rhIL-15

P1, N=50, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=6, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Sep 2023 --> May 2022

P1, N=50, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

P1, N=8, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Mar 2025 --> May 2022

P2, N=2, Terminated, National Cancer Institute (NCI) | Completed --> Terminated; This study was terminated early due to manufacturer withdrawal of support (study medication) due to lack of enrollment.

P1, N=1, Terminated, National Cancer Institute (NCI) | Completed --> Terminated; The study was closed after > 1 year of inactivity.

P1, N=8, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Mar 2022 --> Mar 2021

P1, N=8, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Mar 2025

P1, N=50, Recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2022 --> Dec 2022 | Trial primary completion date: Sep 2022 --> Dec 2022

P1, N=50, Recruiting, National Cancer Institute (NCI) | Trial primary completion date: Sep 2021 --> Sep 2022

P1, N=6, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Mar 2023 --> Nov 2020

P1, N=5, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=30 --> 5

P1, N=11, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Dec 2021 --> Jun 2021 | Trial primary completion date: Dec 2021 --> Jun 2021

P1, N=50, Recruiting, National Cancer Institute (NCI) | Trial primary completion date: Sep 2022 --> Sep 2021

P1, N=11, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2025 --> Dec 2021 | Trial primary completion date: Jan 2023 --> Dec 2021

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.

Immune suppressive factors including VEGF and IDO were also decreased by combination treatment. hIL15-ABD combined with anti-PD-L1 antibody increased the activity of anti-tumor effector cells involved in both innate and adaptive immunities, decreased the TME's immunosuppressive cells, and showed greater anti-tumor effect than that of either monotherapy.

To generate CIML and control cells, purified NK cells were pre-activated for 16h with rhIL-12 (10 ng/mL), plus rhIL-18 (50 ng/mL) and rhIL-15 (50 ng/mL) or control conditions (rhIL-15 1ng/mL)... Our results strongly suggest that NK cells acquire more potent anti-tumor capabilities against sarcoma cells after pre-activation with cytokine cocktail. Enhanced IFNγ production is responsible, at least in part, for increased killing potency of CIML-NK cells. Together, these findings raise CIML-NK cells as a promising step forward in sarcoma treatment.

To generate CIML and control cells, purified NK cells were pre-activated for 16h with rhIL-12 (10 ng/mL), plus rhIL-18 (50 ng/mL) and rhIL-15 (50 ng/mL) or control conditions (rhIL-15 1ng/mL)... Our results strongly suggest that NK cells acquire more potent anti-tumor capabilities against sarcoma cells after pre-activation with cytokine cocktail. Enhanced IFNγ production is responsible, at least in part, for increased killing potency of CIML-NK cells. Together, these findings raise CIML-NK cells as a promising step forward in sarcoma treatment.

To generate CIML and control cells, purified NK cells were pre-activated for 16h with rhIL-12 (10 ng/mL), plus rhIL-18 (50 ng/mL) and rhIL-15 (50 ng/mL) or control conditions (rhIL-15 1ng/mL)... Our results strongly suggest that NK cells acquire more potent anti-tumor capabilities against sarcoma cells after pre-activation with cytokine cocktail. Enhanced IFNγ production is responsible, at least in part, for increased killing potency of CIML-NK cells. Together, these findings raise CIML-NK cells as a promising step forward in sarcoma treatment.

To generate CIML and control cells, purified NK cells were pre-activated for 16h with rhIL-12 (10 ng/mL), plus rhIL-18 (50 ng/mL) and rhIL-15 (50 ng/mL) or control conditions (rhIL-15 1ng/mL)... Our results strongly suggest that NK cells acquire more potent anti-tumor capabilities against sarcoma cells after pre-activation with cytokine cocktail. Enhanced IFNγ production is responsible, at least in part, for increased killing potency of CIML-NK cells. Together, these findings raise CIML-NK cells as a promising step forward in sarcoma treatment.

P1, N=3, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=20 --> 3

P1, N=24, Recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2021 --> Dec 2022 | Trial primary completion date: Sep 2021 --> Jun 2022

P1, N=50, Recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2021 --> Sep 2022 | Trial primary completion date: Sep 2021 --> Sep 2022

The enriched NK cell product was cultured for 12-16 hours in X-VIVO 15 media containing rhIL-12, rhIL-15, and rhIL-18 to generate CIML NK cells (Figure 1A). Patients in the current cohort were lymphodepleted with fludarabine 25mg/m2 daily for 3-5 days and cyclophosphamide 60mg/kg daily for 2 days followed by CIML NK cells at a dose of 5-10 x 106 cells/kg and IL-2 106 IU/m2 QOD for 7 doses...In addition, CIML NK cell infusion can reduce the burden of pathogenic variant alleles to below the limit of detection, including the burden of high-risk mutations such as in TP53. Though our results are preliminary, the massive in vivo expansion and long-term persistence of adoptively transferred CIML NK cells underscores the unique biology of these cells that makes them an attractive option for cellular therapy protocols.

