P1, N=40, Recruiting, SOTIO Biotech AG | Not yet recruiting --> Recruiting

P2, N=320, Active, not recruiting, SOTIO Biotech AG | Recruiting --> Active, not recruiting | Trial primary completion date: Sep 2023 --> Apr 2025

P1, N=200, Active, not recruiting, SOTIO Biotech AG | Trial completion date: Dec 2023 --> Nov 2024 | Trial primary completion date: Dec 2023 --> Aug 2024

P2, N=52, Active, not recruiting, SOTIO Biotech AG | Recruiting --> Active, not recruiting | Trial completion date: Nov 2025 --> Nov 2024 | Trial primary completion date: Nov 2025 --> Aug 2024

P1, N=77, Terminated, Sanofi | Completed --> Terminated; Sponsor terminated the study for non-safety reasons

P1, N=77, Completed, Sanofi | Active, not recruiting --> Completed

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=40, Not yet recruiting, SOTIO Biotech AG

We, therefore, hypothesized the use of CTLA-4 blockade with ipilimumab (IPI) would deplete Tregs in vivo and thus allow enhanced proliferation, activation, and anti-tumor responses of the adoptively transferred CIML NK cells...All patients received lymphodepletion with fludarabine (25 mg/m2 x 5 days) and cyclophosphamide (60 mg/kg x 2 days) and haploidentical CIML NK cell infusion (5-10 x 106 cells/kg) followed by IL-15 superagonist (N-803) (15 mcg/kg subcutaneously) starting on day +1 every 21-days (4x)...The use of IPI was associated with a relative depletion of Tregs with concurrent expansion of CD56dimCD16+ NK cells that had enrichment of proliferative (MYC), metabolically active (mTORC1), and cytokine reactive (TNFa) gene sets. Further work is required to elucidate the mechanism by which IPI exposure is associated with the expansion of specific subsets of CIML NK cells.

In the current study, we hypothesized the use of ipilimumab (IPI) will abrogate Treg-mediated inhibition and thus allow enhanced proliferation, activation, and anti-tumor responses of the adoptively transferred CIML NK cells...All patients received lymphodepletion with fludarabine (25 mg/m 2 x 5 days) and cyclophosphamide (60 mg/kg x 2 days) during days -6 to -2 prior to haploidentical CIML NK cell infusion on day 0 (5-10 x 10 6 cells/kg=dose level 0) followed by N-803 (15 mcg/kg subcutaneously) starting on day +1 every 21-days for 4-doses...Tumor regression was associated with CD56 dimCD16 + NK cell expansion. Further work is required to elucidate the mechanism by which IPI exposure is associated with the expansion of specific subsets of CIML NK cells.

The immune stimulatory mechanisms triggered by NL-201 and RT resulted in superior tumor growth inhibition and survival benefit in both localized and metastatic cancers. Our results support further preclinical and clinical investigation of this novel synergism regimen in locally advanced and metastatic settings.

In summary, RRV-mediated RLI immunotherapy results in immunostimulatory changes that are further potentiated by systemically administered temozolomide. This tumor-localized gene therapy has the potential to synergize with standard of care treatment to reverse the immunosuppressed GBM tumor microenvironment and provide a significant treatment benefit.

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.

Furthermore, co-culture with RD-IL15-secreting GD-CAR NK cells markedly enhanced proliferation and cytotoxicity of bystander immune cells in a paracrine manner. Our results demonstrate that GD-CAR NK cells co-expressing the IL-15 superagonist mediate potent direct and indirect antitumor effects, suggesting this strategy as a promising approach for the further development of functionally enhanced cellular therapeutics.

P2, N=64, Recruiting, SOTIO Biotech AG | Not yet recruiting --> Recruiting

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

P1, N=104, Not yet recruiting, AskGene Pharma, Inc.

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

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

These immunotherapeutic approaches have demonstrated remarkable efficacies in preclinical studies and have successfully transitioned to early phase clinical trials, to establish safety and initial signal of clinical activity. Here, we briefly discuss some of the most recent and impactful developments in the AML immunotherapy field and provide our perspectives for the future directions of this exciting and new therapeutic opportunity.

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

P1, N=14, Active, not recruiting, Jiangsu HengRui Medicine Co., Ltd. | Trial completion date: Dec 2022 --> Mar 2023 | Trial primary completion date: Sep 2022 --> Mar 2023

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.

The United States Food and Drug Administration (FDA) approved valrubicin (1998) and pembrolizumab (2020) for the treatment of BCG-unresponsive (BCGu) NMBIC...However, the FDA previously rejected the application for oportuzumab monatox (OM) due to a lack of data comparing it with pembrolizumab on August 20, 2021. Interestingly, the clinical efficacy and safety of ALT-803 were higher than that of pembrolizumab and OM, suggesting that ALT-803 may be approved by FDA. This review aims to further knowledge of the preclinical and clinical evidence of ALT-803 in the treatment of NMIBC and discuss its translational potential.

These findings highlight the potential of a novel immune-based intervention utilizing a cytokine-based therapeutic option for the treatment of SCLC. We hypothesize that N-803 may provide benefit to the majority of SCLC patients, including those with immunologically cold tumors lacking MHC expression.

P2, N=64, Not yet recruiting, SOTIO Biotech AG

The antitumor activity of exercise by means of enhanced immune activation is documented, but better identification of the underlying mechanisms is required to develop new therapeutic strategies. Recent work from the Dr Bar-Sagi group reveals that exercise engages IL-15 signaling and pharmacological activation of the IL-15/IL-15R axis mimics the exercise-driven immune cell-mediated cytotoxicity in pancreatic cancer.

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.

Using human PBMCs and isolated NK cells, we showed that SOT101 added concomitantly or used for immune cell pre-stimulation potentiated clinically approved monoclonal antibodies Cetuximab, Daratumumab and Obinutuzumab in killing of tumor cells in vitro. These results suggest that SOT101 might significantly augment the anti-tumor activity of therapeutic antibodies by increasing NK cell-mediated activity in patients. These results support the evaluation of SOT101 in combination with Daratumumab in clinical studies and present a rationale for an optimal clinical dosing schedule selection.

Combination therapy with IL15SA and ICB resulted in the greatest tumor killing and maintained an effector CD8+ T-cell population in the presence of imatinib. Our findings highlight the impact of oncogene inhibition on intratumoral CD8+ T cells and support the use of agonistic T-cell therapy during TKI and/or ICB administration.

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