CIML NK Cells + N-803 for Ovarian Cancer

Recruiting at 1 trial location

Overseen By DFCI Clinical Trials Hotline DFCI Clinical Trials Hotline

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Systemic corticosteroids, Antiretrovirals

Disqualifiers: Distant metastasis, Bowel obstruction, Autoimmune disease, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 14

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new treatment for individuals with recurrent high-grade ovarian cancer. Researchers are studying the safety and effectiveness of a special type of immune cell therapy called cytokine-induced memory-like (CIML) natural killer (NK) cells, combined with a drug called N-803 (an IL-15 superagonist complex). The trial seeks participants with confirmed recurrent ovarian cancer that has resisted or not tolerated previous treatments. Eligible participants should have cancer confined to the abdomen or pelvis and have already tried at least one other treatment.

As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

Will I have to stop taking my current medications?

The trial requires a 'washout' period (time without taking certain medications) for anti-tumor chemotherapy, investigational agents, immunotherapy, and systemic corticosteroids before receiving NK cell infusion. You should discuss your current medications with the study team to confirm if they need to be stopped.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that a special type of immune cell, called cytokine-induced memory-like (CIML) natural killer (NK) cells, may help fight ovarian cancer. These cells have been tested in labs and animals, where they effectively attacked cancer cells. In these studies, CIML NK cells survived and functioned even in challenging conditions, such as when surrounded by fluid from the abdomen of ovarian cancer patients.

The safety of N-803, a compound that boosts immune cell activity, has also been studied. In clinical trials, N-803 remained in the targeted area and did not enter the bloodstream. Most side effects were mild, such as irritation during urination.

This study is in the early stages, so researchers are closely monitoring safety. They are currently focused on finding a dose that is both safe and effective. While these treatments are not yet approved for ovarian cancer, the early research appears promising. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CIML NK cells and N-803 for ovarian cancer because they bring an innovative approach to treatment. Unlike traditional chemotherapy, which attacks cancer cells directly and can harm healthy cells in the process, CIML NK cells use the body's own immune system to target and destroy cancer cells more precisely. CIML NK cells are specially enhanced natural killer cells, making them potentially more effective at identifying and eradicating cancer cells. Additionally, N-803, an interleukin-15 superagonist, boosts the activity and persistence of these NK cells, potentially improving their effectiveness against cancer. This combination aims to provide a more targeted, immune-based attack on ovarian cancer, offering hope for better outcomes with fewer side effects.

What evidence suggests that CIML NK Cells + N-803 could be effective for ovarian cancer?

This trial will evaluate the combination of cytokine-induced memory-like (CIML) natural killer (NK) cells and N-803 for treating ovarian cancer. Research has shown that CIML NK cells can be highly effective against ovarian cancer, even in the presence of ascites fluid, which often occurs in ovarian cancer patients. Studies have demonstrated their effectiveness both in the lab and in living organisms. N-803 enhances the immune system by boosting NK cell activity, helping these cells kill ovarian cancer cells more effectively and increasing the production of the cancer-fighting protein IFNγ. Together, CIML NK cells and N-803 offer a promising new approach to treating high-grade ovarian cancer. Participants in this trial will receive these treatments as part of the study's experimental arms. ^{1 2 4 6 7}

Who Is on the Research Team?

Rebecca Porter, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for individuals with high-grade ovarian cancer that has come back after treatment. Participants should have a certain level of physical fitness and adequate organ function. Specific details about who can or cannot participate are not provided here.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document.

I agree to use effective birth control during the study.

I have a history or symptoms of heart disease and need a heart function assessment.

Exclusion Criteria

History of severe or anaphylactic allergic reactions attributed to compounds of similar composition to N-803 or other study agents.

Pregnant or breastfeeding women are excluded.

Anaphylactic reactions to murine-based antibody therapy or iron dextran.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Collection and Preparation

Collection of natural killer (NK) cells through leukapheresis and preparation for treatment

1 week

1 visit (in-person)

Lymphodepleting Chemotherapy

Participants receive lymphodepleting chemotherapy prior to NK cell infusion

5 days

Daily visits (in-person)

CIML NK Cell Infusion

Infusion of CIML NK cells and administration of low-dose IL-2

1 day

1 visit (in-person)

IL-2 Administration

Subcutaneous low-dose IL-2 administration every other day for additional doses

7 days

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Regular imaging every 8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• CIML NK Cells
• N-803

Trial Overview The study is testing the combination of CIML NK cell therapy, which uses immune cells designed to remember and attack cancer, with N-803, an agent that boosts the immune system's response against ovarian cancer.

