Defective function of lymphokine-activated killer cells and natural killer cells in patients with hepatocellular carcinoma

Lymphokine-activated killer activity and natural killer activity in hepatocellular carcinoma patients were assessed. Maximum lymphokine-activated killer activity was induced at 3 to 5 days of incubation, and lymphokine-activated killer activity tended to increase in a manner dose dependent of recombinant interleukin-2. However, the maximum increase of lymphokine-activated killer activity in hepatocellular carcinoma was not as high as that of normal subjects or liver cirrhosis patients. Lymphokine-activated killer activity was impaired in hepatocellular carcinoma as compared to that in normal subjects. Hepatocellular carcinoma seemed to consist of two groups: i.e. a high-lymphokine-activated killer activity group and a low-lymphokine-activated killer activity group. Reduction of natural killer activity was also observed in hepatocellular carcinoma as compared with that in normal subjects and patients with liver cirrhosis. No correlation could be demonstrated between natural killer activity and lymphokine-activated killer activity in normal subjects, liver cirrhosis patients and hepatocellular carcinoma patients. With regard to the presence of HBsAg or alpha-fetoprotein concentration in the sera, there was no significant difference in natural killer and lymphokine-activated killer activity in hepatocellular carcinoma patients. Patients with a small mass lesion showed a low lymphokine-activated killer activity, and depressed lymphokine-activated killer activity was not necessarily related to tumor size. In comparison with the high-lymphokine-activated killer group, the low-lymphokine-activated killer group showed a significant decrease in gamma-interferon production and a preserved function of indocyanine green clearance.     

Lymphokine-activated killer cell activity in patients with primary and metastatic malignant liver tumors

Lymphokine-activated killer cells were generated from peripheral blood mononuclear cells of 33 patients with liver tumors (benign, 6; primary malignant, 10; metastatic, 17) and 10 healthy individuals. Although peripheral blood mononuclear cell yield was significantly lower (p less than 0.01) in patients with hepatocellular carcinoma or with metastatic colorectal cancer, natural killer activity in the peripheral blood mononuclear cell fraction was comparable in all groups tested. Optimal lymphokine-activated killer activity was demonstrated after 9 to 12 days of culture in recombinant interleukin 2. Lymphokine-activated killer activity, interleukin 2-induced lymphocyte proliferation and total lytic activity generated per culture in all patient groups studied were similar to those of normal control cells cultured under the same conditions. These in vitro data demonstrate the feasibility of obtaining lymphokine-activated killer cells from the blood of patients with liver tumors and provide a rationale for the future use of lymphokine-activated killer cells in adoptive immunotherapy of patients with primary and metastatic hepatic neoplasms.     

Depressed lymphokine-activated killer activity and analysis of the precursor cells in peripheral blood of patients with hepatocellular carcinoma

The in vitro lymphokine-activated killer activity and natural killer activity of peripheral blood mononuclear cells from 33 patients with hepatocellular carcinoma were investigated. Lymphokine-activated killer and natural killer activities of patients were significantly decreased compared with those of healthy volunteers. Peripheral blood mononuclear cells showed significantly lower lymphokine-activated killer and natural killer activities in patients with larger tumors (greater than or equal to 5 cm in diameter) than in patients with smaller tumors (less than 5 cm in diameter). Of 20 patients with larger tumors, 8 and 6 generated very little or no lymphokine-activated killer and natural killer activities. respectively. Lymphokine-activated killer precursors and natural killer cells were present mainly in the Leu-11+ fraction and partially in the Leu-7+ fraction in patients and normal volunteers. A flow cytometric study showed that the percentage of Leu-7+ 11+ and Leu-7-11+ fractions in peripheral blood mononuclear cells was lower in patients than in normal volunteers. The percentages of Leu-7-11+ and Leu-7+ 11+ fractions were diminished in the peripheral blood mononuclear cells of the patients with little or no lymphokine-activated killer activity. It is suggested that deficient lymphokine-activated killer and natural killer activities partially results from a reduction in the number of their precursor cells in patients with hepatocellular carcinoma.     