P1, N=10, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=30 --> 10

Trial primary completion date: Sep 2020 --> Sep 2021

These data identify gene signatures of resting and activated dog and human NK cells and can be used to generate a predictive signature of responding/non-responding patients treated with NK-based immunotherapies.

Collectively, our work demonstrates superior activity of RLI compared with rhIL-15 in modulating and activating NK cells and provides additional evidences for a therapeutic strategy using RLI as antimetastatic molecule.

In translation, a phase I trial was initiated involving IL-15 (rhIL-15), nivolumab and ipilimumab in patients with malignancy (NCT03388632)...To translate IL-15-mediated increases in NK cells, we investigated combination therapy of IL-15 with anticancer monoclonal antibodies including rituximab in mouse models of EL-4 lymphoma transfected with human CD20 and with alemtuzumab (CAMPATH-1H) in a xenograft model of adult T cell leukemia (ATL)...These results provided the scientific basis for trials of IL-15 combined with alemtuzumab (anti-CD52) for patients with ATL (NCT02689453), with obinutuzumab (anti-CD20) for patients with CLL (NCT03759184), and with avelumab (anti-PD-L1) in patients with T-cell lymphoma (NCT03905135) and renal cancer (NCT04150562). In the first trial, there was elimination of circulating ATL and CLL leukemic cells in select patients.

N-803 results in prolonged elevation of drug serum concentrations, contrasting with rapid clearance of recombinant human IL-15 (ie, half-life of ~20 vs < 1 hour). N-803 administration was well-tolerated in healthy volunteers, without evidence of adverse systemic inflammatory responses, and resulted in proliferation of NK cells and CD8+ T cells, as well as sustained increases in NK cell number. Findings in this study are consistent with published results from N-803 administration in treating liquid tumors and lung cancer.

P1, N=50, Recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2020 --> Sep 2021 | Trial primary completion date: Sep 2020 --> Sep 2021

Obinutuzumab is a glycoengineered, humanized type 2 anti-CD20 monoclonal antibody thought to engage the immune system by directly activating antibody- dependent, cell-mediated cytotoxicity (ADCC); it is approved for treatment of chronic lymphocytic leukemia in combination with chlorambucil...Preclinical murine lymphoid malignancy models have shown increased efficacy of monoclonal antibodies when administered together with rhIL-15; BL/6 mice inoculated with EL4-CD20 cells (a syngeneic lymphoma line); including significant prolongation of survival with the IL-15/Rituximab combination compared to either drug given as single agent (90% v. 30% alive at 75 days)...Primary objective: determine the safety, toxicity profile, dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of civ rhIL-15 administration in combination with obinutuzumab treatment Secondary objectives: 1) evaluate the potential antitumor activity of the combination of rhIL-15 and obinutuzumab by assessing the clinical response rate, minimal residual disease (MRD) status, progression-free survival, and overall survival in patients with relapsed and refractory CLL; 2) define the effects of rhIL-15 on the ADCC mediated by obinutuzumab using ex vivo peripheral blood mononuclear cells (PBMCs); 3) characterize the biological effects of rhIL-15 administered with obinutuzumab on the percentages and absolute numbers of circulating lymphocytes (T and NK cells) and the T- cell subsets (including naïve, central, and effector memory subsets) by flow cytometry Exploratory objectives: identify biomarkers predictive of response to rhIL-15 and obinutuzumab treatment, such as circulating tumor DNA (ctDNA) and baseline cytokine levels Eligibility criteria: 1) age ≥ 18 years; 2) ECOG ≤ 1; 3) Diagnosis of CLL or small lymphocytic lymphoma (SLL) with ≥ 50% of B cells expressing CD20; 4) measurable or evaluable disease that is refractory or relapsed following therapy with a BTK inhibitor OR have relapsed/refractory CLL and are intolerant to BTK inhibitor therapy; patients with del(17p) must also be refractory or relapsed after, or intolerant to, therapy with venetoclax; 5) adequate organ function parameters as defined within the protocol; 6) active disease requiring treatment, as defined within the protocol...One patient has started treatment to date. Enrollment is ongoing.