How do patient characteristics, T cell starting material, and drug product attributes affect CAR T-cell therapy outcomes?

Little is known about the effect of patient characteristics, T cell starting material, and chimeric antigen receptor (CAR) T drug product attributes on the efficacy, safety, and pharmacokinetics (PK) of CAR T cells.

To understand how these features affect CAR T-cell therapy outcomes, random forest-based multifactorial analyses were performed on data from 172 patients with relapsed/refractory (R/R) large B cell lymphoma (LBCL), who were enrolled in the phase 1 TRANSCEND-NHL-001 (NCT02631044) study and treated with the CD19-directed CART cell product, lisocabtagene maraleucel (liso-cel).¹

Methods¹

The key objectives of the study were, PK, progression-free survival (PFS), duration of response (DOR), complete response (CR), objective response (OR), and safety. Features considered were: T cell starting material and drug product characteristics (CMC), patient demographic features and blood chemistry (clinical), and CMC plus clinical (all).

Random forest regression classification and random survival forest were used to model clinical endpoints, to assess attribute importance, and outcome dependency on each attribute tested.

Results¹

Clinical and CMC attributes that demonstrated associations with PK:

• Age, with younger patients experiencing higher CAR T-cell expansion
• Number of prior treatments, with patients receiving fewer lines of prior treatments experiencing higher CAR T-cell expansion
• Effector cytokine secretion, with less effector cytokine secretion in CD8⁺ drug products (more naive-like phenotype) being associated with higher CAR T-cell expansion

Clinical and CMC attributes that demonstrated associations with efficacy:

• Higher functional cytokine production of the liso-cel drug product was associated with longer PFS and a higher chance of achieving CR
• Patients with lower tumor burden, LBCL transformed from follicular lymphoma (FL) or primary mediastinal B-cell lymphoma (PMBCL) achieved longer PFS. Patients with lower tumor burden were also more likely to achieve CR

Clinical and CMC attributes that demonstrated associations with adverse events:

• Patients with higher tumor burden, or those needing bridging therapy between apheresis and infusion, were more prone to experiencing neurotoxicity or cytokine release syndrome of any grade

Conclusion

The results of this study showed that patient and manufacturing characteristics, such as tumor burden and functional cytokine production of the CAR-T drug product, were the most important attributes associated with liso-cel CAR T-cell expansion, efficacy, and safety in patients with R/R LBCL treated in the TRASCNEND-NHL-001 trial. These results might help with the early identification of specific patient populations that will benefit the most from CAR T-cell therapy and thus improve its clinical experience and outcomes.