medwireNews: Combining lisocabtagene maraleucel (liso-cel) with NKTR-255 enhances chimeric antigen response (CAR)-T cell expansion and durable complete responses (CRs) in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), suggests a phase 1b clinical trial.
NKTR-255 is “an investigational polymer-conjugated interleukin-15 agonist that enhanced the efficacy of subtherapeutic CD19 CAR-T cell doses in a xenograft lymphoma model,” presenter Alexandre Hirayama (Fred Hutchinson Cancer Center, Seattle, Washington, USA) told delegates at the EHA2025 Congress.
He explained at the meeting in Milan, Italy, that durable responses with traditional CAR-T cell therapy remain limited, “with an estimated 3-year progression-free survival [PFS] of 44–51% in the second-line setting.”
Limited proliferation and survival of in vivo CAR-T cells are “key causes” of such failure, Hirayama added. The current trial therefore aimed to determine the potential for improved PFS with the addition of NKTR-255 to liso-cel.
The team screened 38 patients with R/R LBCL, who had received at least one line of treatment and were eligible to receive lymphodepletion and liso-cel.
Twenty-three patients were randomly assigned to receive intravenous NKTR-255 given every 3 weeks at one of four doses: 1.5 μg/kg from day 14 (n=6); 3.0 μg/kg from day 14 (n=11); 6.0 μg/kg from day 14 (n=3); and 3.0 μg/kg on day 10 for one cycle followed by 6.0 μg/kg thereafter (n=3).
These participants were a median of 66 years old, with 57% aged at least 65 years, and 78% were men. The majority had high-grade B-cell lymphoma (35%), DLBCL not otherwise specified (26%), or DLBCL transformed from follicular lymphoma (22%).
Almost all the participants (96%) had advanced disease, as indicated by an Ann Arbor stage of III or IV, 87% had extranodal disease, 78% were primary refractory or early relapsed, and the patients had received a median of two prior therapies.
Patients were unable to receive a planned NKTR-255 infusion if they had grade 3 or worse cytokine release syndrome (CRS) within the prior 72 hours, or fever or grade 1 or more severe CRS within 24 hours. Nor were patients eligible for infusion if they had immune effector cell-associated neurotoxicity syndrome (ICANS) at grade 2 or higher within 24 hours of infusion or any ICANS at grade 3 or higher lasting more than 72 hours. Patients were also unable to receive NKTR-255 if they had received tocilizumab and/or dexamethasone in the preceding 48 hours or experienced a previous grade 4 infusion-related reaction to NKTR-255.
The combination of liso-cel and NKTR-255 was “well tolerated and safe,” said Hirayama. Cases of CRS and ICANS before NKTR-255 infusion were “as expected” for liso-cel alone, and the first NKTR-22 infusion was delayed in only three patients due to liso-cel toxicities.
The overall rates of CRS and ICANS of any grade were 61% and 22%, respectively, with corresponding grade 3 or worse rates of 4% and 9%. The presenter pointed out that “only 2 patients (9%) developed CRS and/or ICANS following NKTR-255 infusion.”
The most common grade 3 or worse events were cytopenias, primarily neutropenia occurring in 70% of patients. The most common NKTR-255-related AE of any grade was infusion-related reaction, affecting 83% of patients, but resolving within 24 hours with supportive care. There were no dose-limiting toxicities or death.
At 3 months, the overall response rate across the cohorts was 74% and the CR rate was 65%, which the presenter said “compare favorably” with pivotal data for liso-cel the TRANSCEND NHL 001 trial (73% and 53%, respectively) and reported real-world data (73% and 42%).
Hirayama also noted that “five of 13 patients, or 38%, who achieved a partial response at first restaging later converted to a complete response.”
Overall, the responses were durable, with median PFS unreached over a median follow-up of 9.1 months in the whole patient group as well as those with CR, and the 12-month rates were estimated to be 59.0% and 92.3%, respectively. Again, these rates compared favorably against the previously published pivotal (44.1 and 65.1%) and real-world data (40.2% and no available data), the presenter commented.
“CAR-T cells re-expanded following NKTR-255 infusion in most patients,” the researcher said, primarily CD8-positive cells, with a median 1.7-fold increase. Higher expansion and persistence of CAR-T cells, compared with liso-cel alone, was seen in patients given the 1.5 or 3.0 μg/kg dose. Based on this finding, “the optimal biological regimen” to be taken forward to phase 2 trials “was defined as NKTR-255 infusion on or after day 14 at 1.5–3.0 μg/kg,” said Hirayama.
He concluded that the findings “support ongoing and future studies combining NKTR-255 and CAR-T cell therapy.”
