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 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
The primary endpoint will be assessed at day 21 (3 weeks after the Day 0 NK cell infusion).
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety of escalating NK cell doses
Richard W Childs, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
United States: Federal Government
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