avipendekin pegol (NKTR-255) / Nektar Therapeutics - LARVOL DELTA

NKTR-255 Enhances Complete Response Following CD19 CAR-T in Patients with Relapsed/Refractory Large B-cell Lymphoma. (PubMed, Blood Adv) - P2/3 | "In this phase 2, randomized, double-blind, placebo-controlled, multicenter study of NKTR-255 versus placebo following CD19 CAR T-cell therapy, eligible patients with R/R LBCL were treated with one of two FDA-approved CAR T-cell products, axicabtagene ciloleucel (axi-cel) or lisocabtagene maraleucel (liso-cel). NKTR-255 was well-tolerated, safe, and augmented CR6 for LBCL patients. Based on the findings, additional confirmatory studies with NKTR-255 as adjuvant treatment to CAR T-cell, including other cellular therapies, are warranted (ClinicalTrials.gov number NCT05664217)."

Clinical • Journal • B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • CD8

NCI-2022-02316: NKTR-255 in Combination With CAR-T Cell Therapy for the Treatment of Relapsed or Refractory Large B-cell Lymphoma (clinicaltrials.gov) - P1 | N=27 | Completed | Sponsor: Fred Hutchinson Cancer Center | Active, not recruiting ➔ Completed

Trial completion • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Mediastinal Large B-Cell Lymphoma • CD19

Avelumab (Ave) in combination with other anticancer agents as first-line maintenance (1LM) treatment for advanced urothelial carcinoma (aUC): Primary analysis from the JAVELIN Bladder Medley phase 2 trial. (ASCO-GU 2026) - P2, P3 | "In the interim analysis of the JAVELIN Bladder Medley trial (NCT05327530), 1LM with Ave + sacituzumab govitecan (SG; Trop-2–directed antibody-drug conjugate) improved progression-free survival (PFS) vs Ave monotherapy (mono), thereby meeting the study's primary endpoint. In the primary analysis of the JAVELIN Bladder Medley trial, Ave + SG as 1LM in pts with aUC without progression after 1L PBC showed improved PFS vs Ave mono. While OS data are still immature, OS trends favored Ave + SG, Ave + M6223, and Ave + NKTR-255 vs Ave mono. No new safety signals were identified."

Clinical • Combination therapy • Metastases • P2 data • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • IL15 • TIGIT

A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia. (PubMed, Blood) - P1 | "The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854)."

CAR T-Cell Therapy • Journal • P1 data • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • CD22 • CD8 • CXCL10 • CXCL9 • IL15

IL-15 Superagonists for Reprogramming the Immunosuppressive Microenvironment in Gastrointestinal Adenocarcinomas. (PubMed, Cancer Lett) - "In this regard, IL-15 superagonists such as N-803, NIZ985, RLI, and NKTR-255 have emerged as promising immunotherapeutic candidates, as they selectively expand natural killer (NK) cells and CD8+ T-cells without the systemic toxicity and regulatory T-cell activation observed with IL-2 therapy. Together, these advances define a new paradigm for cytokine-immunotherapy, with IL-15 superagonists serving as key mediators of reprogramming of the tumor microenvironment. Therapeutic strategies targeting IL-15 have the potential to restore cytotoxic immunity, improve access to immune cells, and promote responsiveness to the checkpoint blockade, making them a promising yet investigational approach to converting immune-cold GI malignancies into more treatment-responsive disease states, though further clinical validation is required."

Journal • Review • Fibrosis • Gastric Cancer • Immune Modulation • Immunology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD8 • IL10 • TGFB1

Circumventing Ewing sarcoma tumor microenvironment resistance by IL1RAP CAR-modified TGFβ1-imprinted natural killer cells in combination with IL-15 agonist and anti-GD2 antibody. (PubMed, J Immunother Cancer) - "Our preclinical data demonstrate that combinatorial innate immunotherapy leveraging tumor-targeting TGFβ1-imprinted IL1RAP-CAR-NK cells combined with an IL-15 agonist and an anti-GD2 antibody is a promising novel therapeutic strategy for targeting metastatic/relapsed/refractory ES."

