NKTR-255 Plus Anti-CD19 CAR T Shows Safety, Efficacy in R/R LBCL
NKTR-255 with CD19 chimeric antigen receptor T-cell therapy improved 6-month complete response rates in relapsed/refractory large B-cell lymphoma.
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The combination of NKTR-255 with CD19-directed chimeric antigen receptor (CAR) T-cell therapy improved complete response (CR) rates at 6 months in relapsed/refractory large B-cell lymphoma (LBCL) compared with placebo, according to phase 2 trial results (NCT05664217) presented at the 2025 Transplantation & Cellular Therapy Meetings.1
In the intent-to-treat (ITT) population, the 6-month CR rate was 73% among patients who received NKTR-255 at any dose level (n = 11) vs 50% among those who received placebo (n = 4). The 6-month CR rates among efficacy-evaluable patients in the NKTR-255 (n = 10) and placebo (n = 4) arms were 80% and 50%, respectively.
Among patients in the ITT population who received NKTR-255 at dose levels of 1.5 mcg/kg (n = 5), 3.0 mcg/kg (n = 3), and alternating 3.0 mcg/kg and 6.0 mcg/kg (n = 3), the 6-month CR rates were 80%, 67%, and 67%, respectively. The 6-month CR rates among efficacy-evaluable patients in these respective populations were 100% (n = 4/4), 67% (n = 2/3), and 67% (n = 2/3), respectively. Notably, 1 patient who received NKTR-255 at 1.5 mcg/kg converted from stable disease to partial response (PR) to CR at 6 months, and 1 patient who received NKTR-255 at 3.0 mcg/kg converted from PR to CR at 6 months.
“The CR rate [with NKTR-255 was] superior to published historical benchmarks and real-world meta-analyses with CAR T-cell therapy,” lead study author Sairah Ahmed, MD, stated in the presentation.
Ahmed is an associate professor in the Department of Lymphoma/Myeloma in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, where she is also the director of the CAR T Program.
NKTR-255 Mechanism of Action and Phase 2 Trial Background
“CAR T-cell therapy has been transformative for relapsed or refractory LBLC,” Ahmed explained. “However, more than half of patients have either disease relapse or progression with short median overall survival, and strategies to improve long-term efficacy are needed. In pivotal trials, CR at 6 months seems to be prognostic of CR beyond 2 years, and therefore, potentially, interventions that improve CR rates at 6 months may improve event-free survival.”
NKTR-255 is an investigational, polymer-conjugated interleukin-15 (IL-15) agonist. Previously, a phase 1 trial (NCT04136756) showed that this agent expanded CAR T and CD8-positive T cells in patients with relapsed/refractory non-Hodgkin lymphoma who had previously received CAR T-cell therapy.2
NKTR-255 binds to the IL-15 alpha and beta gamma receptors. It has also been shown to activate, proliferate, and expand the number and function of natural killer cells, CD8-positive effector cells, and memory T cells in vivo to increase the duration of response with CAR T-cell therapy and other cellular therapies.1 It enhances antibody-dependent cell-mediated cytotoxicity (ADCC) antibodies such as daratumumab (Darzalex), rituximab (Rituxan), and cetuximab (Erbitux), and has the potential to combine with any targeted antibody with an ADCC mechanism of action. It also enhances CAR T-cell therapy regimens beyond those targeting CD19, such as anti-BCMA and anti-CD38 products, and has the potential to expand development with other hematological and solid tumor CAR T-cell therapies and other cellular therapies.
Trial Design
This phase 2 trial enrolled patients at least 18 years of age with relapsed/refractory LBCL who were planning to receive CD19-directed CAR T-cell therapy and had an ECOG performance status of 0 or 1. Patients needed to have evidence of CD19-positive disease and fluorodeoxyglucose-avid disease on PET/CT.
Patients were excluded if they had received prior treatment with any CD19-directed CAR T-cell therapy other than the planned treatment; an active central nervous system malignancy; steroid use of greater than 5 mg of prednisone or equivalent; or the presence of uncontrolled fungal, bacterial, viral, or other infection.
Patients were evaluated prior to each study drug infusion to determine whether they met the following dosing criteria: appropriate laboratory test results; no fever of at least 38.0°C or grade 1 or higher cytokine release syndrome (CRS) within 24 hours of receiving the planned study drug infusion; no grade 3 or higher CRS within 72 hours before the study drug infusion; no grade 2 or higher immune effector cell–associated neurotoxicity syndrome (ICANS) on the day of the study drug infusion; no previous grade 4 infusion-related reaction (IRR) to the study drug infusion in cycle 2 and beyond; and no receipt of tocilizumab (Actemra) and/or dexamethasone within 48 hours before the study drug infusion.
In total, 36 patients consented to participate in the trial and were screened. Twenty-one patients did not pass screening due to insufficient counts (n = 6), long resolution of adverse effects (AEs; n = 5), patient withdrawal (n = 3), CAR T-cell product out of trial specification and needed to be given in a separate clinical trial (n = 2), nonmeasurable disease status following chemotherapy bridging (n = 2), and other reasons (n = 3). A total of 15 patients received at least 1 dose of NKTR-255 or placebo.
