The study, published in the Journal for ImmunoTherapy of Cancer, is a preclinical project carried out in cell and animal models, and shows that a minimal change in the CAR-T structure allows better tumour control in situations of low expression of the BCMA antigen, one of the main causes of relapse after this type of therapy.
The study was coordinated by Carlos Fernández de Larrea, Head of the Hematology Department at Clínic and of the IDIBAPS group on Myeloma, Amyloidosis, Macroglobulinemia and other Gammopathies, and Luis Gerardo Rodríguez Lobato, hematologist at Clínic and researcher in the same group. The first authors were Oriol Cardús and Joan Mañé Pujol.
Multiple myeloma and the challenge of relapse after CAR T therapy
Multiple myeloma is a blood cancer that affects plasma cells in the bone marrow. Although treatments have improved substantially, the disease remains incurable for most patients, who typically experience several relapses throughout its course.
BCMA‑targeted CAR T therapies have represented a major advance for people with relapsed or refractory multiple myeloma. However, a significant proportion of patients eventually redevelop the disease. Relapse mechanisms include reduced BCMA expression on tumour cells, T‑cell exhaustion and limited persistence of CAR T cells in the body.
An academic CAR T developed at Clínic-IDIBAPS
Hospital Clínic Barcelona and IDIBAPS developed the academic CAR T therapy ARI0002h (cesnicabtagene autoleucel), which has already shown positive results in patients with refractory multiple myeloma in an academic clinical trial.
Building on this foundation, the research team designed a new construct, ARI2h TM28, which preserves the components of the original CAR except for one specific modification: replacing the CD8α transmembrane domain with a CD28 transmembrane domain. This region acts as an anchor for the receptor and can influence how the T cell is activated.
Improved sensitivity to tumours with low BCMA expression
In cell culture experiments, ARI2hTM28 showed similar activity to ARI0002h against tumour cells with normal BCMA levels. “However, when tested against myeloma models with reduced antigen expression, ARI2hTM28 was clearly more effective at recognising and eliminating tumour cells,” says Luis Gerardo Rodríguez Lobato.
The study also includes experiments in animal models that reproduce relapse scenarios by introducing myeloma cells with low BCMA expression. In this context, the new CAR T provided better tumour control and improved survival, particularly in the early stages after the cancer reappeared.
The team also analysed the internal functioning of the CAR T cells. ARI2h TM28 showed a more efficient metabolic profile, with reduced exhaustion and better persistence — suggesting a greater ability to sustain antitumour activity.
“Although the results will need to be confirmed in future clinical trials, the study shows that small structural modifications can enhance the effectiveness and persistence of academic CAR T therapies in the face of relapse mechanisms such as BCMA loss,” concludes Carlos Fernández de Larrea.
The study received support from CRIS Cancer Foundation, the Spanish Association Against Cancer (AECC), the Carlos III Institute of Health, the European Union, the International Myeloma Society, the Government of Catalonia and the University of Barcelona.
Study reference:
Cardus O, Mañé Pujol J, de Daniel A, Moreno DF, Oliveira TGM, Battram AM, Salsench SV, Perez-Amill L, Llobregat H, Carpio Mármol J, Martin-Antonio B, Oliver-Caldes A, Munárriz D, Juan M, Urbano-Ispizua A, Rodríguez-Lobato LG, Fernández de Larrea C. Enhanced antitumoral activity of the academic CAR-T ARI0002h against normal and low BCMA-expressing myeloma cells after incorporating a transmembrane CD28 domain. J Immunother Cancer. 2026 Mar 3;14(3):e011864. doi: 10.1136/jitc-2025-011864.