Biomarker • IO biomarker • Journal • Ewing Sarcoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • IL15 • IL1RAP • IL21 • TGFB1

Optimizing Therapeutic Approach for Rituximab-Resistant Burkitt Lymphoma With Combinatorial Natural Killer Cell-Based Immunotherapy (ASPHO 2026) - "Obinutuzumab (OB), a glycoengineered humanized type‑II anti‑CD20 antibody, exhibits enhanced Fc receptor binding and antibody‑dependent cellular cytotoxicity (ADCC) and is significantly better than NK alone against relapsed and refractory BL (Awasthi/Cairo, BJH 2015)...We hypothesize that combining OB and NKTR-255 may further enhance NK cells' anti‑tumor activity and overcome rituximab resistance in BL... Our results demonstrate the efficacy of combinatorial NK immunotherapy in targeting rituximab-resistant BL cells."

Burkitt Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • CXCL12 • CXCR4 • GZMB • IFNG

Chemokine engineering significantly enhanced migration and tumor infiltration of ex vivo-expanded natural killer cells in osteosarcoma (AACR 2025) - "To evaluate NK cell tumor infiltration, we injected human NK cells with an IL-15 agonist, NKTR-255, and harvested and dissociated tumors 5-7 days after NK injection for flow cytometry analysis...Our in vitro and in vivo data demonstrated that secretion of CXCL9, -10, and -11 from OS significantly enhanced NK migration and NK infiltration into the OS TME. We are actively investigating the in vivo anti-tumor efficacy of expanded NK cells against CXCL9, -10, or -11-secreting disseminated OS tumors."

Preclinical • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CXCL9 • CXCR3 • IL15 • IL2 • PTPRC

Targeting Acute Myeloid Leukemia By IL-1RAP.CAR NK Cells with or without NKTR-255 or Cam161533 Tri-Specific Killer Cell Engager (TriKE) (TCT-ASTCT-CIBMTR 2026) - "IL-1RAP is a novel therapeutic target for CAR NK cell therapy in AML. The addition of NKTR- 255 or cam161533 TriKE significantly enhanced the cytotoxicity and cytokine release of IL-1RAP.CAR NK cells.Preclinical evaluation in AML xenograft models is ongoing - Interleukin -1 receptor associated protein (IL-1RAP) is a novel therapeutic target on the surface of acute myeloid leukemia (AML) cells and myeloid stem cells. - Targeting IL-1RAP with natural killer (NK) cell immunotherapy is promising."

IO biomarker • Trispecific • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • CD33 • FLT3 • IL15 • KIT

C-TIL051 in Non-Small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=1 | Terminated | Sponsor: AbelZeta Inc. | N=20 ➔ 1 | Trial completion date: Aug 2027 ➔ Dec 2025 | Recruiting ➔ Terminated; Sponsor decision

Enrollment change • Trial completion date • Trial termination • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

NKTR-255, a polymer-conjugated IL-15, synergizes with CAR-T cell therapy to activate endogenous anti-tumor immunity and improve tumor control. (PubMed, bioRxiv) - "Consequently, NKTR-255 and CAR-T combination therapy induced complete elimination of ROR1 + tumor and significantly improved survival, with enhanced tumor control dependent on activity of both CAR-Ts and endogenous T cells. Altogether, our data suggest that combining NKTR-255 with CAR-T therapy is a promising strategy to enhance both CAR-T and endogenous anti-tumor immunity to promote coordinated control of aggressive tumors."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL15 • ITGAM • PD-1 • ROR1

REStoring lymphoCytes Using NKTR-255* After chemoradiothErapy in Solid Tumors (RESCUE) (clinicaltrials.gov) - P2 | N=39 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Trial primary completion date: Dec 2025 ➔ Dec 2027

Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Enhancing CD33.CAR NK cell therapy for acute myeloid leukemia through TGFβ imprinting and NKTR-255 (ASH 2025) - "TGFβ imprinting and NKTR-255 independently and additively enhanced and sustained anti-AML activity of NK and CD33.CAR NK cells, supporting a novel strategy to improve NK-basedimmunotherapy for AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Neuroblastoma • Solid Tumor • CD33 • IFNG • IL15 • IL2RA • NCAM1 • STAT5 • TGFB1 • TGFBI

CXCL10-induced chemotaxis of ex vivo-expanded natural killer cells combined with NKTR-255 enhances anti-tumor efficacy in osteosarcoma. (PubMed, Mol Ther Oncol) - "Single-cell RNA sequencing and mass cytometry revealed upregulated apoptosis and transforming growth factor-β (TGF-β) signaling as the potential mechanisms of response/resistance to NK cell therapy in vivo. Our findings highlight potential application of chemokine-enhanced NK tumor infiltration in combination with an IL-15 agonist as a novel approach to effective treatment of OSA."

