Biologic Synergy in Focus: Liso-cel and NKTR-255 in Advanced LBCL

Alexandre V. Hirayama, MD, assistant professor, Clinical Research Division, Fred Hutchinson Cancer Center discusses promising findings from a phase 1b study of NKTR-255 given in combination with lisocabtagene maraleucel (liso-cel) for the treatment of patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL).

Although chimeric antigen receptor (CAR) T-cell therapies like liso-cel have transformed treatment for patients with R/R LBCL, roughly half still fail to achieve durable remission. The study evaluated whether combing liso-cel with NKTR-255, a pegylated IL-15 agonist, could improve CAR T-cel expansion and overall outcomes for patients.

The rationale behind the trial lies in the role IL-15 has in supporting T-cell proliferation and survival. In the study, patients received standard lymphodepletion followed by liso-cel infusion and then were given NKTR-255 at varying dose levels and starting times. Notably, patients who received NKTR-255 starting on day 14 or later at lower doses (1.5 to 3 mcg/kg), demonstrated better CAR T-cell expansion, especially within the CD8+ subset, which is critical for tumor killing.

Importantly, the trial revealed high response rates consistent with liso-cel alone, but with a key difference: among complete responders, only one patient relapsed at the time of last follow-up. If these results are sustained over time, this combination could potentially redefine expectations for long-term remission in CAR T-cell therapy.

Dr.  Hirayama highlights that CD8+ CAR T cells, which express high levels of IL-15 receptor alpha, showed the most significant response to NKTR-255. This biologic synergy could be crucial for enhancing anti-tumor activity.

Concluding the interview, Dr. Hirayama emphasizes the need for larger confirmatory phase 2 or phase 3 trials to validate these findings. Further research will also help determine whether this approach can improve outcomes across broader patient populations receiving commercial CAR T-cell therapies.