Know Cancer

forgot password

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

Phase 1
18 Years
70 Years
Open (Enrolling)
Lung or Prostatic Neoplasms, Colorectal or Kidney Neoplasms, Pancreatic Neoplasms, Leukemia, Myelogenous, Chronic Lymphocytic Leukemia, BCR-ABL Positive, Melanoma, CLL

Thank you

Trial Information

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).

Inclusion Criteria


1. Diagnosed with histologically confirmed metastatic solid tumor - cancer of the
lung (small cell or non small cell), prostate (adenocarcinoma), colorectum,
kidney (renal cell carcinoma), pancreas (adenocarcinoma), or malignant melanoma,
and disease confirmed to be metastatic and unresectable for which standard
curative or beneficial treatments are no longer effective.


Diagnosed with a hematological malignancy (multiple myeloma, chronic myelogenous
leukemia [CML] or chronic lymphocytic leukemia [CLL] or small lymphocytic
lymphoma [SLL]) and disease resistant or refractory to standard therapy and
CLL/SLL patients are required to have failed prior treatment with at least one
nucleoside analogue. Myeloma patients are required to have disease which has
progressed following treatment with bortezomib.

2. At least 4 weeks since any prior systemic therapy (excluding corticosteroid
therapy) to treat the underlying malignancy (standard or investigational).

3. At least 2 weeks since prior palliative radiotherapy.

4. Ages greater than or equal to 18 years and less than or equal to 70 years.

5. Evidence of progressive disease over a 3-month interval.

6. RBC transfusion independent (solid tumor patients only).


1. Disease not evaluable radiographically (applies to solid tumor patients only).

2. Disease involving greater than 25% of the liver radiographically (estimated based on
review of liver lesions seen on CT scan).

3. History of an allogeneic hematopoietic stem cell transplant.

4. Brain metastases (with the exception of patients with a single brain metastasis less
than 1cm treated with either sterotactic or gamma knife radiotherapy) due to poor
prognosis and potential for neurological dysfunction that would confound evaluation
of neurological and other adverse events).

5. Peripheral neuropathy of grade greater than 1, which would require reduction of
bortezomib dose.

6. Acute diffuse infiltrative pulmonary disease.

7. Acute pericardial disease.

8. Life expectancy less than 3 months.

9. ECOG performance status 2, 3 or 4.

10. Uncontrolled concurrent illness including, but not limited to, symptomatic congestive
heart failure, unstable angina pectoris, life threatening cardiac arrhythmia.
Patients with symptoms of coronary artery disease, cardiac arrhythmias or an abnormal
thallium stress test must be evaluated and cleared by cardiology prior to enrollment.

11. Ongoing or active infection

12. Contraindication for administration of pentostatin, bortezomib, and/or interleukin-2.

13. Allergy or hypersensitivity to bortezomib, boron or mannitol by history.

14. Concurrent use of corticosteroids.

15. For all tumor types:

Marrow function characterized by

-Absolute neutrophil count less than 1,500/mcL (must be present off growth factors)

Organ function characterized by

- Total bilirubin greater than 3 times upper limit of normal

- AST (SGOT)/ALT (SGPT) greater than 4 times upper limit of normal

- Creatinine clearance less than 50 cc/min based on a 24 hour urine collection

- Left ventricular ejection fraction less than 40% by echocardiogram (ECHO)

- Hypercalcemia greater than 2.5 mmol/L

For all Hematologic malignancies:

Marrow function characterized by

- Neutrophil count less than or equal to 500/mcl

- Platelets less than or equal to 20,000/mcl

16. HIV-positive patients

17. Hepatitis C positive patients (Hep C PCR positive)

18. Active Hepatitis B infection (Hep B surface antigen positive)

19. Pregnant or nursing

20. Psychiatric illness/social situations that would limit compliance with study
requirements and ability to comprehend the investigational nature of the study and
provide informed consent.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety of escalating NK cell doses

Principal Investigator

Richard W Childs, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Heart, Lung, and Blood Institute (NHLBI)


United States: Federal Government

Study ID:




Start Date:

July 2008

Completion Date:

Related Keywords:

  • Lung or Prostatic Neoplasms
  • Colorectal or Kidney Neoplasms
  • Pancreatic Neoplasms
  • Leukemia, Myelogenous, Chronic Lymphocytic Leukemia, BCR-ABL Positive
  • Melanoma
  • CLL
  • Metastatic Solid Tumor
  • Chronic Myelogenous Leukemia (CML)
  • Small Lymphocytic Lymphoma (SLL)
  • Tumor Cytotoxicity
  • Chronic Lymphocytic Leukemia (CLL)
  • Lung Cancer
  • Prostate Cancer
  • Colon Cancer
  • Kidney Cancer
  • Pancreatic Cancer
  • Leukemia
  • Chronic Myelogenous Leukemia
  • CML
  • Small Lymphocytic Lymphoma
  • SLL
  • Chronic Lymphocytic Leukemia
  • CLL
  • Neoplasms
  • Kidney Neoplasms
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Melanoma
  • Pancreatic Neoplasms
  • Prostatic Neoplasms



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892