Elsevier

Cytotherapy

Volume 10, Issue 6, 2008, Pages 625-632
Cytotherapy

Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial

https://doi.org/10.1080/14653240802301872Get rights and content

Background

Renal cell cancer and malignant melanoma are two types of cancer that are responsive to immunotherapy. In this phase I dose-escalation study, the feasibility of large-scale expansion and safety of administering ex vivo-expanded NK-92 cells as allogeneic cellular immunotherapy in patients with refractory renal cell cancer and melanoma were determined.

Methods

Twelve patients (aged 31–74 years) were enrolled, three per cohort at cell dose levels of 1 × 108/m2, 3 × 108/m2, 1 × 109/m2 and 3 × 109/m2. One treatment course consisted of three infusions. Eleven patients had refractory metastatic renal cell cancer; one patient had refractory metastatic melanoma.

Results

The NK-92 cells were expanded in X-Vivo 10 serum-free media supplemented with 500 U/mL Proleukin recombinant human interleukin-2 (rhIL-2), amino acids and 2.5% human AB plasma. Final yields of approximately 1 × 109 cells/culture bag (218–250×expansion) over 15–17 days were achievable with ≥80% viability. Infusional toxicities of NK-92 were generally mild, with only one grade 3 fever and one grade 4 hypoglycemic episode. All toxicities were transient, resolved and did not require discontinuation of treatment. One patient was alive with disease at 4 years post-NK-92 infusion. The one metastatic melanoma patient had a minor response during the study period. One other patient exhibited a mixed response.

Discussion

This study establishes the feasibility of large-scale expansion and safety of administering NK-92 cells as allogeneic cellular immunotherapy in advanced cancer patients and serves as a platform for future study of this novel natural killer (NK)-cell based therapy.

Introduction

Treatment options remain very limited for patients with metastatic renal cancer and metastatic melanoma. Median survival is 7–10 months for metastatic renal cancer and metastatic melanoma and both diseases are resistant to chemotherapy and/or radiotherapy [1]. Both cancers, however, seem to be responsive to immunotherapy [2., 3., 4.] and cellular immunotherapy is increasingly being considered as a form of treatment that is non-cross-reactive with prior chemotherapy and radiation [5, 6].

Natural killer (NK) cells are particularly attractive for adoptive cellular immunotherapy because of their unique ability to lyse target cells without priming [7]. Autologous NK cells from cancer patients, however, may be dysfunctional and may not recognize the malignant target. Autologous NK cells may also be inhibited by ‘self’ HLA expression and some tumors may in fact express functional HLA antigens (Ag) capable of inhibiting NK cell function. Allogeneic NK cells, therefore, potentially represent a better NK cell product for immunotherapy. NK-92 is a human NK-cytotoxic cell line that represents a pure allogeneic activated NK cell source. NK-92 is interleukin-2 (IL-2) dependent, lacks killer cell inhibitory receptors (KIR) and is broadly cytotoxic against a variety of hematologic and solid tumor cell lines, including leukemia, lymphoma, malignant melanoma, prostate cancer and breast cancer [8]. Ex vivo expansion of NK-92 under good tissue practice (GTP) conditions for clinical use has allowed its entry into phase I study as a novel immunotherapy in advanced cancers [9]. The NK-92 cell line is originally derived from a non-Hodgkin's lymphoma with large granular lymphocyte morphology and a CD56+CD3CD16 immunophenotype. Studies in SCID mice have confirmed that NK-92 inoculation itself is not leukemogenic. The tumoricidal activity of NK-92 against human leukemias has been tested in vitro against leukemic cell lines and primary leukemia cells, as well as in vivo by adoptive transfer of NK-92 cells into xenografted SCID mice, with the result of prolonged survival and no signs of leukemia development [10]. NK-92 infusion has further been found to prolong survival in SCID mice inoculated with human malignant melanoma cells, an observation that served as the basis for this clinical trial [11].

The objective of this study was to determine the safety of infusing NK-92 cells in patients with advanced renal cell cancer and melanoma. The three infusions, each given 48 h apart, had no severe side-effects and several patients showed objective anti-tumor responses, suggesting further exploration of this cellular treatment modality in selected cancer indications is warranted.

Section snippets

Patient eligibility

The study was open from April 2002 to June 2004 at Rush University Medical Center (Chicago, IL, USA). The protocol was approved by the Institutional Review Board and had obtained FDA investigational new drug application status for the ex vivo expansion of NK-92 cells. All patients signed informed consent before any study-related procedures. Patients with histologically confirmed metastatic renal cell cancer or malignant melanoma refractory to, or having failed, standard therapy, including

Patient characteristics

The characteristics of the 12 patients enrolled in the study are summarized in Table 1. The median age was 50 years (range 31–74 years); eight patients were male and four were female. Eleven patients had refractory metastatic renal cell cancer, predominantly clear cell type. One patient had refractory metastatic melanoma, spindle cell type. Prior therapies included nephrectomy, high-dose IL-2, IFN, radiation, chemotherapy and SCT.

Toxicity

All 12 patients received the three infusions of NK-92 per

Acknowledgements

We thank the nurse practitioners, Kelly Kindy, Patricia Friend and Christina Havey, and staff of 10 Kellogg at Rush University Medical Center, Chicago, IL, for their help in co-ordination of patient care and data collection; Guitta Maki for NK-92 laboratory support; Michele Prod for technical HLA laboratory support, and Philip Lavori at Stanford for statistical consultation.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content

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