How Is the Trial Designed?

Group I: Dose Level 0 Experimental Treatment 2 Interventions

Participants will be enrolled in a staggered fashion into a 3+3 dose de-escalation per protocol to establish a maximum tolerated dose (MTD). Dosage will start at dose level 0. * Baseline visit. * MRIs, PET scans, and/or CT scans every 8 weeks. * Cycle 0: * Day -7 of 8 day cycle: Apheresis for autologous NK cell collection. * Days -6 through -2 of 8 day cycle: Predetermined dose of lymphodepleting chemotherapy per protocol. * Days -5 through -4 of 8 day cycle: * Predetermined dose of lymphodepleting chemotherapy per protocol. * Predetermined dose of premedication per institutional standards. * Day 0 of 8 day cycle: * Predetermined dose of CIML NK cells once * Subcutaneous low-dose IL-2 once * Cycle 1: \- Days 2-8: Subcutaneous low-dose IL-2 every other day for 4 additional doses * Off-Treatment: * Long-term follow up for 5 years after last CIML NK cell infusion.

Group II: Dose Level -1 Experimental Treatment 2 Interventions

3+3 de-escalation to dose level -1 per protocol if DLTs occur in Cohort 1 dose Level 0. * Baseline visit. * MRIs, PET scans, and/or CT scans every 8 weeks. * Cycle 0: * Day -7 of 8 day cycle: Apheresis for autologous NK cell collection. * Days -6 through -2 of 8 day cycle: Predetermined dose of lymphodepleting chemotherapy per protocol. * Days -5 through -4 of 8 day cycle: * Predetermined dose of lymphodepleting chemotherapy per protocol. * Predetermined dose of premedication per institutional standards. * Day 0 of 8 day cycle: * Predetermined dose of CIML NK cells once * Subcutaneous low-dose IL-2 once * Cycle 1: \- Days 2-8: Subcutaneous low-dose IL-2 every other day for 4 additional doses * Off-Treatment: * Long-term follow up for 5 years after last CIML NK cell infusion.

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

ImmunityBio, Inc.

Industry Sponsor

Trials

75

Recruited

5,000+

Richard Adcock

ImmunityBio, Inc.

Chief Executive Officer since 2024

Information not available

Dr. Patrick Soon-Shiong

ImmunityBio, Inc.

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

The combination of IL15 'superagonist' N-803 and immune checkpoint blockade (ICB) shows promise in enhancing natural killer (NK) cell function and antitumor activity in ovarian cancer, as demonstrated in both patient samples and preclinical models.

While N-803 initially stimulated NK cell expansion, its effects were not sustained beyond two weeks; however, combining N-803 with ICB significantly improved NK cell persistence and expansion, suggesting a potential strategy to overcome resistance to cytokine therapy in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reverse Translation Identifies the Synergistic Role of Immune Checkpoint Blockade and IL15 to Enhance Immunotherapy of Ovarian Cancer. Felices, M., Wesley, E., Bendzick, LE., et al.[2023]

N-803, an IL-15 superagonist developed to enhance NK cell function, significantly boosts the proliferation and activity of NK cells derived from CD34+ hematopoietic progenitor cells, improving their ability to kill leukemia cells and secrete important immune signals like IFNγ.

In preclinical models, N-803 not only increased the persistence of HPC-NK cells in the body but also reduced tumor growth in immunodeficient mice with ovarian cancer, suggesting its potential to enhance the effectiveness of NK cell-based cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-15 superagonist N-803 improves IFNγ production and killing of leukemia and ovarian cancer cells by CD34+ progenitor-derived NK cells. Van der Meer, JMR., Maas, RJA., Guldevall, K., et al.[2022]

ALT-803 significantly enhances the cytotoxicity and cytokine production of natural killer (NK) cells against ovarian cancer, as demonstrated in both normal donor cells and NK cells derived from ovarian cancer patients.