Journal • Preclinical • Hematological Disorders • Hematological Malignancies • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor • CXCL10 • CXCL9 • CXCR3 • IL15 • TGFB1

Optimizing Ex-Vivo Expanded NK Cell- Mediated Cellular Cytotoxicity By Obinutuzumab Combined with NKTR-255 in Burkitt Lymphoma (BL) (ASH 2023) - "NKTR-255 is an IL-15 receptor agonist designed to activate the IL-15 pathway and NK cells and promote the survival and expansion of memory CD8+ T cells without inducing suppressive regulatory T cells (Kuo/Zalevsky, Cancer Res. We found that NKTR-255 significantly enhanced the ADCC of expanded NK cells with Obinutuzumab against rituximab-resistant BL cells in vitro with enhanced IFN- g, granzyme B and perforin release. The in vivo effects of NKTR-255 with expanded NK cells and Obinutuzumab against rituximab-resistant BL cells using humanized NSG models are very promising. Mechanisms studies of BL relapsed from the combination therapy are under investigation."

IO biomarker • Preclinical • Burkitt Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CD8 • GZMA • GZMB • IFNG • IL15 • IL21

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) (ASH 2024) - P1, P2/3 | "Eligible patients with R/R LBCL were treated with one of two FDA-approved CAR-T products (axicabtagene ciloleucel or lisocabtagene maraleucel). Conclusions : Preliminary data from the randomized, double-blind, placebo-controlled study showed NKTR-255 adjuvant to CD19 CAR-T cell therapy in LBCL was well-tolerated, safe and efficacious to enhance the CR rate of CD19 CAR-T cell therapy alone at month 6. Additional confirmatory studies with NKTR-255 as adjuvant treatment to CAR-T therapy and other cellular therapies are warranted."

Clinical • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • CD8 • IL15

Summary of Financial Results (PRNewswire) - "R&D expense in the third quarter of 2025 was $27.3 million as compared to $35.0 million for the third quarter of 2024....R&D expense decreased in the first nine months of 2025 primarily due to a decrease in expense for the development of NKTR-255, partially offset by an increase in expenses for the development of rezpegaldesleukin and NKTR-0165."

Commercial • Atopic Dermatitis • Immunology • Oncology

Combination IL-1RAP-Targeted Chimeric Antigen Receptor Natural Killer Cell Therapy and Adjuvant Immunomodulation to treat Acute Myeloid Leukemia (SITC 2025) - "NK cells secreted significantly higher levels of Granzyme B, IFNγ, and perforin compared to unmodified NK cells, and their secretions were further significantly augmented by NKTR-255 or cam161533 (figure 1C).Conclusions IL-1RAP.CAR NK cells, in combination with IL-15- based immunomodulation, exhibited potent in vitro anti-AML cytotoxicity. These results support further evaluation of this combinatorial approach in human AML xenograft models.Acknowledgements Supported by DOD HT94252410682"

Clinical • Immunomodulating • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33 • GZMB • IFNG • IL15 • IL1RAP

Enhanced Cytotoxicity of Anti-ROR1 CAR NK Cells Against Glioblastoma via Combined Treatment with Oncolytic Virus and NKTR-255 (SITC 2025) - "Our group has successfully ex vivo expanded functional peripheral blood NK cells (exPBNK) and electroporated with anti-ROR1 CAR mRNA.3 Oncolytic herpes simplex viruses C134, a neurovirulent deleting γ134.5 and expressing the human cytomegalovirus IRS1, is a promising experimental therapy.4 We previously demonstrated enhanced cytotoxicity against neuroblastoma using HSV expressing human IL-21(HSV C021) in combination with ROR1.CAR.5 NKTR-255 is an investigational IL-15Rα-dependent, polymer-conjugated IL-15 agonist that promotes NK cell expansion. Increased IFNγ secretion was also confirmed by ELISA assay (p < 0.05) (figure 1C).Conclusions The combination of HSV C021 with NKTR-255 significantly enhanced ROR1.CAR cytotoxicity against GBM in vitro, accompanied by elevated IFNγ secretion. In vivo evaluation using humanized NSG models is currently underway."

