Anti-ganglioside GM2 monoclonal antibody-dependent killing of human lung cancer cells by lymphocytes and monocytes

Ganglioside GM2 (GM2) frequently appears on the cell surface of human cancers of neuroendocrine origin. A mouse-human chimeric monoclonal antibody (mAb), KM966, against GM2 was previously found to promote the lysis of various cancer cells by human blood mononuclear cells (MNC). In this study, we analyzed the effector cells responsible for the chimeric mAb-dependent cell-mediated cytotoxicity (ADCC) against small cell lung cancer (SCLC) cells and examined the enhancing effect of various cytokines on the ADCC activity. The ADCC activity was assessed by 4-h 51Cr release assay. Highly purified lymphocytes (> 99%) and monocytes (> 90%) were separated by centrifugal elutriation from peripheral blood MNC of the same healthy donor. KM966 induced lysis of SCLC cells mediated by both lymphocytes and monocytes to similar extents, in a dose-dependent manner. Pretreatment of lymphocytes with various cytokines [interleukin (IL)-2, IL-12 and interferon-gamma] and that of monocytes with macrophage-colony-stimulating factor significantly augmented the killer activity against SCLC cells in the presence of KM966 mAb. KM966 was also effective for the lysis of non-small cell lung cancer cells in direct proportion to the GM2 expression levels. These findings suggest that combined treatment of KM966 mAb with cytokines may be therapeutically useful for in vivo killing of lung cancer cells expressing GM2 through the ADCC reaction.


Systemic chemotherapy alters interleukin-1 beta and its receptor antagonist production by human alveolar macrophages in lung cancer patients

The purpose of this study was to determine whether cytotoxic chemotherapy influences the number and function of alveolar macrophages (AM) in patients with lung cancer. AM were obtained by bronchoalveolar lavage from 24 patients with lung cancer and 17 control patients. The functional integrity of AM was determined by their ability to produce interleukin-1 beta (IL-1 beta) and interleukin-1 receptor antagonist (IL-1ra) before and after platinum-containing systemic chemotherapy. The productions of IL-1 beta and IL-1ra were quantitated by enzyme immunoassays. The proportions of multinucleated cells among AM were significantly decreased after systemic chemotherapy in lung cancer patients. No significant difference in spontaneous and lipopolysaccharide (LPS)-stimulated IL-1 beta or IL-1ra production by AM was observed between lung cancer patients and control patients. Significant increase of IL-1 beta and significant decrease of IL-1ra production by AM were demonstrated in patients with small cell lung cancer who experienced response to systemic chemotherapy. These results suggest that systemic chemotherapy may influence functional roles of AM in the lung, and consideration of influence of systemic chemotherapy on host functions is important in cancer treatment.


Influence of systemic chemotherapy on anti-P-glycoprotein antibody-dependent cell-mediated cytotoxicity in patients with small cell lung cancer

Anti-P-glycoprotein antibody (MRK-16)-dependent cell-mediated cytotoxicity (ADCC) by blood mononuclear cells (MNC) was examined in patients with small cell lung cancer (SCLC) before and after systemic chemotherapy. The effect of in vitro treatment of MNC with interleukin (IL)-2 and macrophage-colony-stimulating factor (M-CSF) was also examined. The ADCC reaction was assessed by a 6 h 51Cr-release assay using a multidrug-resistant (MDR) SCLC cell line (H69/VP cells). The MRK-16 monoclonal antibody was able to augment spontaneous cytotoxicity by MNC, even in SCLC patients. Pretreatment of MNC with IL-2 significantly augmented their ADCC ability in SCLC patients, while M-CSF had no effect on ADCC activity. After the first cycle of systemic chemotherapy, the ADCC activity tended to decline, but ADCC of MNC pretreated with IL-2 was not affected. The results suggest that anti-P-glycoprotein antibody, in combination with a cytokine such as IL-2, may be therapeutically useful against human SCLC resistant to chemotherapeutic drugs.


Contrasting effect of interleukin-13 on interleukin-1 receptor antagonist and proinflammatory cytokine production by human alveolar macrophages

We investigated the effect of interleukin-13 (IL-13) on production of IL-1 receptor antagonist (IL-1ra) and proinflammatory cytokines by human alveolar macrophages (AM). AM were obtained by bronchoalveolar lavage from healthy donors. The production of IL-1ra and proinflammatory cytokines, such as IL-1 beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha), were quantitated by enzyme immunoassays. AM spontaneously produced IL-1ra, and this production was significantly augmented by IL-13. On the other hand, IL-13 alone did not affect production of proinflammatory cytokines by freshly isolated AM. Upon stimulation with lipopolysaccharide (LPS), AM produced a significantly amount of proinflammatory cytokines as well as IL-1ra, but this production was suppressed by IL-13 in a dose-dependent manner. In contrast, IL-13 caused a small but reproducible increase in LPS-induced IL-1ra production. These regulatory effects of IL-13 were also observed in blood monocytes and macrophages generated in vitro by maturation of blood monocytes with granulocyte/macrophage colony-stimulating factor. These observations suggest that IL-13 may act as an anti-inflammatory cytokine through regulation of cytokine production by AM in the lung.

American Journal of Respiratory Cell and Molecular Biology


Serum levels of interleukin 6 in patients with lung cancer

Journal of Japan Association of Breast Cancer Screening


Interleukin-2-inducible killer activity and its regulation by blood monocyte from autologous lymphocytes of lung cancer patigents

The ability of blood lymphocytes of newly diagnosed lung cancer patients to respond to interleukin 2 (IL-2) to become IL-2-activated killer (LAK) cells and its regulation by autologous monocytes were examined. LAK activity was measured by 51Cr release assay. The abilities of lymphocytes among blood mononuclear cells (MNC) of subjects of different ages without malignancies to generate LAK activity against NK-cell resistant Daudi cells and lung adenocarcinoma (PC-9) cells were very similar. The LAK activity of blood MNC of lung cancer patients was also nearly the same as that of blood MNC of control subjects. There was no significant difference in IL-2-inducible LAK activity between MNC of patients with small cell lung cancer (SCLC) and those of patients with non-SCLC. Monocytes and lymphocytes were separated from blood MNC on a one-step Percoll gradient. Monocytes of lung cancer patients were found to augment in vitro induction of LAK activity by IL-2 of autologous blood lymphocytes. In contrast, endotoxin-stimulated monocytes suppressed LAK induction of autologous lymphocytes of cancer patients. These findings suggest that administration of IL-2 and LAK cells induced in vitro may be of benefit in the treatment of lung cancer.


Role of recombinant GM-CSF in regulation of LAK cell induction by human monocyte-macrophages

ヒト単球-マクロファージのIL-2活性化キラー(LAK)発現調節におけるGM-CSFの役割


Production of tumor necrosis factor (TNF) by alveloar macrophages (AM)

ヒト肺胞マクロファージ(AM)の腫瘍壊死因子(TNF)産生能


Intraarterial lymphocyte injection therapy for lyphedema of the extremities


「徳島治験ネットワーク」における治験の共同実施について 国際共同治験実施の現状

「徳島治験ネットワーク」における治験の共同実施について 国際共同治験実施の現状