NK Cells + N-803 for Kidney and Bladder Cancer
Recruiting in Palo Alto (17 mi)
+2 other locations
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
Disqualifiers: Autoimmune disease, Cardiovascular disease, HIV, others
No Placebo Group
Trial Summary
What is the purpose of this trial?The goal of this research study is to establish the safety and then to explore the effectiveness of infusing the combination of cytokine-induced memory-like (CIML) natural killer (NK) cells, a type of immune cell in the blood that is collected and bathed in special proteins to help identify and treat curtained advanced cancers, combined with low dose IL-2, which is a cytokine that activates immune cells, in advanced clear cell renal cell carcinoma and urothelial carcinoma.
Names of the study therapies involved in this study are/is:
* CIML NK cell therapy (a NK cell therapy)
* IL-2 (a type of cytokine)
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop taking your current medications. However, you cannot have had anti-tumor chemotherapy or investigational agents within 2 weeks prior to enrollment, or immunotherapy within 4 weeks prior. Also, you cannot be on systemic corticosteroid therapy at a dose of 10 mg or more of prednisone (or equivalent) for at least 2 weeks before enrolling.
What data supports the effectiveness of the treatment NK Cells + N-803 for Kidney and Bladder Cancer?
Research shows that cytokine-induced memory-like natural killer (CIML NK) cells, which are part of this treatment, have demonstrated enhanced anticancer functionality and promising clinical activity in early trials. Additionally, similar treatments using cytokine-induced killer (CIK) cells have shown effectiveness in treating renal cell carcinoma, with some patients experiencing complete or partial responses.
12345Is the NK Cells + N-803 treatment safe for humans?
Early clinical trials and preclinical studies suggest that cytokine-induced memory-like (CIML) NK cells, which are part of the NK Cells + N-803 treatment, are generally safe for humans, with promising results in treating certain cancers like acute myeloid leukemia.
45678What makes the NK Cells + N-803 treatment unique for kidney and bladder cancer?
This treatment is unique because it uses cytokine-induced memory-like (CIML) natural killer (NK) cells, which are enhanced by a combination of cytokines (IL-12, IL-15, and IL-18) to improve their longevity and anticancer functionality. This approach aims to overcome the limitations of traditional NK cell therapies by boosting their ability to remember and respond more effectively to cancer cells.
345910Eligibility Criteria
This trial is for adults with advanced renal cell carcinoma or urothelial carcinoma. Participants must have measurable disease and be able to provide a sample of their tumor tissue. They should not have had any other cancer treatments like chemotherapy, radiation, or surgery within the last 4 weeks.Inclusion Criteria
I am fully active and can carry on all my pre-disease activities without restriction.
I am 18 years old or older.
Ability to understand and the willingness to sign a written informed consent document.
+8 more
Exclusion Criteria
I have lasting side effects from previous treatments, but they are not severe.
Prior recipients of organ transplantation including allogeneic stem cell transplantation.
I have heart problems that affect my daily life.
+14 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
1-2 weeks
1 visit (in-person)
Leukapheresis and Chemotherapy
Collection of NK cells through leukapheresis and administration of lymphodepleting chemotherapy
1 week
Multiple visits (in-person)
Treatment
Administration of CIML NK Cell Therapy and low dose IL-2
4 weeks
Daily visits for infusion and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment
5 years
Every 3 months in-clinic, with CT, MRI, or PET scan; every 4 months follow-up in-clinic, by phone, or remotely
Participant Groups
The study tests CIML NK cell therapy combined with N-803 in patients. CIML NK cells are immune cells treated to target cancer better, while N-803 boosts these cells' activity. The aim is to see if this combo is safe and how well it works against kidney and bladder cancers.
2Treatment groups
Experimental Treatment
Group I: Dose Level 0: CIML NK + low dose IL-2Experimental Treatment2 Interventions
Participants will be enrolled in a staggered fashion into a 3+3 dose de-escalation design per protocol to establish a maximum tolerated dose (MTD) of CIML NK Cells. Dose will start at Dose Level 0.
* Baseline visit.
* Day -7: Apheresis for autologous NK cell collection.
* Days -6 through -2: Predetermined dose of standard of care lymphodepleting chemotherapy per protocol.
* Days 0: Predetermined dose of CIML NK Cell Therapy infusion 1x daily administered in-clinic or hospital.
* Days 1 through 8: Low dose IL-2 every other day
* Day 28 and then ever 2-3 months: CT/MRI/PET
* In-clinic visit every 3 months with CT, MRI, or PET scan.
* End of Treatment: in-clinic visit
* Follow Up: every 4 months in-clinic, by telephone, or remotely.
* If 2 or more out of 5 participants experience dose-limiting toxicities (DLTs), subsequent dose will be de-escalated to Dose Level -1.
Group II: Dose Level -1: CIML NK + low dose IL-2Experimental Treatment2 Interventions
Participants will complete:
* Baseline visit.
* Day -7: Apheresis for autologous NK cell collection.
* Days -6 through -2: Predetermined dose of standard of care lymphodepleting chemotherapy per protocol.