During the screening period, following consent, patients underwent leukapheresis, after which CAR T-cell manufacturing occurred for 21 days. Patients then received lymphodepleting chemotherapy, followed by CAR T-cell infusion. Treatment started on day 14 (+ 7) post-CAR T-cell infusion.
Patients were randomly assigned 1:1:1:1 to receive CD19-directed CAR T-cell therapy plus NKTR-255 at 1.5 mcg/kg, CD19-directed CAR T-cell therapy plus NKTR-255 at 3.0 mcg/kg, CD19-directed CAR T-cell therapy plus NKTR-255 at alternating doses of 3.0 mcg/kg and 6.0 mcg/kg, or CD19-directed CAR T-cell therapy plus placebo.
CR rate at month 6 of treatment served as the primary end point. Secondary end points included safety and tolerability, as well as pharmacokinetics and pharmacodynamics.
Patient Characteristics
Patient characteristics were fairly well matched between the arms, according to Ahmed. Among the patients in the combined NKTR-255 population, the median age was 62 years (range, 40-72), 36% were at least 65 years of age, 73% were male, 45% had an ECOG performance status of 2, 64% had de novo diffuse LBCL (DLBCL), 9% had high-grade B-cell lymphoma, 82% had stage III or IV disease, and 36% had bulky disease. In total, 91% of patients received axi-cel, and 9% of patients received liso-cel. Most patients (55%) had received at least 2 prior lines of therapy, and the median lactate dehydrogenase (LDH) level was 249 U/L (range, 147-1260).
In comparison, among the patients in the placebo arm, the median age was 67.5 years (range, 44-76), 50% were at least 65 years of age, none were male, 50% had an ECOG performance status of 2, 50% had de novo DLBCL, 25% had DLBCL transformed from indolent lymphoma, 25% had high-grade B-cell lymphoma, 50% had stage III or IV disease, and 50% had bulky disease. In total, 50% of patients received axi-cel, and 50% of patients received liso-cel. Most patients (75%) had received at least 2 prior lines of therapy. Notably, the median LDH level was 218 U/L (range, 170-602), which was much lower than that seen in the combined NKTR-255 population.
Pharmacodynamics and Pharmacokinetics
Correlative analyses showed that NKTR-255 enhanced CAR T-cell persistence and improved CD8-positive, CD4-positive, and CD3-positive CAR T cell levels in the first 28 days and beyond. Additionally, blood samples that were collected after NKTR-255 treatment at different time points did not indicate notable cytokine AEs. Ahmed explained that investigators also observed transient increases of MCP-1 and MIP-1β in patients who received NKTR-255 vs those who received placebo that aligned with those seen in clinical reports from prior publications that had indicated that treatment with NKTR-255 plus CAR T-cell therapy trafficked CAR T cells and NKTR-255 into tumor tissues in patients with similar cytokine profiles.
Safety Findings and Next Steps
Among patients who received NKTR-255 at 1.5 mcg/kg, NKTR-255 at 3.0 mcg/kg, NKTR-255 at 3.0 mcg/kg or 6.0 mcg/kg, and placebo, the most common grade 1/2 treatment-related AEs (TRAEs) were anemia (n = 1; n = 1; n = 1; n = 0), decreased neutrophil counts (n = 1; n = 1; n = 1; n = 1), pyrexia (n = 1; n = 1; n = 1; n = 0), and decreased white blood cell (WBC) counts (n = 1; n = 0; n = 2; n = 2).
“All events of IRR and fever…occurred…6 to 8 hours post-infusion and resolved without any additional treatment with tocilizumab.”
The most common grade 3 TRAE was decreased neutrophil counts, which occurred in 2, 0, 2, and 0 patients, respectively. Grade 4 TRAEs included decreased neutrophil counts in 1 patient who received NKTR-255 at 3.0 mcg/kg, decreased platelet counts in 1 patient who received NKTR-255 at 3.0 mcg/kg, pneumonia aspiration in 1 patient who received NKTR-255 at 1.5 μg/kg, and decreased WBC counts in 1 patient who received NKTR-255 at 3.0 mcg/kg.
1 grade 5 TRAE (Guillain-Barre syndrome) occurred in 1 patient who received NKTR-255 at 1.5 mcg/kg. Ahmed noted that this patient’s Guillain-Barre syndrome symptoms began prior to NKTR-255 infusion.
No new cases of CRS or ICANS were reported.
“Further studies are warranted to explore the clinical benefits of NKTR-255 as an adjuvant treatment with CAR T-cell therapy, as well as potentially other cellular therapies in other types of diseases, including solid tumors,” Ahmed concluded.
Disclosures: Ahmed has received institutional support for clinical trials from Caribou, Chimagen, Genmab, Janssen, KITE/Gilead, 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.
