Nektar Publishes Phase 1 Data on NKTR-255 with CD19-22 CAR-T in B-cell Acute Lymphoblastic Leukemia

Nektar Therapeutics has unveiled the initial clinical data from a Phase 1 study exploring NKTR-255 in combination with a bispecific chimeric antigen receptor (CAR)-T cell therapy aimed at CD19 and CD22. This study focused on patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) and was published in the medical journal Blood, affiliated with the American Society of Hematology.

NKTR-255 is a unique IL-15 receptor agonist currently undergoing clinical trials in combination with various cell therapies and immune checkpoint inhibitors. Previous research has shown that NKTR-255 can stimulate the proliferation of diverse immune cells and enhance lymphocyte trafficking. Results from the study indicated that eight of the nine patients (89%) who received the CAR19-22 therapy followed by NKTR-255 attained complete remission without measurable residual disease (MRD). Additionally, the data demonstrated that the 12-month relapse-free/progression-free survival for NKTR-255 combined with CD19-22 CAR-T cell therapy was double that of historical controls (67% vs. 38%).

Mary Tagliaferri, MD, Senior Vice President and Chief Medical Officer at Nektar, expressed optimism about the results, stating that they clearly show NKTR-255's potential to enhance CAR-T cell therapy. Tagliaferri noted that NKTR-255, in conjunction with CD19-22 CAR-T cell therapy, resulted in a 67% 12-month relapse-free survival rate in B-ALL patients and led to significant increases in proinflammatory cytokines and chemokines, implying lymphocyte trafficking to tissues.

The single-center, single-arm dose-escalation Phase 1 study was conducted by Stanford Medicine and assessed NKTR-255 alongside CD19-22 CAR-T cell therapy in patients with relapsed or refractory B-ALL. David Miklos, MD, Chief of BMT and Cell Therapy Program at Stanford Medicine, highlighted the significance of the study, mentioning that while CAR-T cell therapies have revolutionized the treatment of B-cell malignancies, there is still a need for durable treatment outcomes as relapses are common.

The study's primary goals were to assess feasibility and safety, with secondary outcomes including pharmacokinetics of NKTR-255 and remission-free survival (RFS). Exploratory outcomes involved cytokine profiling, CAR19-22 expansion in blood, bone marrow, and cerebrospinal fluid (CSF), and long-term CAR-T persistence. Key findings indicated no dose-limiting toxicities related to NKTR-255. Common adverse effects included fevers, chills, and myelosuppression, which were manageable with supportive care. The toxicity profile of the combination treatment was similar to that of CD19-22 CAR-T cell therapy alone.

The study also noted significant increases in IL-15 levels, with higher levels of CXCL9 and CXCL10 correlating with reduced absolute lymphocyte counts and CD8+ CAR T-cells in blood, and a ten-fold increase in CAR-T cells in CSF, indicating lymphocyte trafficking to tissue. Importantly, the combination treatment resulted in favorable efficacy, with eight out of nine patients achieving complete remission without detectable MRD.

Compared to Stanford's control group, which only received CD19-22 CAR-T cell therapy, the inclusion of NKTR-255 increased the 12-month relapse-free survival rate from 38% to 67%. The median RFS for the CAR-T cell-only group was 3.9 months, while for the group treated with both NKTR-255 and CD19-22 CAR-T cell therapy, the median RFS has not been reached with over 14 months of follow-up. Only three patients (33%) who received the combination therapy relapsed, suggesting that NKTR-255 aids in preventing early disease recurrence when added to CD19-22 CAR-T cell therapy.

NKTR-255, a biologic targeting the IL-15 pathway, aims to enhance both innate and adaptive immunity by engaging the IL-15 receptor complex, which could lead to sustained and durable anti-tumor immune responses. Besides its combination with CAR-T cell therapies, NKTR-255 is also being studied in a Phase 1 trial for anti-PD1 resistant metastatic non-small cell lung cancer and in a study for urothelial carcinoma.

Nektar Therapeutics, based in San Francisco, is a clinical-stage biotechnology company developing treatments for autoimmune and chronic inflammatory diseases. Their leading product candidate, rezpegaldesleukin (REZPEG), is under evaluation in Phase 2b trials for atopic dermatitis and alopecia areata, alongside other investigational therapies in their pipeline.