IL-Agonist NKTR-255 Shows Ability to Enhance Responses to CAR T-Cell Therapy in R/R LBCL

Sairah Ahmed, MD

NKTR-255 has the potential to enhance the durability of response to CD19-directed CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (LBCL), according to Sairah Ahmed, MD.

During the 2025 Transplantation & Cellular Therapy Meetings, Ahmed presented data from a phase 2 trial (NCT05664217) which demonstrated that patients in the intention-to-treat population who received NKTR-255 at any dose level after CAR T-cell therapy (n = 11) achieved a 6-month complete response (CR) rate of 73% per blinded independent central review (BICR).1 Comparatively, the CR rate per BICR among patients who received placebo following CAR T-cell therapy (n = 4) was 50%.

“The goal that we all have is to improve outcomes for patients who receive CAR T-cell therapy and try to minimize toxicity,” Ahmed said in an interview with OncLive®. “This is an exciting trial that potentially has an agent that has been broadly studied in the preclinical and clinical fashion that seems to work well. I hope there are going to be further studies to push this product along because it seems, at least in a small study, to be very beneficial for patients.”

In the interview, Ahmed discussed current challenges for patients with relapsed/refractory LBCL who receive CAR T-cell therapy, the mechanism of action of NKTR-255, and key findings from the phase 2 study of NKTR-255. Ahmed is an associate professor in the Department of Lymphoma/Myeloma and director of the CAR T Program at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: What are some challenges when caring for patients with relapsed/refractory DLBCL who are receiving CAR T-cell therapy?

Ahmed: There are multiple challenges [for] patients who are receiving CAR T-cell therapy, but one that is front-and-center is that the majority of patients do not have a durable response. They go through a very complicated procedure with toxicity that is unique, including cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS]. It’s a financial burden [too and] a time period where [the patient] potentially can’t work and their caregiver [may] also be unable to work because they need to take care of the patient.

At the end of the day, [approximately] 40% of patients have a durable response and [approximately] 60% have disease that either does not respond or relapses. [Patients] are undergoing this very intense experience and [many] of them still experience disease return. Ultimately, that’s what we would like to improve. [We want] patients to be able to receive this therapy and for this therapy to work better for those patients.

What is the mechanism of action of NKTR-255 and the rationale for evaluating it in this context?

NKTR-255 is an IL-15 agonist. IL-15 has been demonstrated in other publications to improve CAR T-cell therapy’s efficacy in patients who have higher endogenous levels of IL-15 prior to CAR T-[cell therapy, and these patients] have better response rates and better outcomes after CD19-[directed] CAR T-cell therapy. IL-15 also drives persistence and expansion of CAR T cells and potentially can improve T-cell fitness.

The rationale behind the study was to give exogenous IL-15 to patients who are receiving CD19-directed CAR T-cell therapy in the hopes of improving outcomes, potentially improving CAR T-cell fitness, and hopefully doing so without increasing toxicity.

What were the key findings from the phase 2 study that you presented?

This was a placebo-controlled, double-blinded, randomized trial in which patients received a commercial CD19-[directed] CAR T-cell therapy in 1 of 3 NKTR-255-containing regimens or placebo. Our study demonstrated that patients who received NKTR-255 had improvements in their CR rates.

The NKTR-255 group had a CR rate of 73% compared with 50% in the placebo group. If we look at that in comparison with historical controls, the pivotal trials [data have shown] a 6-month CR rate of [approximately] 45%. Prior published data [have] demonstrated that if a patient is in CR at 6 months after CAR T-cell therapy they are more likely to remain in CR and have a durable response.

The main takeaway from this study was that NKTR-255 improves the CR rate and the 6-month CR rate without increasing the toxicity profile in terms of CRS and ICANS. It does have slightly more hematologic toxicity, but otherwise is very well tolerated.

What additional safety findings were observed in the study?

In these preliminary data, it does not seem that NKTR-255 increases the risk of CRS or ICANS. The time period at which NKTR-255 was given was day 7 after the infusion of CAR T-cell therapy and the reason for that was to try to mitigate adding on toxicity.

Patients had to meet eligibility criteria [to enter the trial] and there was a second set of eligibility criteria to be able to [receive NKTR-255]. Those patients who met the second eligibility criteria were infused with NKTR-255 and did not have any additional toxicity. Beyond that, [during] the maintenance time period when they got NKTR-255, the main toxicities were hematologic and a few fevers, [which] all resolved without tocilizumab [Actemra] or steroids.

What are the next steps for the development of NKTR-255?

This is small study with a small number of patients. The [initial next step] is going to be increasing the sample size and assessing patients who have received commercial CD19-[directed] CAR T-cell therapy. There are also other applications, including [with] other cellular therapies, both in hematologic malignancies and solid tumors, where IL-15 has a very similar mechanism; this potentially could be combined in those settings as well.

Disclosures: Ahmed has received institutional research support for clinical trials from Caribou, Chimagen, Genmab, Janssen, KITE/Gilead Sciences, Merck, Nektar, and Xencor; is a member of the Chimagen scientific advisory committee; serves on the Data Safety Monitoring Board for Myeloid Therapeutics; and serves as a consultant for ADC Therapeutics, Bristol Myers Squibb, and KITE/Gilead Sciences.

Reference

1. Ahmed S, DiPersio J, Essell J, et al. NKTR-255 vs placebo to enhance complete responses and durability following CD19-directed CAR-T therapy in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Presented at: 2025 Transplantation & Cellular Therapy Meetings; February 12-15, 2025; Honolulu, Hawaii. Abstract 14.