CIML NK / Dana-Farber Cancer Institute - LARVOL DELTA

In depth characterization of autologous infused bhv-1100 armored memory-like NK cells in MRD+ multiple myeloma patients receiving autologous stem cell transplant (ASH 2025) - P1 | "2 pts received Daratumumab-Lenalidomide-Bortezomib-Dexamethasone (DaraRVD) and 5 pts RVD as induction therapy. This study provides detailed immune characterization of autologous, BHV-1100-coated CIMLNK cells in MM pts undergoing ASCT in first remission. Findings suggest robust NK cell expansion, BMinfiltration, and cytotoxic activity, with favorable cytokine profiles. These data support the potential ofARM-enhanced CIML NK therapy as an immunologic bridge in MM and warrant further investigation."

Clinical • IO biomarker • Hematological Malignancies • Multiple Myeloma • Septic Shock • Transplantation • CD8 • CST3 • CXCL11 • FLT3LG • GZMB • IFITM3 • IFNG • IL10 • IL12A • IL18 • IL6 • NCAM1 • PRF1 • TNFSF12 • XCL2

CTLA-4 Blockade Results in the Enrichment of Proliferative CD56 dimCD16 + NK Cells Following Infusion of Haploidentical Donor Memory-like Natural Killer Cells Plus IL-15 Superagonist in a Phase 1 Trial (ASH 2023) - P1 | "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."

IO biomarker • P1 data • Graft versus Host Disease • Head and Neck Cancer • Immunology • Oncology • Solid Tumor • CD8 • IFNG • IL12A • IL18 • LAMP1 • NCAM1

Expansion, Persistence, and Characteristics of Autologous, Bhv-1100 Armored Memory-like NK Cells Infused Prior to Autologous Stem Cell Transplant in MRD+ Multiple Myeloma Patients: A First-in-Human Trial (ASH 2023) - P1 | "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"

Clinical • First-in-human • IO biomarker • P1 data • Hematological Malignancies • Multiple Myeloma • Oncology • Transplantation • B3GAT1 • IL12A • IL15 • IL18 • KLRC1 • NCAM1

Mesothelin Targeting IL12-Engineered CAR Memory-like NK Cells Demonstrate Promising Efficacy in Acute Myeloid Leukemia (ASH 2024) - "This study demonstrates MSLN as a novel CAR target in AML and shows that IL-12 can be safely and feasibly incorporated into MSLN-CAR CIML NK cells, providing a potential therapeutic approach to substantially enhance their anti-tumor responses. Our results support further evaluation of this approach in patients with relapsed/refractory MSLN+ AML with otherwise extremely poor prognosis."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • ABCA1 • CD123 • CD33 • CD8 • CXCR4 • GZMB • IFNG • IL12A • IL12B • IL15 • IL18 • IL2RA • IL3RA • IRF1 • KMT2A • MSLN • SOCS3

A phase 1b study of intraperitoneal cytokine-induced memory-like (CIML) natural killer (NK) cell therapy in platinum resistant ovarian cancer (SITC 2025) - P1 | "Natural killer (NK) cells can kill tumor cells without prior sensitization or significant toxicity, but poor expansion and persistence has limited clinical translation.6–9 Cytokine-induced memory-like (CIML) NK cells, generated by brief priming with IL-12, IL-15, and IL-18, exhibit enhanced proliferation, survival, and tumor control in ovarian cancer (OC) models.10–13 CIML-NK cells show promising early results and persistence across several cancers, including a 67% objective response rate (ORR) in rel/ref AML from allogeneic donors.12 14 We hypothesized that intraperitoneally-delivered (i.p.) autologous CIML-NK cells following lymphodepleting chemotherapy (LDC) and followed by low-dose IL-2 would be safe, tolerable and induce anti-tumor responses in patients with PROC.Methods This is a Phase 1b investigator-initiated study with primary objectives to determine safety, tolerability and maximum tolerated dose (MTD) of autologous i.p. CIML-NK cells in patients with..."

