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

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

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

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

Combinational Targeted Chimeric Antigen Receptor NK Cell Therapy to Treat Acute Myeloid Leukemia (ASPHO 2025) - "We hypothesize that anti-CD123 chimeric antigen receptor NK (CD123.CAR NK) cells, combined with adjuvant IL15 Trispecific Killer Engager (TriKE) recognizing CD16 on NK cells and CD33 on AML cells (cam161533), or polymer conjugated IL-15 (NKTR-255), will significantly enhance the anti-tumor activities of NK cells... Combinatorial CD123.CAR NK and adjuvant IL-15 based immunomodulation had significant in vitro anti-AML cytotoxicity. We will investigate the anti-AML effect of the combination utilizing human AML xenografts."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Immunology • Leukemia • Oncology • CD123 • CD33 • CD34 • GZMB • IL15 • IL3RA

A Study of the Safety and Efficacy of Various Combinations of Avelumab as Therapy in Locally Advanced or Metastatic Urothelial Carcinoma (JAVELIN Bladder Medley) (clinicaltrials.gov) - P2 | N=256 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial completion date: Jan 2025 ➔ Jul 2026 | Trial primary completion date: Jan 2025 ➔ Jun 2025

Trial completion date • Trial primary completion date • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer

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

NKTR-255 Plus Anti-CD19 CAR T-Cell Therapy Demonstrates Safety and Preliminary Efficacy in R/R LBCL (OncLive) - P2/3 | N=15 | NCT05664217 | Sponsor: Nektar Therapeutics | "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."

P2/3 data • Diffuse Large B Cell Lymphoma • Large B Cell Lymphoma

NKTR-255 vs Placebo Following CD19-directed CAR-T Therapy in Patients With Relapsed/Refractory Large B-cell Lymphoma (clinicaltrials.gov) - P2/3 | N=15 | Terminated | Sponsor: Nektar Therapeutics | N=400 ➔ 15 | Trial completion date: Jan 2029 ➔ Aug 2024 | Recruiting ➔ Terminated | Trial primary completion date: Jan 2027 ➔ May 2024; Sponsor decided to end the study

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19

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=24 | Recruiting | Sponsor: Fred Hutchinson Cancer Center | Trial completion date: Dec 2025 ➔ Jun 2026 | Trial primary completion date: Dec 2024 ➔ Jun 2025

Trial completion date • Trial primary completion date • 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