CIML NK Cells + N-803 for Ovarian Cancer
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
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
Trial Summary
What is the purpose of this trial?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 in recurrent, high grade ovarian cancer (HGOC).
Names of the study therapies involved in this study are:
CIML NK (cellular therapy) Interleukin-2 (IL-2)
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.
What data supports the effectiveness of the treatment CIML NK Cells + N-803 for ovarian cancer?
Research shows that cytokine-induced memory-like (CIML) NK cells have enhanced function against ovarian cancer cells, and the IL-15 super-agonist (N-803) can boost NK cell activity, improving their ability to attack cancer cells. Additionally, higher percentages of NK cells in ovarian cancer patients are linked to better survival outcomes, suggesting that enhancing NK cell function could be beneficial.
12345Is the CIML NK Cells + N-803 treatment safe for humans?
The treatment using CIML NK Cells and N-803 has been studied for its safety and effectiveness in enhancing immune responses against cancer, including ovarian cancer. N-803, an IL-15 superagonist, has shown promise in boosting the function and persistence of NK cells in both laboratory and animal studies, suggesting it is generally safe for use in humans.
14567How is the treatment CIML NK Cells + N-803 different from other ovarian cancer treatments?
This treatment is unique because it uses specially prepared natural killer (NK) cells, called cytokine-induced memory-like (CIML) NK cells, which are enhanced to better fight cancer cells. It also includes N-803, an IL-15 superagonist, which boosts the NK cells' ability to expand and function, potentially improving their effectiveness against ovarian cancer compared to standard treatments.
12456Eligibility Criteria
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.
+9 more
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.
+13 more
Trial Timeline
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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Dose Level 0Experimental Treatment2 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 -1Experimental Treatment2 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Brigham and Women's HospitalBoston, MA
Dana-Farber Cancer InstituteBoston, MA
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Who Is Running the Clinical Trial?
Dana-Farber Cancer InstituteLead Sponsor
ImmunityBio, Inc.Industry Sponsor
References
Cytokine-induced memory-like natural killer cells have enhanced function, proliferation, and in vivo expansion against ovarian cancer cells. [2021]Natural killer (NK) cells are lymphocytes well suited for adoptive immunotherapy. Attempts with adoptive NK cell immunotherapy against ovarian cancer have proven unsuccessful, with the main limitations including failure to expand and diminished effector function. We investigated if incubation of NK cells with interleukin (IL)-12, IL-15, and IL-18 for 16h could produce cytokine-induced memory-like (CIML) NK cells capable of enhanced function against ovarian cancer.
Peritoneal NK cells are responsive to IL-15 and percentages are correlated with outcome in advanced ovarian cancer patients. [2019]The demonstration that ovarian carcinoma (OC) is an immunogenic disease, opens opportunities to explore immunotherapeutic interventions to improve clinical outcome. In this regard, NK cell based immunotherapy could be promising as it has been demonstrated that OC cells are susceptible to killing by cytokine-stimulated NK cells. Here, we evaluated whether percentage, phenotype, function and IL-15 responsiveness of ascites-derived natural killer (NK) cells is related to progression-free survival (PFS) and overall survival (OS) of advanced stage OC patients. Generally, a lower percentage of NK cells within the lymphocyte fraction was seen in OC ascites (mean 17.4 ± 2.7%) versus benign peritoneal fluids (48.1 ± 6.8%; p < 0.0001). Importantly, a higher CD56+ NK cell percentage in ascites was associated with a better PFS (p = 0.01) and OS (p = 0.002) in OC patients. Furthermore, the functionality of ascites-derived NK cells in terms of CD107a/IFN-γ activity was comparable to that of healthy donor peripheral blood NK cells, and stimulation with monomeric IL-15 or IL-15 superagonist ALT-803 potently improved their reactivity towards tumor cells. By showing that a higher NK cell percentage is related to better outcome in OC patients and NK cell functionality can be boosted by IL-15 receptor stimulation, a part of NK cell immunity in OC is further deciphered to exploit NK cell based immunotherapy.
Naturally Killing the Silent Killer: NK Cell-Based Immunotherapy for Ovarian Cancer. [2020]Ovarian cancer (OC) is diagnosed in ~22,000 women in the US each year and kills 14,000 of them. Often, patients are not diagnosed until the later stages of disease, when treatment options are limited, highlighting the urgent need for new and improved therapies for precise cancer control. An individual's immune function and interaction with tumor cells can be prognostic of the response to cancer treatment. Current emerging therapies for OC include immunotherapies, which use antibodies or drive T cell-mediated cancer recognition and elimination. In OC, these have been limited by adverse side effects and tumor characteristics including inter- and intra-tumoral heterogeneity, lack of targetable antigens, loss of tumor human leukocyte antigen expression, high levels of immunosuppressive factors, and insufficient immune cell trafficking. Natural killer (NK) cells may be ideal as primary or collateral effectors to these nascent immunotherapies. NK cells exhibit multiple functions that combat immune escape and tumor relapse: they kill targets and elicit inflammation through antigen-independent pathways and detect loss of HLA as a signal for activation. NK cells are efficient mediators of tumor immune surveillance and control, suppressed by the tumor microenvironment and rescued by immune checkpoint blockade. NK cells are regulated by a variety of activating and inhibitory receptors and already known to be central effectors across an array of existing therapies. In this article, we highlight interactions between NK cells and OC and their potential to change the immunosuppressive tumor microenvironment and participate in durable immune control of OC.