Locoregional immunochemotherapy in hepatocellular carcinoma

Hepatocellular carcinoma remains a disease with a poor and dismal prognosis, and all forms of currently available conventional therapies are rarely beneficial. However, in recent years, combined targeting locoregional immunochemotherapy has been reported with very promising results. Adoptive immunotherapy with LAK cells (lymphokine-activated killer cells) and recombinant interleukin-2 is becoming one of the new modalities to reconstitute the depressed immune status of the tumor-bearing host. Interleukin-2, gamma-interferon, and interleukin-12 induce cytolytic activity of LAK and natural killer cells and are considered for cellular activation to locoregional immunotherapy before, after resection or even in unresectable hepatocellular carcinomas. Spleen is a suitable organ for LAK cell induction because it has densely packed lymphocytes. The strategy of administration of both interleukin-2 and gamma-interferon into the spleen for in vivo immunostimulation is based on the well-known synergism of the above cytokines. LAK cells have cytotoxic activity against a variety of tumor cells. In particular, LAK cells exhibit efficacy against lung and liver malignant lesions, as suggested by their trafficking pattern; activated killer cells injected i.v. into humans appeared in the lung early and were subsequently rapidly redistributed to the liver and spleen. Lipiodol-Urografin emulsion is probably an ideal cytokine/anti-cancer drug carrier suitable for the combined locoregional immunochemotherapy because during its preferential retention in the vascular network of the spleen and tumor, a gradual release of both immuno- and chemotherapeutical drugs bound to emulsion droplets is achieved ensuring a prolong half life for these drugs. Recent data point to the potential of considering intratumoral or intravascular use of adenovirus carrying interleukin-12 gene, and/or p53-based gene therapy as possible therapeutic strategies in patients with hepatocellular carcinoma.     

Intestinal immune reactivity to interleukin 2 differs among Crohn's disease, ulcerative colitis, and controls

When stimulated by the lymphokine interleukin 2, human intestinal mucosal mononuclear cells mediate lymphokine-activated killer cell activity. When supplied with optimal doses of exogenous interleukin 2, lamina propria mononuclear cells isolated from inflammatory bowel disease and control tissue display comparable levels of cytotoxicity in vitro. However, cultures of Crohn's disease- and ulcerative colitis-derived cells contain significantly decreased interleukin 2 activity, suggesting that in vivo the availability of interleukin 2 may be limited, perhaps resulting in impaired cytotoxic function. To test this hypothesis, lamina propria mononuclear cells from inflammatory bowel disease and control patients were stimulated to produce endogenous interleukin 2, which was then used to induce autologous lymphokine-activated killer cells. When tested against K562 and Daudi target cells, Crohn's disease cells, despite producing only one-third of the amount of interleukin 2 generated by control cells, exhibited comparable levels of cytotoxicity. In contrast, ulcerative colitis cells produced substantially less interleukin 2 and exhibited remarkably low lymphokine-activated killer cell activity. When the same cells were supplied with an amount of human recombinant interleukin 2 equivalent to the average titer found in control cultures, similar results were obtained, and Crohn's disease cells even showed a significantly greater cytolytic activity than controls. These results suggest that the observed differences in lymphokine-activated killer cell activity cannot be attributed to the level of interleukin 2 alone, and that response to this lymphokine is different among Crohn's disease, ulcerative colitis, and control intestine. In Crohn's disease, there is either an increased number of interleukin 2-responsive cells or an exacerbated reactivity to interleukin 2. In ulcerative colitis, a loss of interleukin 2-responsive cells, a hyporesponsiveness to interleukin 2, or both might be present. In conclusion, this study demonstrates that reactivity to interleukin 2 distinguishes inflammatory bowel disease from control intestinal mononuclear cells, and, under appropriate experimental conditions, it can be used to uncover abnormalities of intestinal immunity.     

