Dual CD19-CD70 CAR-T Therapy Shows Superior Lymphoma Control in Preclinical Models, CD70 Identified as Relapse Biomarker
核心洞察
CD70 (搜索) overexpression at diagnosis predicts relapse and shorter progression-free survival in follicular lymphoma (搜索) patients with over 11 years of follow-up.
A novel dual CD19-CD70 CAR-T (搜索) therapy, combining ARI-0001 with a CD27-based anti-CD70 (搜索) CAR, demonstrated enhanced antitumor activity in patient-derived models.
The dual-target strategy achieved superior disease control compared to conventional CD19 (搜索)-directed CAR-T in preclinical follicular lymphoma (搜索) models.
A research team led by IDIBAPS has identified CD70 (搜索) overexpression as a predictive biomarker for relapse in follicular lymphoma (搜索) and developed a dual-target CD19-CD70 CAR-T (搜索) cell therapy that demonstrates superior tumor control in preclinical models. The findings, published in Blood, open a path toward biomarker-driven, personalized immunotherapy for patients at high risk of treatment failure.
CD70 (搜索): A Biomarker for Relapse Risk at Diagnosis
Follicular lymphoma (搜索) is among the most common types of lymphoma. While most patients respond to initial treatment and CD19 (搜索)-directed CAR-T therapies have markedly improved outcomes in advanced cases, a subset of patients ultimately relapse with limited therapeutic options. To investigate the mechanisms underlying these relapses, the research team analyzed tumor samples obtained at diagnosis from a uniformly treated cohort of follicular lymphoma patients with more than 11 years of clinical follow-up.
Using transcriptomics, digital pathology, and functional analyses, the team discovered that patients who subsequently relapsed exhibited elevated expression of the CD70 (搜索) protein in both tumor cells and certain populations of immune cells surrounding the tumor. This characteristic was associated with significantly shorter progression-free survival.
"The identification of CD70 (搜索) at the time of diagnosis allows us to distinguish those people with a higher risk of relapse before the disease progresses. In the future, this biomarker could help to better stratify patients and adapt their therapeutic strategies according to their risk, moving towards a more personalised medicine in follicular lymphoma (搜索)," said Patricia Pérez-Galán, head of the research group on Microenvironment in lymphoma pathogenesis and therapy at IDIBAPS, researcher at CIBERONC (搜索), and co-leader of the study.
Engineering a Dual-Target CAR-T Approach
Building on this discovery, the team proposed converting ARI-0001—the academic CD19 (搜索)-directed CAR-T developed at the institution and already approved for clinical use under the hospital exemption—into a dual CAR-T therapy by incorporating a second CAR directed against CD70 (搜索). The dual construct combines the ARI-0001 CD19 CAR with a CD27-based anti-CD70 CAR, creating a single therapeutic product capable of targeting both antigens simultaneously.
This dual CAR-T was evaluated in patient-derived tumoroids and in animal models of follicular lymphoma (搜索). The results demonstrated higher antitumor activity compared to conventional CAR-T cells directed only against CD19 (搜索), with more effective elimination of tumor cells and superior disease control.
"Our results demonstrate that the CD19 (搜索)-CD70 (搜索) dual target is a viable strategy with great therapeutic potential. In preclinical models, the new CAR-T therapy has achieved better tumour control and has reduced the resistance mechanisms associated with relapses," said Sònia Guedan, head of the research group on Cellular immunotherapies for cancer at IDIBAPS and co-leader of the project.
Broader Implications Beyond Follicular Lymphoma (搜索)
The research team notes that this dual-target strategy could extend beyond follicular lymphoma (搜索) to benefit patients with other aggressive lymphomas, including mantle cell lymphoma and diffuse large B-cell lymphoma. In these diseases, relapses have been associated with reduced expression of CD19 (搜索)—a resistance mechanism that the CD19-CD70 (搜索) dual target may help overcome. Ferran Araujo-Ayala and Maria Ros, both researchers at IDIBAPS and co-first authors of the study, indicated that preliminary results in preclinical models of these additional neoplasms are promising.
Path Toward Clinical Translation
The results support moving this next-generation immunotherapy toward clinical evaluation. The next steps include completing safety studies, optimizing manufacturing processes, and preparing the regulatory dossier to enable application for authorization of a clinical trial.
The project was made possible through funding from La Marató de 3Cat, which supported the identification of CD70 (搜索) as a prognostic biomarker, and the Follicular Lymphoma Foundation (搜索), which funded the generation of the dual CAR-T. Collaboration with Carlos E. de Andrea of Clínica Universidad de Navarra was instrumental in validating results at the protein level. The work also involved four CIBERONC (搜索) groups and received support from AGAUR and the Interreg POCTEFA programme through the THERAVLINFO project.