Jerina Hoxha
19.12.25
New research in Cancer Cell links CD4 CAR T cells to outcomes and side effects in multiple myeloma
A newly published study in Cancer Cell sheds light on the “secret sauce” behind the success of Cilta-cel, a BCMA-targeting CAR T cell therapy for relapsed/refractory multiple myeloma. Led by researchers from the Universitätsklinikum Leipzig and a multidisciplinary consortium, the study challenges previous assumptions by highlighting the critical role of CD4-positive CAR T cells, not just CD8, in driving both therapeutic responses and side effects.
Background
Until now, most clinical and immunological attention in CAR T therapies has focused on CD8 cytotoxic T cells, known for their tumour-killing properties. However, this study reports that in the case of Cilta-cel, a distinct population of cytotoxic CD4 CAR T cells, expressing eomesodermin and granulysin, expands significantly and correlates with both patient outcomes and observed toxicities.
Using a longitudinal, single-cell multi-omic atlas, the researchers explored patient samples over time to understand the immune dynamics post-treatment. The results open a new chapter in CAR T cell biology, with direct implications for treatment design and clinical monitoring.
Key Points
Robust expansion of CD4+ cytotoxic CAR T cells following Cilta-cel infusion.
These cells express eomesodermin and granulysin, correlating with both anti-tumour effects and side effects such as neurotoxicity.
The pre-existing TCR repertoire and its dynamics are important to predict outcomes and side effects.
Soluble BCMA is a great marker to predict and monitor response.
Plasmacytoid dendritic cells (pDCs) are the cells with the highest BCMA-expression outside the B-cell compartment.
BCMA-directed therapies eradicate BPDCN cell lines offering a new treatment for patients with this rare disease.
Conclusions
This study offers practical clinical insights to optimise CAR T therapy in real-world settings:
Monitor CAR T cell populations post-infusion to detect emerging side effects early.
Use CAR T cells like any other cellular therapy in multiple myeloma, as consolidation and not to induce remissions.
Optimise patient status prior to infusion with effective holding/bridging therapies.
Monitor B-cell and T-cell recovery to time preventive measures (IVIGs, vaccinations, bactrim/acic).
These findings reinforce the importance of a personalised and proactive approach to CAR T cell therapy, one that balances clinical efficacy with patient safety. The results also provide strong foundations for the CERTAINTY Virtual Twin, which aims to model such complex dynamics and support real-time clinical decision-making.
Access the publication
Read the full open-access article in Cancer Cell: https://www.cell.com/cancer-cell/fulltext/S1535-6108(25)00490-8