Immunotherapy of hepatocellular carcinoma with autologous lymphokine-activated killer cells and/or recombinant interleukin-2

Summary Five patients with hepatocellular carcinoma were subjected to immunotherapy: three patients were treated by adoptive immunotherapy with lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2), and two patients by systemic administration of rIL-2 alone. In one patient with diffuse-type hepatocellular carcinoma and portal vein thrombosis who was treated by infusion of LAK cells (a total number of 1.5x10¹⁰ cells/13 doses) and continuous rIL-2 administration (a total dose of 1.25x10⁸ units) via a percultaneously placed hepatic arterial catheter, the size of the tumor reduced dramatically and the portal vein thrombosis retracted. In two patients who had LAK cells infused (totals of 6.6x10⁹ cells/4 doses and 3.1x10⁹ cells/2 doses, respectively) during hepatic angiogram followed by systemic administration of rIL-2 twice a day, no clinical improvement was noticed. In two patients who received rIL-2 alone systemically (total doses of 8.9x10⁷ and 5.5x10⁷ units, respectively), neither clinical improvement nor severe side effects were observed. The results suggest that adoptive immunotherapy combined with continuous local administration of rIL-2 via a percutaneously placed hepatic arterial catheter may be an effective therapy without apparent side effects for patients with hepatocellular carcinoma who cannot be treated by conventional cancer therapy.     

Increased serum soluble interleukin 2 receptor levels in patients with viral liver diseases

Soluble interleukin 2 receptors (sIL 2R) in the sera of patients with viral liver diseases were quantified with a solid-phase enzyme immunoassay using two monoclonal antibodies against the receptors. The sIL 2R levels in patients with acute hepatitis, chronic hepatitis, liver cirrhosis and hepatocellular carcinoma were significantly higher than those in control subjects. In acute hepatitis patients, the high levels of sIL 2R observed during the florid stage returned to normal during remission. Levels in patients with chronic active hepatitis were significantly higher than in those with chronic persistent and lobular hepatitis, and levels observed during the exacerbation phase of chronic hepatitis were higher than they were during remission. Thus, in chronic hepatitis, sIL 2R levels increased in proportion to the inflammatory activity, and correlated well with serum transaminase (glutamic oxaloacetic transaminase: SGOT, glutamic pyruvic transaminase: SGPT) activities, but not with blood urea nitrogen or creatinine concentrations. In patients with a high degree of focal and piecemeal necrosis, serum sIL 2R levels increased further during recombinant interleukin 2 therapy. In post-hepatitic liver cirrhosis and hepatocellular carcinoma, sIL 2R levels correlated with serum cholinesterase and creatinine concentrations, but not with transaminase activities. Measurement of serum sIL 2R levels in patients with liver disease but without renal injury, may help in the diagnosis of inflammation in hepatitis, a process in which interleukin 2 may participate.     

Adoptive immunotherapy for stage IV renal cell carcinoma: a novel protocol utilizing periodate and interleukin-2-activated autologous leukocytes and continuous infusions of low-dose interleukin-2

In a pilot study involving 13 patients with advanced stage IV renal cell carcinoma, anti-tumor effects and toxicity of a novel form of adoptive immunotherapy were determined. The protocol utilizes infusions of autologous mononuclear leukocytes treated with the oxidizing mitogen sodium periodate (IO4-) and cultured in medium containing human recombinant interleukin-2 (IL-2), and continuous infusions of low-dose IL-2 (mean +/- SD dose = 39.5 +/- 8.6 X 10(3) U/kg/24 hours). Leukocytes (5 to 10 X 10(9] were removed by leukapheresis three times per week, mononuclear cells were separated, activated with IO4- and cultured in medium containing IL-2 (500 U/ml) for 48 to 72 hours. The cells were re-infused following the next leukapheresis procedure. IL-2 was administered five days per week. Treatment was continued for two three-week cycles. An increase in peripheral blood mononuclear cells bearing the natural killer cell (NK) surface marker, Leu 11, an increase in NK- and antibody-dependent cell-mediated cytotoxicity, and a slight increase in spontaneous cytotoxicity for non-NK targets were noted. Regressions (more than 50 percent decrease in tumor mass) of pulmonary, liver, bone, or soft tissue metastases were induced in six patients. Severe fluid retention did not develop in any patient and no patient required treatment in the intensive care unit. Five of the patients who showed a response have experienced a relapse at 5.2 +/- 1.0 (mean +/- SD) months. These observations indicate that IO4-/IL-2-activated killer cells plus continuous infusions of low-dose IL-2 can result in regression of metastatic renal cell carcinoma.     

