NKTR-255

Our preclinical studies demonstrate that immunotherapy via the innate immune system by combining tumor-targeting CAR-NK cells with an IL-15 agonist and a CD47 blockade is a promising novel therapeutic approach to targeting MCAMhigh malignant metastatic ES.

P2, N=256, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Recruiting --> Active, not recruiting

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).

P1/2, N=25, Completed, Nektar Therapeutics | Phase classification: P1b/2 --> P1/2

P1, N=20, Recruiting, AbelZeta, Inc. | Not yet recruiting --> Recruiting

P1, N=56, Active, not recruiting, Crystal Mackall, MD | Recruiting --> Active, not recruiting

P1, N=24, Recruiting, Fred Hutchinson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jan 2024 --> Dec 2024

P1, N=20, Not yet recruiting, AbelZeta, Inc.

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.

Overall, 252 patients with advanced UC who are progression-free following first-line platinum-based chemotherapy will be randomized 1:2:2:2 to receive maintenance therapy with avelumab alone (control group) or combined with sacituzumab govitecan (anti-Trop-2/topoisomerase inhibitor conjugate), M6223 (anti-TIGIT) or NKTR-255 (recombinant human IL-15). Primary end points are progression-free survival per investigator and safety/tolerability of the combination regimens. Secondary end points include overall survival, objective response and duration of response per investigator, and pharmacokinetics.

P1, N=30, Completed, Nektar Therapeutics | Active, not recruiting --> Completed

P2, N=39, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Apr 2023 --> Jan 2023

P1b/2, N=25, Completed, Nektar Therapeutics | Active, not recruiting --> Completed | N=326 --> 25 | Trial completion date: Aug 2024 --> Mar 2023

Our data provide a ra onale for a preclinical evalua on of IL1RAP-CAR NK/TGFbi-NK combined with NKTR-255 and dinutuximab in limi ng ES xenogra tumor growth and/or metastasis and prolonging animal survival in-vivo. Count: 400 words (Limit 400 words) This study was funded by NCI Cancer Moonshot U54 grant (CA232561-01A1).

Our data demonstrated successful engineering of anti-GD2 CAR NK cells and increased cytotoxic capacity in the anti-GD2 CAR NK when compared to the mock NK cell. We plan to test the anti- GD2 CAR NK cells on the GD2+ M054K GBM cell line and a GD2+ DIPG cell line. Afterwards, we will test the synergistic effect of the combination of NKTR-255 and anti-ROR1 antibody with the CAR NK cells against the same cell lines.

P1, N=30, Active, not recruiting, Nektar Therapeutics | Enrolling by invitation --> Active, not recruiting | N=118 --> 30 | Trial completion date: Oct 2023 --> Jun 2023 | Trial primary completion date: Mar 2023 --> Jun 2023

P1b/2, N=326, Active, not recruiting, Nektar Therapeutics | Recruiting --> Active, not recruiting

Our data demonstrate that blockade of the immune checkpoint protein, B7-H3 with the IL-15 receptor agonist, NKTR-255, or the BCL2 inhibitor, ABT-199, synergistically induces NK cell mediated cytotoxicity against B7-H3+ AML cells.

Together, our work shows that NKTR-255 dramatically improves the persistence, function, and anti-tumor activity of ROR1 CAR-T cells in an aggressive autochthonous model of ROR1+ lung cancer. Our findings provide rationale to combine NKTR-255 with CAR-T cell therapy as a strategy to enhance the anti-tumor efficacy of CAR-T cells in patients with solid tumors.

P2/3, N=400, Recruiting, Nektar Therapeutics | Not yet recruiting --> Recruiting

P2/3, N=400, Not yet recruiting, Nektar Therapeutics

Following lymphodepletion with fludarabine and cyclophosphamide, patients received the recommended Phase 2 dose of 3.0 x 10 6 /kg CAR-T cells (Spiegel, Patel, Muffly et al, Nature Medicine 2021). NKTR-255 administered at 1.5mcg/kg following CAR-T cell therapy was safe and appeared to promote CAR expansion in CNS and peripheral blood. Dose escalation is ongoing; additional safety data and longitudinal correlative assessments, including qPCR and cytokine data, will be presented at the meeting.

Subjects will receive lymphodepletion chemotherapy with cyclophosphamide and fludarabine followed by liso-cel infusion per Breyanzi® package insert, and NKTR-255 at 1.5 µg/kg intravenously every 3 weeks starting at approximately 10 to 14 days after CAR-T cell infusion. Conclusion s : This clinical trial will evaluate the safety and efficacy of NKTR-255 in combination with liso-cel aiming to increase the response rates and durability of response compared with CD19 CAR-T cells alone. Based on the biological rationale of IL-15 supplementation, correlative data from CD19 CAR-T cell studies, and results from preclinical studies with xenogeneic mouse models, NKTR-255 has the potential to augment currently approved cellular therapies.

