Dissecting the Immunobiological Effects of Bacillus Calmette-Guérin (BCG) In Vitro: Evidence of a Distinct BCG-Activated Killer (BAK) Cell Phenomenon

Abstract

Several immunobiological effects of intravesical bacillus Calmette-Guérin (BCG) during immunotherapy of superficial bladder cancer have been suggested as possible mediators of the mode of action. In an attempt to elucidate which of these effects is relevant to tumoricidal activity, an in vitro cytotoxicity assay was employed in which the direct effects of BCG and of cytokines against four transitional carcinoma cell lines were studied. Furthermore, peripheral blood mononuclear cells (PBMNC) were analyzed for their cytotoxic potential against these target cells. We found that none of the cytokines interleukin-1, interleukin-2, interferon-gamma, tumor necrosis factor alpha, lymphotoxin, or BCG alone were cytotoxic against the bladder carcinoma cell lines. However, a pronounced cytotoxicity against these targets resistant to natural killer cells could be induced in PBMNC by coincubation with viable BCG. We termed this the BCG-activated killer (BAK) cell phenomenon. In contrast to lymphokine-activated (LAK) cells, these BAK cells needed prolonged activation for 7 days and did not enhance the cytotoxicity against K562 target cells sensitive to natural killer cells. Nonviable, heat-inactivated BCG was significantly less effective, and sonificated fractions of BCG were not effective in stimulating PBMNC towards BAK cell activity. In vitro dissection of effects observed during BCG intravesical therapy may give more insight into the mode of action of BCG and may help to separate primary tumoricidal effector mechanisms from secondary concomitant phenomena. Further characterization of the BAK cell may result in an improvement of intravesical BCG immunotherapy.

An Armamentarium of Wart Treatments

“…238 The mode of action is based on stimulation of the local immune response. 239,240 The immune responses to malignant and virally transformed cells are similar. 241,242 Therefore, topical bacillus Calumette-Guérin treatment has been attempted in the treatment of venereal warts.…”

Polarisation of a T-helper cell immune response by activation of dendritic cells with CpG-containing oligonucleotides: a potential therapeutic regime for bladder cancer immunotherapy

“…Effective BCG therapy requires induction of a T-cell-mediated immune response (Ratliff et al, 1987;Ratliff, 1992) and the activation of a natural killer (NK) cell-like population with an apparent ability to distinguish between normal and cancer cells (Bohle et al, 1993;Brandau et al, 2001). Significantly, both T-celland NK-cell-deficient mice respond poorly to BCG therapy (Brandau et al, 2001).…”

BCG’s Mechanism of Action – Increasing our Understanding

“…Following pre-incubation of mononuclear cells with BCG for several days, a significant increase in cellular cytotoxicity towards several bladder tumour cell lines was detectable. This BCG-induced cytotoxicity was similar to LAK-cell cytotoxicity, with comparable efficacy of both effector cell types [59, 67, 68]. A large body of evidence indicates that LAK- and BCG-activated killer (BAK)-cells are two different effector cell populations, with a different type of cell pattern.…”