Modulation of intestinal immune reactivity by interleukin 2

There is evidence indicating that interleukin 2 may be important in the regulation of intestinal immunity, as suggested by its capacity to induce nonspecific cytotoxic (lymphokine-activated killer) activity from human intestinal mucosal mononuclear cells. The present study was designed to further explore the phenotypic and functional changes induced by interleukin 2 on intestinal lymphocytes derived from inflammatory bowel disease and control tissues. Immunohistology of intestinal mucosa demonstrated few cells bearing the activation antigen recognized by anti-Tac (anti-interleukin 2 receptor) monoclonal antibody. However, when isolated lamina proprial mononuclear cells were exposed to interleukin 2 in culture, the number of Tac-positive cells increased dramatically, a phenomenon paralleled by the generation of lymphokine-activated killer cell activity. This cytotoxic function was critically dependent on the continuous availability of interleukin 2, but not on the expression of the Tac antigen, since Tac-negative cells were also cytotoxic. Depletion of natural killer cells, fractionation into T cell-enriched and -depleted cells before and after culturing with interleukin 2, and separation into Tac-positive and -negative cells after interleukin 2 activation failed to eliminate lymphokine-activated killer cell activity, suggesting that this phenomenon is mediated by phenotypically and functionally heterogeneous cell subsets. During the induction of lymphokine-activated killer cells variable amounts of interferon-gamma were produced, but these did not correlate with the degree of cytotoxicity. No differences were observed between the response to interleukin 2 by inflammatory bowel disease and control cells. Therefore, in view of its capacity to induce significant phenotypic and functional changes in different subpopulations of intestinal mucosal mononuclear cells, interleukin 2 should be regarded as an important modulator of intestinal immune reactivity.     

Induction and clinical utilization of lymphokine-activated killer cells in patients with gastrointestinal tract cancers

In 18 patients with cancers of the gastrointestinal tract, lymphokine-activated killer (LAK) cell activity was studied and compared with that of healthy subjects. After cultivation with 10(3) iu/mL of recombinant interleukin-2, the cytotoxicity of patients' lymphoid cells was increased from 13.6 +/- 6.8% to 76.2 +/- 19.5% against Daudi cells and from 12.8 +/- 8.1% to 76.2 +/- 19.5% against K-562 cells. Based on these results, autologous LAK cells were given to patients. LAK cells injected into subdermal metastatic tumours demonstrated a significant inhibitory effect on tumour growth in comparison with that of control tumour nodules. Of four patients with metastatic tumours in the liver, to whom LAK cells were administered via the hepatic artery, tumour size was reduced by about 25% (minor response) in one patient, with a decrease of computerized tomography attenuation in the tumours occurring in the other three patients.     

Lysis of primary hepatic tumours by lymphokine activated killer cells

Lymphokine activated killer cell is a newly described lytic system against a variety of solid tumours and is distinct in several respects from the classic cytolytic T cell and the natural killer systems. This study was conducted to evaluate the lytic activity of lymphokine activated killer cells against fresh autologous and allogeneic, as well as cultured hepatocellular carcinoma cells. Lymphokine activated killer cell was generated by incubating peripheral blood mononuclear cells with various concentrations of recombinant IL-2 (rIL-2, Cetus, USA) for various periods of time. A four hour 51Cr release assay was used to measure cytotoxicity. The results show that fresh and cultured hepatocellular carcinoma cells were only slightly susceptible to natural killer cells. Normal hepatocytes were resistant to lymphokine activated killer-mediated lysis. Lymphokine activated killer cells could be generated from mononuclear cells of hepatocellular carcinoma patients and normal subjects with lytic activity against fresh autologous and allogeneic and cultured hepatocellular carcinoma cells, but lymphokine activated killer cells from the former was less efficient than that from the latter. It is concluded that the adoptive immunotherapy with combined rIL-2 and lymphokine activated killer may be worth trying in early cases of primary hepatocellular carcinoma.     

