Natural Killer Cells and Bortezomib to Treat Cancer
|First Received Date ICMJE||July 22, 2008|
|Last Updated Date||October 4, 2014|
|Start Date ICMJE||July 2008|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE
||Safety of escalating NK cell doses|
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT00720785 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||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.|
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Natural Killer Cells and Bortezomib to Treat Cancer|
|Official Title ICMJE||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|
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:
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 four dose levels may be studied.
Interleukin-2 drug therapy to maintain NK cell activity.
Evaluations during therapy including:
Subjects who respond well after one treatment cycle may be eligible to continue NK cell therapy.
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 ICMJE||Interventional|
|Study Phase||Phase 1|
|Study Design ICMJE||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Intervention ICMJE||Drug: NK cells +CliniMACs CD3 and CD56 systems
|Study Arm (s)||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||55|
|Completion Date||Not Provided|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
|Ages||18 Years to 70 Years|
|Accepts Healthy Volunteers||No|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00720785|
|Other Study ID Numbers ICMJE||080186, 08-H-0186|
|Has Data Monitoring Committee||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||National Heart, Lung, and Blood Institute (NHLBI)|
|Collaborators ICMJE||Not Provided|
|Information Provided By||National Institutes of Health Clinical Center (CC)|
|Verification Date||March 2014|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP