Enhanced activation of natural killer cells using an NK cell activator and a hydrogen peroxide scavenger or inhibitor

Abstract

A method for providing activated natural killer (NK) cells comprising the steps of administering to a population of cells which includes lymphocytes and monocytes, an effective amount of an NK cell activating cytokine or a NK cell activating flavonoid, wherein said NK cell activating cytokine is not IL-2 or IFN-alpha; and administering a compound effective to inhibit the production or release of hydrogen peroxide selected from the group consisting of histamine, other H2 receptor agonists, and serotonin.

Description

[0001] This application is a continuation of application Ser. No. 09 / 516,641, filed on Mar. 1, 2000, which is a continuation of application Ser. No. 08 / 681,108, filed Jul. 22, 1996, now U.S. Pat. No. 6,071,509, which is a continuation of application Ser. No. 08 / 287,200, filed Aug. 8, 1994, now abandoned.This application is related to U.S. application Ser. No. 07 / 843,052, filed Mar. 2, 1992.[0002] The present invention relates generally to methods for the enhanced activation of natural killer (NK) cells, useful for example, in the treatment of cancer and viral infection. More specifically, the present invention relates to the activation of NK cells using a combination of a natural killer cell activator and a hydrogen peroxide inhibiting compound or scavenger. It also relates to the prevention of inactivation of NK cells.DESCRIPTION OF THE RELATED ART[0003] Natural killer (NK) cells are a subset of spontaneously cytotoxic lymphocytes that lytically destroy tumor cells without apparent...

AI Technical Summary

Benefits of technology

0046] Effects of Catalase and Other Scavengers

0047] To study the relationship between the monocyte-derived inhibitory signal and the respiratory burst activity of monocytes, we added catalase and various other scavengers of reactive oxygen metabolites to NK cells, alone or admixed with monocytes. We then measured the cytotoxicity of the NK cells against NK cell sensitive K562 target cells as described above. The results of this testing are shown in Table I.

0048] Catalase, which effectively degrades H.sub.2O.sub.2, had no effect on the cytotoxicity of NK cells in the absence of monocytes but was found to completely abrogate the monocyte-induced inhibition of baseline NK cell cytotoxicity. Catalase was effective at concentrations exceeding 5 U/ml. Histamine (histamine dihydrochloride; Sigma) at concentrations exceeding 10.sup.-7 M abrogated the monocyte induced suppression of NK cells but was ineffective in the presence of catalase.

0049] It was also discovered that superoxide dismutase (SOD), a scavenger of O.sub.2.sup.- did not alter the suppressive effect of monocytes on NK cells over a wi...

Problems solved by technology

Despite the beneficial effects obtained with IL-2 therapy in experimental animals and despite the remarkable effects of IL-2 on the killing activity of human NK cells in vitro, the results of the clinical trials of IL-2 in human cancer have, as yet, been disappointing.

In addition, IL-2 produces severe side effects, including hypotension, fluid retention ("capillary leak syndrome"), fever, lethargy and nausea.

Although IFN-.alpha. has been shown to be effective with some neoplasias, the overall results of therapy with high doses of IFN-.alpha. have been disappointing.

In addition, patients treated with IFN-.alpha. often have acute toxic reactions including fever, chills, myalgias, anorexia, fatigue, headache, nausea and vomiting.

Clinical trials of FAA have been disappointing, however, due to non-linear pharmokinetics, low dose potency and problems of drug precipitation.

Images