Function of the immune system in liver cirrhosis

Malfunction of the immune system at different levels is typical for patients with liver cirrhosis. Both non-specific as well as antigen-specific functions may be compromised. The best studied and clinically most important problem is the diminished clearance capacity of the reticulo-endothelial system in liver cirrhosis. This transfers into a significantly higher rate of bacterial infections associated with a poorer prognosis in these patients. The clinical relevance of concomitant immune disorders like neutrophil dysfunction is less clear. An impaired activation of natural killer cells (NK) and lymphokine-activated killer cells (LAK) may have a role in the development of hepatocellular carcinoma but additional studies are needed. Clinically important is a moderately reduced efficacy of standard immunization protocols, which can be overcome by an increased dose in most vaccines.     

Induction of allogeneic tumour- and lymphokine-activated lymphocytes against hepatocellular carcinoma

For clinical application of adoptive immunotherapy against hepatocellular carcinoma (HCC), it is not easy to prepare tumour specific effector cells such as cytotoxic T lymphocytes (CTL). To induce potent and broad-spectrum effectors, allogeneic cultured hepatoma cell lines (JHH-4 and HuH-6) were used as stimulators of peripheral blood lymphocytes (PBL) instead of autologous HCC cells. Allogeneic tumour- and lymphokine-activated killer cells (ATLAK) were generated by a mixed culture of lymphocytes and allogeneic cultured tumour cells with recombinant interleukin-2 (rIL-2). The tumour-killing activity of ATLAK induced by HuH-6 was confirmed against HuH-6 and other different HCC cell lines (JHH-2, HuH-7 and PLC). These activated lymphocytes were significantly more potent than lymphokine-activated killer cells (LAK) in [51Cr]-releasing assay. The JHH-4 stimulated ATLAK was reactive not only with JHH-4 but also with JHH-2. The lysis of allogeneic targets could be partially inhibited by anti-CD8 and anti-CD3 but not by anti-CD4. Anti-tumour cytotoxicity in these cultures might be mediated by CD3+CD56- and CD3+CD56+ effectors. These results imply that adoptive immunotherapy for HCC with ATLAK may be more feasible than that with LAK.     

Effects of recombinant interleukin 2 on immunological effector cells of the peripheral blood in patients with HBe antigen-positive chronic hepatitis

Changes in peripheral blood immunological effector cells after systemic administration of recombinant interleukin 2 (rIL2) were studied in 14 patients with HBe antigen-positive chronic hepatitis. The patients were intravenously injected with rIL2 for 4 weeks, and the experiments were performed using mononuclear cells isolated from the peripheral blood during and after rIL2 administration. No significant changes in OKT4-positive cell population, OKT8-positive cell population, OKT4/OKT8 ratio and Leu7-positive cell population were detected during and after intravenous injection of rIL2. However, the natural killer (NK) cell and lymphokine-activated killer (LAK) cell activities significantly increased in the fourth week of rIL2 administration, while the K cell activity in the antibody-dependent cell-mediated cytotoxicity reaction, antibody response, lectin-induced lymphocyte transformation and IL1 production of LPS-stimulated monocytes were not affected. These results suggest that IL2 increases the NK cell and LAK cell activities in vivo.     

