Natural Killer Cells and Bortezomib to Treat Cancer
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|ClinicalTrials.gov Identifier: NCT00720785|
Recruitment Status : Recruiting
First Posted : July 23, 2008
Last Update Posted : March 2, 2021
Natural killer (NK) cells are white blood cells that have a limited ability to kill cancer cells. This ability might be enhanced if they are given 24 hours after an injection of the drug bortezomib. This study will determine the following:
- What dose of NK cells can be given safely to subjects with metastatic solid tumors or leukemia.
- The effectiveness and side effects of NK cell therapy
- How the body handles NK cells.
People between 18 and 70 years of age who have a solid tumor or leukemia, and for whom standard treatments are not effective, may be eligible for this study. Participants undergo the following procedures:
Apheresis to collect NK cells. For this procedure, a catheter (plastic tube) is placed in a vein in the subject s arm. Blood flows from the vein into a cell separator machine, which separates the white cells from the other blood components. The white cells are extracted and the rest of the blood is returned to the body through a second tube placed in a vein in the other arm.
Chemotherapy with the drug pentostatin to suppress the immune system and prevent it from attacking the NK cells that will be infused.
Chemotherapy with bortezomib to increase NK cell function.
Infusion of the NK cells. In this dose-escalating study, successive groups of patients entering the study receive increasingly higher numbers of cells to determine the highest safe dose level. Up to ten dose levels may be studied.
Interleukin-2 drug therapy to maintain NK cell activity.
Evaluations during therapy including:
- Clinical assessment, history and review of medications
- Blood draws for routine and research tests.
- Pharmacokinetics study after the NK infusion to see how the body handles the cells. For this test, the number of NK cells in the blood are measured over time. This requires drawing about 1 teaspoon of blood at 15 minutes, 30 minutes, 1, 2, 4, 8, 12, and 24 hours after the infusion (day 1); then every 24 hours on days 2 through 7, then once on days 10, 14, and 21.
- Bone marrow biopsy (subjects with leukemia only).
- Chest x-ray.
- CT scan, bone scan and PET scan, if indicated, for disease evaluation.
Subjects who respond well after one treatment cycle may be eligible to continue NK cell therapy.
|Condition or disease||Intervention/treatment||Phase|
|Chronic Myeloid Leukemia (CML) Pancreatic Ca Colon/Rectal Ca Multiple Myeloma Carcinoma, Non-Small -Cell Lung||Drug: Bortezomib Biological: NK cells||Phase 1|
Natural killer (NK) cells are innate immune lymphocytes that are identified by the expression of the CD56 surface antigen and the lack of CD3. Unlike antigen specific T cells, NK cells do not require the presence of a specific tumor antigen for the recognition and killing of cancer cells. Our in vitro studies have demonstrated that pretreatment of malignant cells with bortezomib significantly enhances NK-mediated tumor cytotoxicity by sensitizing cells to TNF-related apoptosis-inducing ligand (TRAIL). TRAIL is a member of tumor necrosis factor family of cytokines that promotes apoptosis. Importantly, in our laboratory, in vitro expanded NK cells isolated from patients with metastatic cancers or hematological malignancies exhibited significantly more cytotoxicity against their tumor cells when tumors were pre-treated with bortezomib compared with untreated tumor controls. These findings suggest that drug-induced sensitization to TRAIL could be used as a novel strategy to potentiate anticancer effects of autologous adoptively infused NK cells in patients with cancer.
Murine studies conducted in our laboratory have also established that bortezomib treatment sensitizes tumors in vivo to killing by adoptively infused syngeneic NK cells; murine renal cell carcinoma line (RENCA) tumors in BALB/c mice grew significantly slower and survival was prolonged when syngeneic NK cell infusions were given following bortezomib treatment compared to mice receiving NK cell infusions alone or bortezomib alone. This anti-tumor effect was further potentiated by eradicating T-regulatory cells prior to adoptive NK cell infusion and by administering interleukin-2 after adoptive NK cell infusion.
Recently, our laboratory has developed techniques for the in vitro isolation and expansion of NK cells to levels suitable for the treatment of cancer patients. Furthermore, we have also established good viability and sterility of these expanded NK cells which, compared to fresh NK cells, have increased surface expression of TRAIL and have enhanced cytotoxicity against tumor cells.
We therefore propose this non-randomized, Phase I, dose escalating study designed to evaluate the safety and the anti- tumor effects of escalating doses of adoptively infused ex vivo expanded autologous natural killer (NK) cells against metastatic cancers or hematological malignancies sensitized to NK TRAIL cytotoxicity with Bortezomib.
The primary study objective is to determine the safety (maximum tolerated dose) of escalating NK cell doses of adoptively infused ex vivo expanded autologous NK cells in subjects with treatment refractory metastatic tumors or hematological malignancies that are sensitized to NK cell cytotoxicity using bortezomib. Secondary objectives will include the anti-neoplastic effects of this treatment regimen (assessed using standard disease specific response criteria) and the toxicity profile associated with extended cycles of protocol therapy.
The primary endpoint will be assessed at day 21 (3 weeks after the Day 0 NK cell infusion).
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||61 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Safety and the Anti-Tumor Effects of Escalating Doses of Adoptively Infused Ex Vivo Expanded Autologous Natural Killer (NK) Cells Against Metastatic Cancers or Hematological Malignancies Sensitized to NK TRAIL Cytotoxicity With Bortezomib|
|Actual Study Start Date :||August 1, 2008|
|Estimated Primary Completion Date :||January 1, 2022|
|Estimated Study Completion Date :||January 1, 2022|
NK Cell Infusion (cell /kg pt wt)
Biological: NK cells
NK Cell Infusion
1.3 mg/m2/dose administered as a 3 to 5 second bolusintravenous injection
Parenteral formulation. It is supplied as a 3.5 mg single use vial containing a sterile lyophilized powder that requires reconstitution.
- safety of escalating NK cell doses of adoptively infused ex vivo expanded autologous NK cells in subjects with treatment refractory metastatic tumors or hematological malignancies that are sensitized to NK cell toxicity with bortezomib. [ Time Frame: After each 3 week cycle ]Safety
- The anti-neoplastic effects of this treatment regimen (assessed using standard disease specific response criteria) and the toxicity profile associated with extended cycles of protocol therapy.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00720785
|Contact: Tatyana Worthy, R.N.||(301) firstname.lastname@example.org|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 email@example.com|
|Principal Investigator:||Richard W Childs, M.D.||National Heart, Lung, and Blood Institute (NHLBI)|