Published in the journal Molecular Therapy, the study was coordinated by Sònia Guedan, the head of the research group Cellular immunotherapies for cancer, and Álvaro Urbano, the director of Hospital Clínic Barcelona’s CAR-T programme and head of the IDIBAPS research group Haematopoietic progenitor cell transplantation. This article has earned a specific comment within the journal (signed by three authors from University College London) that states that ARI0003 ushers in a new era in the treatment of non-Hodgkin lymphoma.
What is non-Hodgkin lymphoma?
Non-Hodgkin lymphoma is a type of haematological cancer that affects lymphocytes, a type of white blood cell responsible for defending the body against infections. It is the seventh-most common cancer worldwide and accounts for 4% of all new cancer cases in Spain. The disease may cause symptoms such as swollen lymph nodes, fever, weight loss and fatigue, and can be resistant to conventional treatments. It is estimated that over 10,000 new cases of this disease are diagnosed in Spain each year.
A new strategy to overcome current limitations
CAR-T therapies consist of genetically modifying the patient's T lymphocytes so they can recognise and destroy tumour cells. Although CAR-T therapies directed against the CD19 antigen, such as ARI-0001, have proven effective in many patients, some tumour cells manage to escape treatment by decreasing CD19 expression, which causes relapses.
To overcome this limitation, the research team has developed CAR-T ARI0003, a dual therapy that combines the ability to attack CD19 and a second antigen, BCMA, which is also present in tumour cells of patients with non-Hodgkin lymphoma. A CAR-T therapy against BCMA, ARI0002h, has already been developed at IDIBAPS-Hospital Clínic.
‘This strategy allows us to expand the field of action and maintain efficacy, even in tumours with low CD19 expression’, Sònia Guedan explains.
Preclinical validation with advanced technology
The study compared different strategies to generate dual CAR-T cells containing a combination of ARI-0001 and ARI-0002h.
The process to select the best candidate included the use of 3D models derived from patients with non-Hodgkin lymphoma who had relapsed after initial treatment with ARI-0001, mouse models with low CD19 expression and advanced protein structure prediction technologies in collaboration with the Centre for Genomic Regulation (CRG).
The results validate the use of BCM as a target to co-direct CAR-T cells, together with CD19, and show that ARI0003 can eliminate tumour cells with high and low CD19 expression both in vitro and in animal models.
‘Thanks to the results achieved, the Spanish Agency for Medicines and Health Products (AEMPS) has approved a clinical trial to test the safety and efficacy of ARI0003 in patients with non-Hodgkin lymphoma who have relapsed or have not responded to other treatments. The study has already begun recruiting and treating patients’, Alvaro Urbano explains.
This study was funded by Fundació ”la Caixa” and the European Innovative Medicines Initiative (T2Evolve) consortium, with the support of the Ramon y Cajal Programme.
Study reference:
Bachiller M, Barceló-Genestar N, Rodriguez-Garcia A, Alserawan L, Dobaño-López C, Giménez-Alejandre M, Castellsagué J, Colell S, Otero-Mateo M, Antoñana-Vildosola A, Español-Rego M, Ferruz N, Pascal M, Martín-Antonio B, Anguela XM, Fillat C, Olesti E, Calvo G, Juan M, Delgado J, Pérez-Galán P, Urbano-Ispizua Á*, Guedan S*. ARI0003: Co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma. Mol Ther. 2024 Nov 19:S1525-0016(24)00755-X. doi: 10.1016/j.ymthe.2024.11.028. (*both authors contributed equally)