Induction of antitumor immunity and treatment of preestablished tumor by interleukin-6-gene-transfected melanoma cells combined with low-dose interleukin-2

Transfer of cytokine genes into tumor cells has proven a valuable approach for cancer treatment. In order to generate a more effective cancer vaccine, we transfected the human interleukin-6 (IL-6) gene into B16 melanoma cells. A B16 cell clone secreting the highest level of IL-6 was obtained by G418-resistant selection, limiting dilution and IL-6 assay. The IL-6-gene-transfected tumor cells exhibited in vitro growth inhibition, reduced tumorigenicity and decreased metastatic competence. After immunization with the inactivated IL-6-gene-transfected vaccine, the murine cytotoxic T lymphocyte activity, natural killer activity and lymphokine-activated killer activity increased markedly. After treatment with the vaccine, the tumorbearing mice showed significant growth inhibition of subcutaneous tumor, reduction in pulmonary metastases and extension of survival time. The above therapeutic effect was better when low-dose IL-2 was administered simultaneously, although this dosage of IL-2 had no in vivo antitumor effect. These data demonstrated that IL-6-gene-transfected cancer vaccine has a potent antitumor effect via efficient induction of antitumor immunity, and a better therapeutic effect could be achieved when the vaccine is combined with lowdose IL-2 as adjuvant.Abbreviations IL interleukin - NK natural killer - LAK lymphokine-activated killer - CTL cytotoxic T lymphocytes Research supported by the National Natural Science Foundation of China (grant: 39421009)     

Defective immunological functions associated with abnormal lymphokine-activated killer activity in patients with hepatocellular carcinoma

The in vitro lymphokine-activated killer (LAK) activity of peripheral blood mononuclear cells (PBMC) from 36 patients with hepatocellular carcinoma was investigated. The activity was greatly diminished in 13 patients and enhanced in seven patients. A flow cytometric study showed that the percentage of OKM1+, Leu-7+-11b+, and Leu-7-11b+ fractions in PBMC was decreased and the percentage of OKT8+ and Leu7+11- fractions was increased significantly in the 13 patients with lower LAK activity, compared with the values of the seven higher LAK activity patients. Furthermore, the response of PBMC to interleukin-2 (IL-2) was deficient in the lower activity group. However, there was no significant difference in IL-2 production by PBMC, IL-2 receptor (p55) expression of PBMC and mitogen (Con-A, PHA) response of PBMC between the two groups. These findings indicate the possibility that diminished LAK activity in hepatoma patients is due to a decreased number of LAK precursor cells and a defective response of LAK precursor cells to IL-2.     

Cimetidine reduces impairment of cellular immunity after transcatheter arterial embolization in patients with hepatocellular carcinoma

BACKGROUND/AIMS: Natural killer cells have an intrinsic ability to recognize and attack some tumor cells and infected cells. Natural killer cell cytotoxicity is depressed in patients with hepatocellular carcinoma. In particular, cell-mediated immunity is impaired after transcatheter arterial embolization, which is an effective therapy for hepatocellular carcinoma. There have been reports that cimetidine can activate cellular immunity and increase the survival time in patients with some cancers. Therefore, we investigated whether cimetidine could improve cellular immunity after transcatheter arterial embolization, especially in relation to natural killer activity. METHODOLOGY: Thirty-four patients with hepatocellular carcinoma and cirrhosis who underwent transcatheter arterial embolization at our hospital were studied prospectively after giving informed consent. The patients were divided into three groups. In group A, 14 patients were administered 800 mg of cimetidine a day. In group-B, 13 patients were administered 40 mg of famotidine or 300 mg of nizatidine a day. In group-C 7 patients did not receive histamine 2 receptor antagonists. Natural killer cell activity in peripheral blood was measured before transcatheter arterial embolization and on days 1 and 7. RESULTS: The % natural killer cell activity on day 1 was 74 in group A, 52 in group B, and 52 in group. The % activity on day 7 was 98 in group A, 71 in group B, and 82 in group C. Cimetidine group showed the significant higher % natural killer cell activity on day 1 (p = 0.032). CONCLUSIONS: Our study raises the possibility that cimetidine has the effect to preserve cell-mediated immune response during transcatheter arterial embolization.     