In a mouse model, treatment with ALT-803 led to a significant reduction in tumor size, indicating its potential as an effective immunotherapeutic agent for enhancing NK cell function in ovarian cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-15 super-agonist (ALT-803) enhances natural killer (NK) cell function against ovarian cancer. Felices, M., Chu, S., Kodal, B., et al.[2021]

In advanced ovarian carcinoma patients, a higher percentage of CD56+ natural killer (NK) cells in ascites is linked to improved progression-free survival (PFS) and overall survival (OS), suggesting that NK cell levels could be a potential biomarker for patient outcomes.

The functionality of ascites-derived NK cells is comparable to that of healthy donors, and their reactivity can be significantly enhanced by stimulation with IL-15 or its superagonist ALT-803, indicating a promising avenue for NK cell-based immunotherapy in treating ovarian carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peritoneal NK cells are responsive to IL-15 and percentages are correlated with outcome in advanced ovarian cancer patients. Hoogstad-van Evert, JS., Maas, RJ., van der Meer, J., et al.[2019]

Cytokine-induced memory-like (CIML) NK cells, stimulated with IL-12/15/18, showed significantly enhanced characteristics such as increased expression of activating receptors and granzyme B, indicating their potential for improved immune responses against tumors and viral infections.

CIML NK cells demonstrated greater degranulation capacity and higher production of IFN-γ compared to control NK cells, suggesting they could be more effective in immunotherapy applications, with specific biomarkers identified for clinical relevance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced expression of natural cytotoxicity receptors on cytokine-induced memory-like natural killer cells correlates with effector function. Carreira-Santos, S., López-Sejas, N., González-Sánchez, M., et al.[2023]

Cytokine-induced memory-like (CIML) NK cells, generated by incubating NK cells with IL-12, IL-15, and IL-18, showed enhanced function and proliferation against ovarian cancer, demonstrating their potential for improved immunotherapy.

In both in vitro and in vivo models, CIML NK cells exhibited significant antitumor effects and maintained functionality even in the challenging immunosuppressive environment of ovarian cancer, suggesting a promising strategy for future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytokine-induced memory-like natural killer cells have enhanced function, proliferation, and in vivo expansion against ovarian cancer cells. Uppendahl, LD., Felices, M., Bendzick, L., et al.[2021]

Ovarian cancer (OC) is often diagnosed at advanced stages, leading to a high mortality rate, which emphasizes the need for new therapies, particularly immunotherapies that can effectively target tumor cells.

Natural killer (NK) cells show promise in improving ovarian cancer treatment by combating immune escape and tumor relapse, as they can activate against tumors even without specific antigens and may enhance the effectiveness of existing immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naturally Killing the Silent Killer: NK Cell-Based Immunotherapy for Ovarian Cancer. Nersesian, S., Glazebrook, H., Toulany, J., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06321484

NCT06321484 | Intraperitoneal Cytokine-Induced Memory ... This is an open-label, single site, phase 1b study to evaluate the safety and effectiveness of the use of cytokine-induced memory-like (CIML) natural killer (NK) ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6430659/

Cytokine-induced memory-like natural killer cells have ... CIML NK cells have enhanced functionality and persistence against ovarian cancer in vitro and in vivo, even when exposed to ascites fluid.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0090825819300393

Cytokine-induced memory-like natural killer cells have ... CIML NK cells have enhanced functionality and persistence against ovarian cancer in vitro and in vivo, even when exposed to ascites fluid.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/30658847/

Cytokine-induced memory-like natural killer cells ... - PubMed CIML NK cells have enhanced functionality and persistence against ovarian cancer in vitro and in vivo, even when exposed to ascites fluid.

5. dana-farber.org dana-farber.org/newsroom/news-releases/2024/specially-equipped-natural-killer-cells-show-effectiveness-against-the-most-common-form-of-ovarian-cancer

Specially equipped natural killer cells show effectiveness ... Study Title: CAR memory-like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer.

6. dana-farber.org dana-farber.org/clinical-trials/23-493

A Phase 1b Study of Cytokine-Induced Memory like (CIML) ... The goal of this research study is to evaluate the safety and effectiveness of the use of cytokine-induced memory-like (CIML) natural killer (NK) cell therapy ...

7. frontiersin.org frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.884648/full

Cytokine-Induced Memory-Like NK Cells: From the Basics ... We summarize the current knowledge about memory-like NK cells, focusing on IL-12/15/18-induced memory-like NK cells, and discuss their properties and ...