Linking T-Cell Composition to CAR T Efficacy in Multiple Myeloma

This interview segment explores emerging translational data linking higher levels of CD4-positive naïve T cells with longer progression-free survival (PFS) in patients treated with CAR T-cell therapy, offering potential insights into patient selection and future treatment optimization. Krina Patel, MD, MSc, associate professor in the Department of Lymphoma/Myeloma in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, highlights how immune composition at the time of CAR T manufacturing may influence both efficacy and durability of response.

CAR T cell expansion is a critical determinant of clinical benefit, as patients whose infused cells expand effectively tend to experience superior outcomes. Within this context, CD4-positive T cells appear to play a particularly important role. While CD8-positive T cells are traditionally viewed as the primary cytotoxic effectors responsible for directly killing myeloma cells, they are also more prone to rapid exhaustion after repeated activation. CD4-positive T cells, by contrast, function more as memory and helper cells, supporting sustained immune responses and potentially enabling longer-term disease control through improved CAR T persistence.

Evidence from lymphoma studies reinforces this concept, where some CAR T products are manufactured with a controlled CD4-to-CD8 ratio—often 1:1—to enhance expansion, persistence, and overall outcomes. Although this approach has not yet been routinely applied in multiple myeloma, the current data raise important questions about whether similar strategies could improve results in this disease as well.

Patel further discusses how these findings could influence future clinical practice and research. One possibility is modifying patients’ immune profiles before apheresis, using bridging or “holding” therapies that may increase CD4 T-cell counts or improve the CD4-to-CD8 balance prior to CAR T-cell collection. Another potential avenue involves manipulating the CAR T product during manufacturing to enrich for favorable T-cell subsets, though such strategies would need to be tested within clinical trials.

Overall, the correlation between CD4-positive naïve T cells and longer PFS underscores the growing importance of immune biomarkers in CAR T-cell therapy. These insights may ultimately guide patient selection, timing of therapy, and the rational use of adjunct treatments to optimize outcomes for patients with multiple myeloma.