The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells

Study Objective: To study the neuropsychiatric manifestations of therapy with interleukin-2 and lymphokine-activated killer cells. Design: Longitudinal survey of consecutive patients who were given the treatment. Each patient was initially interviewed within 5 days before treatment, and a personal and family psychiatric history was obtained during this first session. Cognitive tests and mood self-rating instruments were administered at the beginning and end of interleukin-2 and lymphokine-activated killer cell treatments, before discharge, and at a follow-up visit 2 to 4 weeks after discharge. Setting: National Cancer Institute inpatient units at the National Institutes of Health. Patients or Other Participants: Sequential samples of 44 patients with metastatic cancer (age range, 28 to 69 years) who were treated systemically with recombinant interleukin-2 combined with autologous lymphokine-activated killer cells between 30 December 1985 and 31 March 1986. Measurements and Main Results: Of the 44 patients studied, 15 developed severe behavioral changes that necessitated acute intervention, and 22 patients had severe cognitive changes (all 22 became disoriented and many also had psychometric evidence of cognitive deterioration). The neuropsychiatric side effects were dose and time related, appearing more frequently at the higher dose and almost uniformly at the end of each treatment phase. All 39 patients who were seen at follow-up had a return to their baseline cognitive scores. None of the factors investigated was found to be predictive of the development of neuropsychiatric toxicity. Conclusions: The development of clinically significant neuropsychiatric changes during the administration of interleukin-2 and lymphokine-activated killer cells was common and may be treatment limiting. A marked latency in the appearance of neuropsychiatric changes after treatment onset was noted in almost all patients. Every patient studied recovered from the neuropsychiatric side effects.     

A recombinant antibody-interleukin 2 fusion protein suppresses growth of hepatic human neuroblastoma metastases in severe combined immunodeficiency mice.

A genetically engineered fusion protein consisting of a human/mouse chimeric anti-ganglioside GD2 antibody (ch14.18) and recombinant human interleukin 2 (rhIL-2) was tested for its ability to target rhIL-2 to tumor sites and stimulate immune effector cells sufficiently to achieve effective tumor cell lysis in vivo. The ch14.18-IL-2 fusion protein proved more effective than equivalent doses of rhIL-2 in suppressing dissemination and growth of human neuroblastoma in an experimental hepatic metastases model of scid (severe combined immunodeficiency) mice reconstituted with human lymphokine-activated killer cells. The ch14.18-IL-2 fusion protein was also more proficient than equivalent doses of rhIL-2 in prolonging the life-span of these animals. This recombinant antibody-cytokine fusion protein may prove useful for future treatment of GD2-expressing human tumors in an adjuvant setting.     

The Correlation between NK Cell and Liver Function in Patients with Primary Hepatocellular Carcinoma

Background/Aims

This study aimed to detect the expression of natural killer (NK) cell receptor natural killer group 2D (NKG2D) in the peripheral blood of patients with primary hepatocellular carcinoma and to discuss the correlation between NK cell cytotoxicity and liver function.

Methods

The number of NK cells and the expression of NK cell receptor NKG2D in peripheral blood were determined by flow cytometry in patients with primary hepatocellular carcinoma, hepatitis B cirrhosis, chronic hepatitis B, and healthy controls.

Results

When compared with patients in the healthy and the chronic hepatitis B groups, the primary hepatocellular carcinoma group showed significant decreases in all parameters, including the cytotoxicity of NK cells on K562 cells, expression rate of NKG2D in NK cells, number of NKG2D⁺ NK cells, expression level of NKG2D, and number of NK cells (p<0.05). The activity of NK cells showed a positive correlation, whereas the Child-Pugh scores in the primary hepatocellular carcinoma and the hepatitis B cirrhosis groups showed a negative correlation with all parameters detected above.

Conclusions

The decrease of NK cell activity in patients with primary hepatocellular carcinoma is closely related to their lower expression of NKG2D. Liver function affects the expression of NKG2D and the activity of NK cells.