P1 data • Platinum resistant • Oncology • Ovarian Cancer • Solid Tumor • IL12A • IL15 • IL18

Preemptive CIML NK Cell Therapy After Hematopoietic Stem Cell Transplantation (clinicaltrials.gov) - P1 | N=15 | Recruiting | Sponsor: Dana-Farber Cancer Institute | Trial completion date: Nov 2026 ➔ Nov 2027 | Trial primary completion date: Feb 2026 ➔ Feb 2027

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • Transplantation

A Phase 0 Pilot Study of Memory-like Natural Killer (NK) Cell Immune Therapy in Patients with Renal Cell Carcinoma or Urothelial Carcinoma (NCT06318871) (KCRS 2025) - P1 | "Participants undergo apheresis for autologous NK cell collection followed by fludarabine and cyclophosphamide lymphodepleting chemotherapy. Correlative studies will evaluate the phenotype and function of CIML NK cells and determinants of treatment response. This data will inform the development of novel NK cell based therapies in RCC and UC, including NK chimeric antigen receptor strategies."

Clinical • Genito-urinary Cancer • Head and Neck Cancer • Hematological Malignancies • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer • IL2

ENGINEERING INTERLEUKIN-12 SECRETING CHIMERIC ANTIGEN RECEPTOR (CAR) NATURAL KILLER CELLS TO TARGET HIGH-RISK ACUTE MYELOID LEUKEMIA (EBMT 2025) - "Incorporating IL-12 into CAR-CIML NK cells is feasible, safe, and significantly enhances their cytotoxic activity against multiple CD70- and MSLN-expressing AML cell lines. These findings provide strong rationale for further clinical evaluation of this approach in patients with high-risk AML, who currently face an extremely poor prognosis."

IO biomarker • Acute Myelogenous Leukemia • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Oncology • ABCA1 • ANXA5 • CD123 • CD27 • CD33 • CD70 • CD8 • CXCR4 • GZMB • IFNG • IL12A • IL12B • IL15 • IL2RA • IL3RA • IRF1 • MSLN • SOCS3

CIML NK Cells With Venetoclax for AML (clinicaltrials.gov) - P1 | N=10 | Recruiting | Sponsor: Dana-Farber Cancer Institute | Active, not recruiting ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

A Phase 1 Trial of CIML NK Cell Infusion for Myeloid Disease Relapse After Hematopoietic Cell Transplantation (clinicaltrials.gov) - P1 | N=50 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Juvenile Myelomonocytic Leukemia • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • Transplantation • IL2

First-in-human evaluation of memory-like NK cells with an IL-15 super-agonist and CTLA-4 blockade in advanced head and neck cancer. (PubMed, J Hematol Oncol) - P1 | "CIML NK cells combined with N-803 and ipilimumab to treat head and neck cancer is safe, and associated with a more proliferative NK cell phenotype. However, the combination leads to reduced HLA mismatched NK cell persistence, resulting in an important limitation affecting NK cell combination therapies in clinical trials. These results inform evaluation of CIML NK therapy for advanced malignancies, with considerations for combination with IPI."

Journal • P1 data • Head and Neck Cancer • Oncology • Solid Tumor • CD8

CIML NK Cell in Head & Neck Cancer (clinicaltrials.gov) - P1 | N=11 | Completed | Sponsor: Dana-Farber Cancer Institute | Active, not recruiting ➔ Completed

Combination therapy • Immune cell • Metastases • Trial completion • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Salivary Gland Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

A Phase 1 Trial of CIML NK Cell Infusion for Myeloid Disease Relapse After Hematopoietic Cell Transplantation (clinicaltrials.gov) - P1 | N=50 | Enrolling by invitation | Sponsor: Dana-Farber Cancer Institute | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Juvenile Myelomonocytic Leukemia • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • Transplantation • IL2

Intraperitoneal Cytokine-Induced Memory Like (CIML) Natural Killer (NK) Cells in Recurrent Ovarian Cancer (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: Dana-Farber Cancer Institute | Not yet recruiting ➔ Recruiting

Enrollment open • Oncology • Ovarian Cancer • Solid Tumor

Memory-like Natural Killer (NK) Cell Therapy in Patients with Renal Cell Carcinoma or Urothelial Carcinoma (clinicaltrials.gov) - P1 | N=5 | Recruiting | Sponsor: Dana-Farber Cancer Institute | Not yet recruiting ➔ Recruiting