IL-15 super-agonist (ALT-803) enhances natural killer (NK) cell function against ovarian cancer. [2021]Natural killer (NK) cells represent a powerful immunotherapeutic target as they lyse tumors directly, do not require differentiation, and can elicit potent inflammatory responses. The objective of these studies was to use an IL-15 super-agonist complex, ALT-803 (Altor BioScience Corporation), to enhance the function of both normal and ovarian cancer patient derived NK cells by increasing cytotoxicity and cytokine production.
Reverse Translation Identifies the Synergistic Role of Immune Checkpoint Blockade and IL15 to Enhance Immunotherapy of Ovarian Cancer. [2023]Immune checkpoint blockade (ICB) has changed the standard of care for many patients with cancer, yet no ICB is approved for ovarian cancer. We hypothesized that maintenance therapy with an IL15 "superagonist" (N-803) and ICB in combination could induce potent immune activation in ovarian cancer. Using flow cytometry, cytometry by time of flight analysis, and cytotoxicity assays, we analyzed patient samples from women with advanced epithelial ovarian cancer treated with N-803 for indications of PD-1/PD-L1 upregulation with this treatment. In addition, ICB and N-803 were evaluated in preclinical studies to determine the functional impact of combination therapy on natural killer (NK) cells in vitro and in vivo. We observed that N-803 stimulated initial NK-cell expansion in patient samples; however, proliferation was not sustained beyond 2 weeks despite continued treatment. This result was reverse translated back to the laboratory to determine the functional relevance of this finding. The addition of ICB with an antibody-dependent cellular cytotoxicity IgG1 antibody against PD-L1 (avelumab) or an IgG4 antibody against PD-1 (pembrolizumab) enhanced N-803 induced NK-cell function in vitro. Using models of human ovarian cancer and NK-cell adoptive transfer in mice, we showed enhanced antitumor control with N-803 and ICB, as well as a combination effect that enhanced NK-cell persistence and expansion in vivo. This work suggests that PD-1/PD-L1 blockade combined with IL15 signaling may overcome resistance to cytokine therapy in ovarian cancer.
IL-15 superagonist N-803 improves IFNγ production and killing of leukemia and ovarian cancer cells by CD34+ progenitor-derived NK cells. [2022]Allogeneic natural killer (NK) cell transfer is a potential immunotherapy to eliminate and control cancer. A promising source are CD34 + hematopoietic progenitor cells (HPCs), since large numbers of cytotoxic NK cells can be generated. Effective boosting of NK cell function can be achieved by interleukin (IL)-15. However, its in vivo half-life is short and potent trans-presentation by IL-15 receptor α (IL-15Rα) is absent. Therefore, ImmunityBio developed IL-15 superagonist N-803, which combines IL-15 with an activating mutation, an IL-15Rα sushi domain for trans-presentation, and IgG1-Fc for increased half-life. Here, we investigated whether and how N-803 improves HPC-NK cell functionality in leukemia and ovarian cancer (OC) models in vitro and in vivo in OC-bearing immunodeficient mice. We used flow cytometry-based assays, enzyme-linked immunosorbent assay, microscopy-based serial killing assays, and bioluminescence imaging, for in vitro and in vivo experiments. N-803 increased HPC-NK cell proliferation and interferon (IFN)γ production. On leukemia cells, co-culture with HPC-NK cells and N-803 increased ICAM-1 expression. Furthermore, N-803 improved HPC-NK cell-mediated (serial) leukemia killing. Treating OC spheroids with HPC-NK cells and N-803 increased IFNγ-induced CXCL10 secretion, and target killing after prolonged exposure. In immunodeficient mice bearing human OC, N-803 supported HPC-NK cell persistence in combination with total human immunoglobulins to prevent Fc-mediated HPC-NK cell depletion. Moreover, this combination treatment decreased tumor growth. In conclusion, N-803 is a promising IL-15-based compound that boosts HPC-NK cell expansion and functionality in vitro and in vivo. Adding N-803 to HPC-NK cell therapy could improve cancer immunotherapy.
Enhanced expression of natural cytotoxicity receptors on cytokine-induced memory-like natural killer cells correlates with effector function. [2023]Label="Introduction">Natural killer (NK) cells are a key component of the innate immune system, involved in defending the host against virus-infected cells and tumor immunosurveillance. Under in vitro culture conditions, IL-12/15/18 can induce a memory-like phenotype in NK cells. These cytokine-induced memory-like (CIML) NK cells possess desirable characteristics for immunotherapies, including a longer lifespan and increased cytotoxicity.