These data support an ongoing phase I clinical trial of combined CD19 CAR-T and NKTR-255 for R/R B-cell malignancies. This trial is registered at www.clinicaltrials.gov as NCT01865617.

In preclinical studies, NKTR-255 enhanced antibody-dependent cellular cytotoxicity (ADCC) of daratumumab, rituximab, and cetuximab, resulting in synergistic antitumor effect. This ongoing Phase 1 trial (NCT04136756) evaluates safety, tolerability, pharmacokinetics (PK) and PD of NKTR-255 monotherapy and with subcutaneous (SC) Darzalex-Faspro (dara) or rituximab in patients with hematologic malignancies... In heavily pretreated patients with heme malignancies NKTR-255, alone and with SC dara was well-tolerated, manageable and biologically active with sustained increases in NK and CD8+ T cells. NKTR-255 administration replenished dara-induced NK cell depletion. Optimal biological response of NKTR-255 monotherapy was observed between 6-9 µg/kg and will be further tested in Phase 2.

Eligible patients who have r/r large B-cell lymphoma and are planned for treatment with an FDA-approved CAR-T product (axi-cel or liso-cel) will be enrolled...The key eligibility criteria following CD19 targeted CAR-T cell infusion include no grade ≥ 1 cytokine release syndrome (CRS) on the day of NKTR-255 administration, no grade ≥ 3 CRS within 72 hours proceeding NKTR-255 administration, no grade ≥ 3 immune effector cell-associated neurotoxicity (ICANS) of > 72 hours duration, no grade ≥ 2 ICANS on the day of NKTR-255 infusion and no tocilizumab and/or dexamethasone within 48 hours proceeding NKTR-255 administration. Based on preclinical and clinical evidence, NKTR-255 has the potential to improve efficacy of currently approved cellular therapies. This trial evaluates safety and efficacy of NKTR-255 following commercial CD19 CAR-T therapy to enhance antitumor effect and durability of responses.

P1, N=118, Enrolling by invitation, Nektar Therapeutics | Recruiting --> Enrolling by invitation | Trial completion date: Jan 2023 --> Oct 2023 | Trial primary completion date: Jun 2022 --> Mar 2023

P1, N=24, Recruiting, Fred Hutchinson Cancer Center | Not yet recruiting --> Recruiting

Finally, we observed that combination of NKTR-255 with the anti-CD38 antibody, daratumumab, was effective against MM cells in vitro and in vivo. Taken together, our data suggest a significant impact of NKTR-255 in inducing NK cell function against MM cells with important translational implications.

P1, N=24, Not yet recruiting, Fred Hutchinson Cancer Center | Initiation date: May 2022 --> Nov 2022

P1, N=24, Not yet recruiting, Fred Hutchinson Cancer Center

P1b/2, N=326, Recruiting, Nektar Therapeutics | N=78 --> 326 | Trial completion date: Apr 2023 --> Aug 2024 | Trial primary completion date: Apr 2022 --> Jun 2023

In preclinical studies, NKTR-255 enhanced antibody-dependent cellular cytotoxicity (ADCC) of each of daratumumab, rituximab, trastuzumab, and cetuximab, resulting in synergistic anticancer activity. In this heavily pretreated relapsed/refractory patient population with hematologic malignancies, NKTR-255 was biologically active, and demonstrated sustained increases in NK and CD8 + T cells. NKTR-255 was well tolerated with minimal treatment-related toxicities and transient upregulation and rapid decline of cytokines to baseline levels. RP2D for NKTR-255 monotherapy has not yet been reached; and dose escalation is ongoing at 9.0 µg/kg.

Following treatment with NKTR-255, there was an increase in CAR-T-cells as well as a reversal of the CD4 + :CD8 + ratio in 1 patient. Additionally, NKTR-255 induced expansion of total CD8 + cell fraction with an increase of proliferation index of Ki67 in all reported patients, supporting its role in enhancing the expansion and proliferative ability of cytotoxic T cells. Low baseline CAR-T/CAR-NK cell counts observed in patients may be due to longer time intervals between CAR-T infusion and the first dose of NKTR-255.

Taken together, these results support the restoration and expansion of NK cell activity in MM with NKTR-255, providing rationale for its clinical use as a novel immunotherapeutic approach for MM patients alone or in combination with monoclonal antibodies or other immunomodulatory drugs.

P1, N=118, Recruiting, Nektar Therapeutics | Trial completion date: Sep 2022 --> Jan 2023

Our results show that the novel immunotherapeutic, NKTR-255, retains the full spectrum of IL-15 biology, but with improved PK properties, over rhIL-15. These findings support the ongoing phase 1 first-in-human trial (NCT04136756) of NKTR-255 in participants with relapsed or refractory hematologic malignancies, potentially advancing rhIL-15-based immunotherapies for the treatment of cancer.

P1, N=118, Recruiting, Nektar Therapeutics | N=87 --> 118