Enrollment open • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer

CIML NK Cell in Head & Neck Cancer (clinicaltrials.gov) - P1 | N=11 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Recruiting ➔ Active, not recruiting | N=25 ➔ 11

Combination therapy • Enrollment change • Enrollment closed • Immune cell • Metastases • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Salivary Gland Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Memory-like Natural Killer (NK) Cell Therapy With N-803 in Patients With Renal Cell Carcinoma or Urothelial Carcinoma (clinicaltrials.gov) - P1 | N=5 | Not yet recruiting | Sponsor: Dana-Farber Cancer Institute | Initiation date: Jun 2024 ➔ Sep 2024 | Trial primary completion date: Feb 2025 ➔ Dec 2025

Combination therapy • Trial initiation date • Trial primary completion date • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer

CAR memory-like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer. (PubMed, Sci Adv) - "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."

Journal • Colorectal Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • MSLN

Mechanisms and Predictors of Adoptive Cytokine-Induced Memorylike NK Cell Therapy in Renal Cell Carcinoma (KCRS 2024) - "We have previously demonstrated that in vitro cytokine (IL-12, IL-15, and IL-18) activation of patient derived NK cells causes differentiation into cytokine induced memory-like NK cells (CIML-NK), which have prolonged survival, enhanced proliferation, and enhanced antibodydependent cellular cytotoxicity...Impact: This project will study how memory-like NK cells function and persist in patients with ccRCC, which will lead to better understanding of why NK immune effector cell dysfunction occurs, and how this may be reversed using this new class of therapeutics with the goal of improving patient outcomes. This proposal addresses the FY22 Kidney Cancer Research Program Focus Areas by exploring a novel therapeutic strategy for ccRCC, and enhancing understanding of the biology of NK cells in ccRCC Principal Investigator: ROMEE, RIZWAN Institution Receiving Award: DANA-FARBER CANCER INSTITUTE Program: KCRP Proposal Number: KC220072P1 Award Number: HT9425-23-1-0478 Funding..."

Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Head and Neck Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • IL12A • IL15 • IL18

CIML NK Cell in Head & Neck Cancer (clinicaltrials.gov) - P1 | N=25 | Recruiting | Sponsor: Dana-Farber Cancer Institute | Trial completion date: Jul 2024 ➔ Dec 2024 | Trial primary completion date: Jun 2024 ➔ Sep 2024

Combination therapy • Immune cell • Metastases • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Salivary Gland Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

CIML NK Cells With Venetoclax for AML (clinicaltrials.gov) - P1 | N=10 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Not yet recruiting ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Preemptive CIML NK Cell Therapy After Hematopoietic Stem Cell Transplantation (clinicaltrials.gov) - P1 | N=15 | Recruiting | Sponsor: Dana-Farber Cancer Institute | Not yet recruiting ➔ Recruiting | Initiation date: May 2024 ➔ Jan 2024

Enrollment open • Trial initiation date • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • Transplantation • IL2

Intraperitoneal Cytokine-Induced Memory Like (CIML) Natural Killer (NK) Cells in Recurrent Ovarian Cancer (clinicaltrials.gov) - P1 | N=18 | Not yet recruiting | Sponsor: Dana-Farber Cancer Institute

Combination therapy • New P1 trial • Oncology • Ovarian Cancer • Solid Tumor

A Phase 0 Pilot Study of Memory-like Natural Killer (NK) Cell Immune Therapy in Combination With N-803 in Patients With Renal Cell Carcinoma or Urothelial Carcinoma (clinicaltrials.gov) - P1 | N=5 | Not yet recruiting | Sponsor: Dana-Farber Cancer Institute

Combination therapy • New P1 trial • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer

CTLA-4 Blockade Leads to Enrichment of Active CD56dimCD16+ NK Cells and Depletion of Regulatory T Cells Following Infusion of Haploidentical Donor Memory-like Natural Killer Cells Plus IL-15 Superagonist in a Phase 1 Trial (TCT-ASTCT-CIBMTR 2024) - P1 | "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."

IO biomarker • P1 data • Graft versus Host Disease • Head and Neck Cancer • Immunology • Oncology • Solid Tumor • B3GAT1 • IFNG • IL12A • IL18 • NCAM1 • TNFA