* Days 0: Predetermined dose of CIML NK Cell Therapy infusion 1x daily administered in-clinic or hospital.
* Days 1 to 8: low dose IL-2 every other day
* Day 28 and then ever 2-3 months: CT/MRI/PET
* In-clinic visit every 3 months with CT, MRI, or PET scan.
* End of Treatment: in-clinic visit
* Follow Up: every 4 months in-clinic, by phone, or remotely.
* If 1 or less DLTs are observed, this will be the maximum tolerated dose. If 2 or more DLTs are observed, accrual will stop.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Brigham and Women's HospitalBoston, MA
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
Kidney Cancer AssociationCollaborator
ImmunityBio, Inc.Industry Sponsor
References
Cytokines for the induction of antitumor effectors: The paradigm of Cytokine-Induced Killer (CIK) cells. [2022]Cytokine-Induced killer (CIK) cells are raising growing interest in cellular antitumor therapy, as they can be easily expanded with a straightforward and inexpensive protocol, and are safe requiring only GMP-grade cytokines to obtain very high amounts of cytotoxic cells. CIK cells do not need antigen-specific stimuli to be activated and proliferate, as they recognize and destroy tumor cells in an HLA-independent fashion through the engagement of NKG2D. In several preclinical studies and clinical trials, CIK cells showed a reduced alloreactivity compared to conventional T cells, even when challenged across HLA-barriers; only in a few patients, a mild GVHD occurred after treatment with allogeneic CIK cells. Additionally, their antitumor activity can be redirected and further improved with chimeric antigen receptors, clinical-grade monoclonal antibodies or immune checkpoint inhibitors. The evidence obtained from a growing body of literature support CIK cells as a very promising cell population for adoptive immunotherapy. In this review, all these aspects will be addressed with a particular emphasis on the role of the cytokines involved in CIK cell generation, expansion and functionalization.
Effects of cytokine-induced killer cell treatment in colorectal cancer patients: a retrospective study. [2020]Cytokine-induced killer (CIK) cells are ex vivo generated heterogeneous NK-like T-lymphocytes, which have anti-tumor effects in vitro and in vivo. This present study was conducted to evaluate the effects of autologous CIK cell immunotherapy on the prognosis of colorectal cancer patients. Progression-free survival (PFS), overall survival (OS) and immune cells were assessed. We found that the percentages of CD8(+), CD3(+) CD56(+), CD3(-) CD56(+) cell subsets were significantly increased from 19.7±6.3%, 13.8±7.9%, 1.0±1.2% to 35.8±11.6% (P
Immunotherapy with cytokine-induced killer cells in metastatic renal cell carcinoma. [2010]Cytokine-induced killer (CIK) cells have shown antitumor activity against several tumor cells both in vitro and in vivo. This study reports on the large-scale expansion of CIK cells and also present preliminary results from a pilot clinical trial. Sixteen (16) patients with renal cell carcinoma (RCC), all of whom had metastases after radical nephrectomy and adjuvant therapy using interferon-alpha (IFN-alpha) and/or interleukin-2 (IL-2), were treated with CIK cells. CIK cells were generated from peripheral blood mononuclear cells (PBMCs) and incubated in the presence of IFN-gamma followed by OKT3 and IL-2. Treatment schedule consisted of two to three cycles of CIK cell infusions at an interval of 3 weeks. A total of 46 infusions were administered to 16 metastatic RCC (mRCC) patients. The median number of transferred cells per treatment was 6.7 x 10(9) (range, 2.5-12.3). At a 60:1 effector-target cell ratio, CIK cells killed 51.4% and 32.1% of two human kidney tumor cell lines (293 and SK-RC-42), respectively. After CIK cell infusion, the percentage of CD3(+), CD8(+), CD3(+)CD56(+), and NKG2D(+) cells and the intracellular products of two type 1 cytokines (IFN-gamma and tumor necrosis factor alpha) significantly increased in the patients' PBMCs. Toxicity was minimal, and there were no immediate adverse reactions to the infusions. Three (3) patients had complete response, 1 patient had partial response, and 6 patients had stable disease. These results showed that adoptive CIK cell immunotherapy is a safe and effective treatment, which may have essential benefits for the improvement of the immunologic function in mRCC patients and play an important role in the treatment of mRCC.
Cytokine-induced memory-like natural killer cells for cancer immunotherapy. [2023]Natural killer cells are an important part of the innate immune system mediating robust responses to virus-infected and malignant cells without needing prior antigen priming. NK cells have always been thought to be short-lived and with no antigen specificity; however, recent data support the presence of NK cell memory including in the hapten-specific contact hypersensitivity model and in certain viral infections. The memory-like features can also be generated by short-term activation of both murine and human NK cells with cytokine combination of IL-12, IL-15 and IL-18, imparting increased longevity and enhanced anticancer functionality. Preclinical studies and very early clinical trials demonstrate safety and very promising clinical activity of these cytokine-induced memory-like (CIML) NK cells, making them an attractive cell type for developing novel adoptive cellular immunotherapy strategies. Furthermore, efforts are on to arm them with novel gene constructs for enhanced tumor targeting and function.
