Exercise-mobilized lymphocytes boost blinatumomab against B-ALL

Researchers reported that donor lymphocytes mobilized by exercise exhibit enhanced activity against B-cell acute lymphoblastic leukemia (B-ALL) when combined with the bispecific T-cell engager blinatumomab. Published in the Journal of Translational Medicine, the study investigated whether exercise-mobilized donor lymphocyte infusions (DLI-X) could improve cytotoxicity against CD19-positive B-ALL cells compared to standard donor lymphocyte infusions (DLI) collected at rest. The findings suggest that physical activity may alter the composition of donor T cells in a way that supports more effective anti-leukemic responses in the context of allogeneic hematopoietic cell transplantation.

Donor lymphocyte infusion is a clinical strategy used to prevent and treat leukemic relapse after allogeneic hematopoietic cell transplantation, although its efficacy against lymphoid malignancies has historically been limited. Blinatumomab, a CD3/CD19 bispecific T-cell engager, is increasingly utilized to enhance the activity of DLI against acute lymphoblastic leukemia. The research team, led by Richard J. Simpson and colleagues, previously demonstrated that exercise-mobilized DLI exhibits superior anti-leukemic activity against myeloid malignancies. This current study extended that investigation to lymphoid malignancies, specifically examining whether the combination of DLI-X and blinatumomab enhances cytotoxicity against CD19-positive B-ALL.

The study utilized peripheral blood mononuclear cells collected from healthy participants under two distinct conditions. In the control condition, cells were collected at rest to create standard DLI. In the experimental condition, cells were collected during the final stage of a 20-minute graded cycling protocol that reached 80% of the participants’ maximum oxygen consumption (VO₂max), creating DLI-X. Cytotoxicity against CD19-positive RS4;11 B-ALL cells was assessed in vitro. Additionally, T-cell activation and effector function were evaluated using 8-color flow cytometry. To determine in vivo efficacy, the researchers used NSG-IL-15 mice engrafted with RS4;11 cells, treating them with DLI or DLI-X in combination with blinatumomab or a vehicle control, while monitoring tumor burden via bioluminescence imaging.

Exercise preferentially mobilized CD8-positive effector memory (EM) and effector memory RA (EMRA) T cells. The exercise protocol also increased NKG7 expression in CD8-positive T cells, rising from approximately 55% in the rest condition to approximately 70% in the exercise condition. These changes enriched the DLI-X product for cytotoxic effector populations relative to the standard DLI. When tested alone, both DLI and DLI-X exhibited limited cytotoxicity against the RS4;11 B-ALL cells. However, the addition of blinatumomab significantly enhanced the cytotoxicity of both products. The DLI-X combined with blinatumomab demonstrated greater than 20% greater tumor killing than the DLI combined with blinatumomab, with tumor killing rates of approximately 85% versus approximately 62%, respectively.

Flow cytometry analysis revealed that DLI-X displayed enhanced blinatumomab-induced T-cell effector function compared to DLI. This included increased CD107a degranulation, greater tumor necrosis factor-alpha (TNF-α) production by CD4-positive T cells, and higher interferon-gamma (IFN-γ) production by CD8-positive T cells. Furthermore, the exercise-mobilized cells showed 10% to 15% greater upregulation of the costimulatory proteins CD137 and OX40. These molecular changes suggest that exercise mobilizes T cells with enhanced responsiveness to blinatumomab, resulting in superior activation and cytotoxicity against CD19-positive B-ALL cells in vitro.

In the in vivo mouse model, the combination of DLI-X and blinatumomab achieved up to 35% greater control of tumor burden than the combination of DLI and blinatumomab. The study concludes that exercise mobilizes T cells with enhanced responsiveness to blinatumomab, leading to improved tumor control. These findings support the potential use of exercise-mobilized donor lymphocyte infusions as a strategy to enhance the efficacy of bispecific T-cell engager therapy following allogeneic hematopoietic cell transplantation. The clinical trial associated with this research was retrospectively registered on ClinicalTrials.gov under protocol NCT06643221 on October 8, 2024.

While the results are promising in both in vitro and in vivo models, the study focuses on the specific interaction between exercise-mobilized lymphocytes and blinatumomab in the context of B-ALL.

Subject of Research: Exercise-mobilized donor lymphocytes and blinatumomab efficacy in B-ALL

Article Title: Exercise-mobilized donor lymphocytes enhance blinatumomab activity against B-ALL

Article References: Sullivan, J. L., Leite, G., Santa Cruz, N., Batatinha, H., Swanson, K., Filioglou, D., Mckenzie, G. M., Kistner, T. M., Arunachalam, P. S., Baker, F. L., Katsanis, E., & Simpson, R. J. (2026). Exercise-mobilized donor lymphocytes enhance blinatumomab activity against B-ALL. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09042-9

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09042-9

Keywords: B-ALL, Blinatumomab, Donor Lymphocyte Infusion, Exercise, T-cells, Allogeneic Transplantation, Cytotoxicity, Immunotherapy, Exercise-mobilized, donor, lymphocytes, enhance