Phase II Study in Metastatic Melanoma or Kidney Cancer Using Autologous Natural Killer Cells Plus Aldesleukin (IL-2) Following a Lymphodepleting Chemotherapy
- Natural killer (NK) cells are large granular lymphocytes that are critical effector
cells in the early innate immune response to pathogens and cancer.
- Previous and current clinical investigations have clearly demonstrated that T
lymphocytes can mediate the regression of metastatic melanoma. However, not all
patients with cancer are eligible for this type of immunotherapy either because
resectable tumor is not available, the TIL do not expand sufficiently, or the tumor
infiltrating lymphocytes (TIL) that do proliferate do not exhibit sufficient tumor
- We have recently developed techniques for the in vitro isolation and expansion of
anti-tumor NK cells to levels suitable for the treatment of cancer patients and are
proposing in this protocol to evaluate therapy using these NK cells.
- In Surgery Branch pre-clinical experiments, we evaluated lysis of fresh melanoma cell
digests, melanoma cell lines, renal cell carcinoma (RCC) lines, and normal peripheral
blood mononuclear cells (PBMCs) by NK cells from several patients and demonstrated that
NK cells could lyse some fresh melanoma digests, as well as melanoma cell lines and
renal cell cancer (RCC) lines, while sparing normal allogeneic and autologous PBMCs.
- Determine the ability of the administration of autologous natural killer (NK) cells
plus aldesleukin (IL-2) following a non-myeloablative lymphodepleting preparative
regimen to mediate tumor regression in patients with metastatic melanoma or kidney
- Determine the rate of repopulation of the natural killer cells in treated patients.
- Determine the toxicity of this treatment regimen.
- Patients, 18 years of age or older with metastatic melanoma or metastatic kidney cancer
who have previously received high dose IL-2, with an Eastern Cooperative Oncology Group
(ECOG) of 0 or 1.
- Patients may not have any active systemic infections, coagulations disorders, major
medical illnesses of the cardiovascular, respiratory or immune systems or any form of
autoimmune disease or immunodeficiency.
Patients must be eligible to receive high-dose IL-2.
- Patients will undergo apheresis on 03-C-0277 (Cell Harvest and Preparation for Surgery
Branch Adoptive Cell Therapy Protocols) to obtain cells for generation of autologous
natural killer cells.
- All patients will receive a non-myeloablative lymphocyte depleting preparative regimen
of cyclophosphamide (60 mg/kg/day IV) on days -8 and -7 and fludarabine (25 mg/m^2/day
IV) on days -6 through -2.
- On day 0 patients will receive the infusion of autologous natural killer lymphocytes
and then begin the first cycle of high-dose IL-2 (720,000 IU/kg IV every 8 hours for up
to 15 doses). A second cycle of IL-2 will be administered approximately 14 days later.
- Clinical and Immunologic response will be evaluated about 4 to 6 weeks
after the second cycle of IL-2.
-Using a small optimal Phase II design, two cohorts of patients, initially 16 in each
cohort, will be enrolled, and if at least one of the first 16 patients has a clinical
response (partial response (PR) or complete response (CR)), accrual will continue to 29
patients, targeting a 15% goal for objective response.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Objective response (complete response (CR) or partial response (PR)) is measured by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response (CR) is the disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.
very 4-6 weeks for up to 1 year, and then every 6 months for up to 5 years.
United States: Federal Government
|National Cancer Institute (NCI)||Bethesda, Maryland 20892|