Human Cytokine-Induced Memory-Like Natural Killer Cells. [2020]Natural killer (NK) cells are innate lymphoid cells that are important for host defense against infection and mediate antitumor responses. Recent reports from several laboratories have identified that NK cells can remember a prior activation event and consequently respond more robustly when restimulated, a property termed innate NK cell memory. NK cell memory has now been identified following hapten exposure, viral infection, and combined cytokine preactivation with IL-12, IL-15, and IL-18. Many questions in the field remain regarding the cellular and molecular mechanisms regulating memory NK cells and their responses, as well as their formation and function in mice and humans. Here we review our current understanding of cytokine-induced memory-like (CIML) NK cells that are generated by combined preactivation with IL-12, IL-15, and IL-18. These cells exhibit enhanced NK cell effector functions weeks after the initial cytokine preactivation. Further, we highlight the preclinical rationale and ongoing therapeutic application of CIML NK cells for adoptive immunotherapy in patients with hematologic malignancies.
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.
Innovative Clinical Perspectives for CIK Cells in Cancer Patients. [2022]Cytokine-induced killer (CIK) cells are T lymphocytes that have acquired, in vitro, following extensive manipulation by Interferon gamma (IFN-γ), OKT3 and Interleukin 2 (IL-2) addition, the expression of several Natural Killer (NK) cell-surface markers. CIK cells have a dual "nature", due to the presence of functional TCR as well as NK molecules, even if the antitumoral activity can be traced back only to the NK-like structures (DNAM-1, NKG2D, NKp30 and CD56). In addition to antineoplastic activity in vitro and in several in-vivo models, CIK cells show very limited, if any, GvHD toxicity as well as a strong intratumoral homing. For all such reasons, CIK cells have been proposed and tested in many clinical trials in cancer patients both in autologous and allogeneic combinations, up to haploidentical mismatching. Indeed, genetic modification of CIK cells as well as the possibility of combining them with specific monoclonal antibodies will further expand the possibility of their clinical utilization.
Cytokine-Induced Memory-Like NK Cells: From the Basics to Clinical Applications. [2022]Natural killer (NK) cells are lymphocytes with a key role in the defense against viral infections and tumor cells. Although NK cells are classified as innate lymphoid cells (ILCs), under certain circumstances they exhibit adaptive and memory-like features. The latter may be achieved, among others, by a brief stimulation with interleukin (IL)-12, IL-15 and IL-18. These cytokine-induced memory-like (CIML) NK cells resemble the trained immunity observed in myeloid cells. CIML NK cells undergo transcriptional, epigenetic and metabolic reprogramming that, along with changes in the expression of cell surface receptors and components of cytotoxic granules, are responsible for their enhanced effector functions after a resting period. In addition, these memory-like NK cells persist for a long time, which make them a good candidate for cancer immunotherapy. Currently, several clinical trials are testing CIML NK cells infusions to treat tumors, mostly hematological malignancies. In relapse/refractory acute myeloid leukemia (AML), the adoptive transfer of CIML NK cells is safe and complete clinical remissions have been observed. In our review, we sought to summarize the current knowledge about the generation and molecular basis of NK cell memory-like responses and the up-to-date results from clinical trials with CIML NK cells.
The functional potency of natural killer cells in response to IL-2/IL-15/IL-21 stimulation is limited by a concurrent upregulation of Tim-3 in bladder cancer. [2019]For reasons not completely clear, natural killer (NK) cells from tumor patients displayed multiple exhaustion features and could not be completely restored even when the inhibitory signals from the intratumoral environment had ceased to exist. Here, we found that the circulating NK cells from bladder cancer patients presented significantly reduced cytotoxicity than the circulating NK cells from healthy volunteers. This impairment in cytotoxicity resulted in part from an overrepresentation of Tim-3+ NK cells in bladder cancer patients. Interestingly, patients with higher frequency of Tim-3+ NK cells tended to present higher frequency of Gal-9+ cells in tumor. Exogenous Gal-9 significantly reduced the cytotoxicity of Tim-3+, but not Tim-3-, NK cells. Patients with better prognosis presented lower levels of Tim-3+ NK cells and Gal-9+ tumor cells. We then attempted to improve the cytotoxicity of NK cells using a combination of exogenous cytokines. IL-2 + IL-15 and IL-2 + IL-21 significantly enhanced, but could not completely restore, the cytotoxicity of NK cells in bladder cancer patients. Notably, when the cytokine concentration increased from intermediate levels to high levels, the cytotoxicity of NK cells from healthy volunteers significantly increased with a strong upward trend, whereas the cytotoxicity of NK cells from bladder cancer patients plateaued at intermediate levels. Further examination revealed that high cytokine concentration significantly increased the Tim-3 expression in NK cells from bladder cancer patients. Blocking Tim-3 not only improved the cytotoxicity of NK cells from bladder cancer patients, but also eliminated the plateauing effect when the NK cells were stimulated with high concentrations of cytokines. Together, these data suggested that proinflammatory cytokines could moderately improve NK cell cytotoxicity in bladder cancer patients. However, the effect was limited due to a concurrent upregulation of Tim-3.
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.