CIML NK

P1, N=18, Recruiting, Dana-Farber Cancer Institute | Not yet recruiting --> Recruiting

P1, N=5, Recruiting, Dana-Farber Cancer Institute | Not yet recruiting --> Recruiting

P1, N=11, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | N=25 --> 11

P1, N=5, Not yet recruiting, Dana-Farber Cancer Institute | Initiation date: Jun 2024 --> Sep 2024 | Trial primary completion date: Feb 2025 --> Dec 2025

CAR arming of the CIML NK cells subtanstially reduced their dysfunction in patient-derived ascites fluid with transcriptomic changes related to altered metabolism and tonic signaling as potential mechanisms. Lastly, the adoptive transfer of MSLN-CAR CIML NK cells demonstrated remarkable inhibition of tumor growth and prevented metastatic spread in xenograft mice, supporting their potential as an effective therapeutic strategy in EOC.

P1, N=25, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Jul 2024 --> Dec 2024 | Trial primary completion date: Jun 2024 --> Sep 2024

P1, N=18, Not yet recruiting, Dana-Farber Cancer Institute

P1, N=5, Not yet recruiting, Dana-Farber Cancer Institute

P1, N=15, Recruiting, Dana-Farber Cancer Institute | Not yet recruiting --> Recruiting | Initiation date: May 2024 --> Jan 2024

P1, N=10, Active, not recruiting, Dana-Farber Cancer Institute | Not yet recruiting --> Active, not recruiting

P1, N=50, Enrolling by invitation, Dana-Farber Cancer Institute | Active, not recruiting --> Enrolling by invitation

P1, N=25, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Mar 2024 --> Jul 2024 | Trial primary completion date: Jan 2024 --> Jun 2024

P1, N=15, Not yet recruiting, Dana-Farber Cancer Institute

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.

P1, N=10, Not yet recruiting, Dana-Farber Cancer Institute

P1, N=15, Not yet recruiting, Dana-Farber Cancer Institute

CIML NK cells were manufactured with a 100% success rate and infused at a target dose of 5-10x106 cells/kg-body weight, 24 hours after 200 mg/m2 melphalan administration. Regulatory T cells increased by D+7 (3% vs 15% total PBMC) and returned to baseline after D+14 most likely reflecting the effect of IL-2 treatment. The functional capacity of the infused product was tested in vitro

P1, N=25, Recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Sep 2023 --> Jan 2024

P1, N=25, Recruiting, Biohaven Pharmaceuticals, Inc. | Trial primary completion date: Oct 2023 --> Oct 2025

P1, N=12, Recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Jun 2023 --> Sep 2023

P1, N=25, Recruiting, Biohaven Pharmaceuticals, Inc. | Trial completion date: Jun 2026 --> Oct 2026 | Trial primary completion date: Jun 2023 --> Oct 2023

P1, N=50, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting

P1, N=25, Recruiting, Biohaven Pharmaceuticals, Inc. | Phase classification: P1/2 --> P1

We hypothesized that use of the 7C6 mAb would allow simultaneous blockade of MICA/B shedding and ADCC by CIML NK cells resulting in enhanced targeting of MM cells, which would further synergize with Bortezomib treatment.ResultsFlowcytometric analysis of surface MICA/B levels on 10 human myeloma cell lines (HMCLs) demonstrated heterogeneous protein expression. Our data support the hypothesis that combination strategies to enhance NK cell activation can be effective to enhance NK cell-mediated immune surveillance in MM. This combined approach highlights their potential use as novel immunotherapy in MM.

We hypothesized that use of the 7C6 mAb would allow simultaneous blockade of MICA/B shedding and ADCC by CIML NK cells resulting in enhanced targeting of MM cells. Here we demonstrate that inhibition of MICA/B shedding with a novel antibody 7C6 enhances CIML NK cellmediated function against MM in vitro and in a xenograft mouse model. Our data support the hypothesis that combination strategies to enhance NK cell activation can be effective to enhance NK cell-mediated immune surveillance in MM. This combined approach highlights their potential use as novel immunotherapy in MM.

Thus, efficient arming of CIML NK cells with an NPM1-mutation-specific TCR-like CAR substantially improves their innate antitumor responses against an otherwise intracellular mutant protein. These preclinical findings justify evaluating this approach in clinical trials in HLA-A2 AML patients with NPM1c mutations.

Given their rapid expansion and long-term persistence in an immune compatible environment, CIML NK cells serve as a promising platform for the treatment of post-transplant relapse of myeloid disease. Further characterization of their unique in vivo biology and interaction with both T cells and tumor targets will lead to improvements in cell-based immunotherapies.

P1, N=50, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Feb 2026 --> Dec 2024 | Trial primary completion date: Apr 2025 --> Dec 2024