Natural Killer Cells and Bortezomib to Treat Cancer
Condition: Chronic Myeloid Leukemia (CML); Pancreatic Ca; Colon/Rectal Ca; Multiple Myeloma; Carcinoma, Non-Small -Cell Lung
MeSH terms: Leukemia; Multiple Myeloma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Carcinoma, Non-Small-Cell Lung
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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 where 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).
    

Intervention name(s): Bortezomib; NK cells
Intervention type(s): Drug; Biological
Intervention description(s): Parenteral formulation. It is supplied as a 3.5 mg single use vial containing a sterile lyophilized powder that requires reconstitution.; NK Cell Infusion
Intervention MeSH terms: Bortezomib
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Metastatic Solid Tumor; Chronic Myelogenous Leukemia (CML); Small Lymphocytic Lymphoma (SLL); Chronic Lymphocytic Leukemia (CLL); Multiple Myeloma