IO biomarker • Oncolytic virus • Brain Cancer • Glioblastoma • Neuroblastoma • Oncology • Solid Tumor • GZMB • IFNG • IL15 • IL21 • ROR1

Synergistic anti-leukemic effect of NKTR-255 and TGFβ-imprinted CD33.CAR natural killer cells (SITC 2025) - "Notably, this combination also significantly rescued the declining cytotoxicity of NK TGFβi alone, rendering a cytotoxicity of 83.8 ± 0.9% at cycle 4, vs 58.2 ± 7.2% for NK + NKTR-255, and 40.7 ± 4.7% for NK TGFβi (p<0.01), suggesting synergism of TGFβ imprinting and NKTR-255 (figure 1A, B).Consistently, flow cytometry demonstrated higher NK persistence and fewer AML cells in TGFβi and NKTR-255 modified conditions at cycle 5 (figure 1C). The improved NK survival correlated with an increase in pSTAT5 and CD25 in TGFβi NK at cycle 1 (figure 1D).Conclusions TGFβ imprinting and NKTR-255 synergistically enhanced and sustained anti-AML activity of NK and CD33.CAR NK cells, supporting a novel strategy to improve NK-based immunotherapy for AML.Acknowledgements Supported by DOD W81XWH-21-1-0841."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33 • IFNG • IL15 • IL2RA • TGFB1 • TGFBI

Targeting Osteosarcoma by ex-vivo Expanded NK Cells in Combination with IL-15 Agonist and Anti-GD2 antibody (SITC 2025) - "Baldrick's Foundation, Pediatric Cancer Research Foundation, Children's Cancer Fund. We thank Nektar Therapeutics for generously providing NKTR-255.Ethics Approval All animal experiments were approved by the Institutional Animal Care and Use Committee at New York Medical College (Protocol #15112) and performed in accordance with the ethical standards of the institutional research committee.Abstract 310 Figure 1Request permissionsExpanded NK cells combined with dinutuximab and NKTR-255 significantly enhanced NK cytotoxicity in vitro (A and B), decreased tumor growth (C) and improved animal survival (D) in OS xenograft mouse model"

Combination therapy • Preclinical • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CD8 • IFNG • IL15 • IL2

NCI-2022-02316: NKTR-255 in Combination With CAR-T Cell Therapy for the Treatment of Relapsed or Refractory Large B-cell Lymphoma (clinicaltrials.gov) - P1 | N=28 | Active, not recruiting | Sponsor: Fred Hutchinson Cancer Center | Recruiting ➔ Active, not recruiting

Enrollment closed • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Mediastinal Large B-Cell Lymphoma • CD19

ENHANCED CAR T-CELL EXPANSION AND DURABLE COMPLETE RESPONSES WITH NKTR-255 PLUS LISOCABTAGENE MARALEUCEL IN RELAPSED/REFRACTORY LARGE B-CELL LYMPHOMA (ICML 2025) - P1 | "The combination of NKTR-255 and liso-cel in R/R LBCL was well tolerated and safe. Higher CAR-T expansion and AUC0–28 were observed in pts treated with the OBR compared to liso-cel alone. CRs appear to be durable, with only 1 relapse."

CAR T-Cell Therapy • Clinical • B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD8 • IL15

ENHANCED CAR T-CELL EXPANSION AND DURABLE COMPLETE RESPONSES WITH NKTR-255 PLUS LISOCABTAGENE MARALEUCEL IN RELAPSED/REFRACTORY LARGE B-CELL LYMPHOMA (EHA 2025) - P1 | "The combination of NKTR-255 and liso-cel in R/R LBCL was well tolerated and safe. Higher CAR T-cell expansion and AUC0-28 were observed in pts treated with the OBR compared to liso-cel alone. CRs appear to be durable, with only one relapse."

CAR T-Cell Therapy • Clinical • B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD8 • IL15

Combinational Natural Killer Cell- Based Therapies Treating Rituximab- Resistant Burkitt Lymphoma (ASPHO 2025) - "Obinutuzumab (OB) is a glycoengineered humanized type-II mAb recognizing a unique CD20 epitope with significantly enhanced antibody-dependent cellular cytotoxicity than rituximab. Our results demonstrated the efficacy of combinatorial NK immunotherapy in treating rituximab-resistant BL cells. Our future studies will determine the in vivo efficacy of NK in combination with cam161519 and OB, and CD20.CAR NK in combination with cam161519 or NKTR-255 in resistant BL models."

Burkitt Lymphoma • Hematological Malignancies • Lymphoma • Oncology • IFNG • IL15