ASTCT Grade 1). No Dose Limiting Toxicities have been observed. The observed PK profile is consistent with a molecule utilising albumin binding for half-life extension and ALETA-001 exposure remained above concentrations expected to have activity. CAR T-cell populations in peripheral blood showed robust expansion in 4/6 patients evaluated to date. Of 10 patients treated, one partial response and two complete responses have been recorded, including one patient who achieved CR from known lymphoma but developed progressive lesions on PET scan, subsequently confirmed to be metastatic prostate cancer on biopsy. The other two responding patients remain on study at the time of data cut off (36 and 12 weeks respectively). Both had biopsy proven r/r LBCL post CAR T-cell therapy at study enrolment. Updated data will be presented at the conference. Conclusions Preliminary data support a highly tolerable safety profile for ALETA-001 at all doses tested, with no ALETA-001-related SAEs greater than Grade 1 observed to date. In keeping with its mechanism of action, robust CAR T-cell expansion was observed in several treated patients. Preliminary efficacy data shows encouraging response in a proportion of patients treated 4 weeks or later after CAR T-cell therapy. ALETA-001 will continue to be evaluated at 10-18 days post CAR-T to explore safety PK, PD and efficacy at this earlier time point.

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