Immunology of Bacille Calmette-Guérin and Related Topics

This supplement is based on a workshop held in Toronto, Ontario, on 11–13 July 1994, at the site of the sponsor, Pasteur-Mérieux-Connaught Canada. The 3-day workshop focused on immunologic responses to BCG, its use in the prevention of tuberculosis and in the treatment and prophylaxis of bladder cancer, and its potential applications for other cancers. This workshop presented an exciting opportunity to bring together 2 distinct groups of researchers: those in infectious diseases and immunology and those in urologic oncology. It was rare to have these 2 groups in the same room talking together, but this workshop represented an important opportunity for both groups, since the mode of action of BCG in both domains appears to be intimately related. Therefore, we discussed tuberculosis (TB), the use of BCG in superficial bladder cancer, and potential applications of BCG to other cancers. It is well known that the incidence of TB in the United States showed a leveling off rather than the predicted continuous decrease beginning in 1986, largely due to the influence of HIV and/or AIDS on the incidence of active TB disease. However, if the situation is bad in the United States, it is much worse in Africa, where very alarming projections show the expected incidence of TB to be greater because of the different prevalence rates of HIV over the next 10 years. The Venn diagram shown in figure 1 puts the TB situation into perspective. Of the world's 5 billion people, one-third, or 1.7 billion, are infected with TB. Among those with primary TB infection, there is an annual incidence of 8 million cases, of whom 3 million will die. In 1994, it was estimated that 13 million people were infected with HIV, of whom 5 million also have primary TB. Those who are coinfected and who live long enough will develop active TB; each year, there are ∼0.5 million HIV-infected people who develop active TB and also have AIDS (TB being an AIDS-defining event). Among HIV-infected people, the incidence of active TB is ∼5% per year or 50% over an estimated 10-year life span, 25 times the incidence of TB among people not infected with HIV. To make the point of how timely this is, the local newspaper the other week contained an article describing 40 Canadian soldiers who had returned from the former Yugoslavia with TB (Toronto Star, July 1994). One might therefore ask whether Canadian soldiers should once again start receiving BCG vaccine. Venn diagram of tuberculosis (TB) and HIV infection and coinfection. If TB is an increasingly recognized problem today, it was a devastating problem at the beginning of this century. In France, it was estimated that 3 of every 1000 persons died of TB annually. Two researchers at the Institut Pasteur in Lille, France, began to work on a TB vaccine in 1904. Their names, bacteriologist Albert Calmette and veterinarian Camille Guérin, became attached to the vaccine; thus, the rod-shaped bacillus in the vaccine became known as bacille Calmette-Guérin, or BCG. Calmette and Guérin initially isolated a strain of Mycobacterium bovis (known as “bovine tuberculosis” and closely related to the human tubercle bacillus Mycobacterium tuberculosis) from the udder of a tuberculous cow. They found that they could attenuate the pathogenicity of the organism by cultivating it in a medium consisting of cow bile, potatoes, and glycerin. By 1915, they had experimentally administered the attenuated strain to several cows and had demonstrated resulting protection against TB. From 1908 to 1921, Calmette and Guérin passaged the organism 230 times. Finally, in 1921, they administered their vaccine orally to a baby whose mother had died of TB and whose grandmother (the primary caregiver since the mother's death) was dying of the disease. The baby suffered no side effects from the vaccine and did not develop TB. After their results were published in 1924, the Institut Pasteur began to mass produce and distribute the vaccine. Subsequently, a primary seed stock of this original vaccine was distributed to numerous manufacturers (including Connaught); figure 2 shows the history of this distribution. History of BCG and some of its current strains. RIVM, Rijksinstituut voor volksgezondheid en milieu; WHO, World Health Organization. There was a disastrous episode in the German city of Lübeck in 1930, when 70 of 252 recipients of BCG vaccine died of TB. The deaths were subsequently proven to be due to the contamination of the BCG culture with Mycobacterium tuberculosis, and BCG was completely exonerated. However, this was only the beginning of the controversy concerning the safety and the efficacy of BCG! During this workshop, we heard reviews of the conflicting data on the efficacy of BCG vaccine against TB from Drs. Donald Smith and Timothy Brewer, the management of BCG adverse reactions from Dr. Mark FitzGerald, and the relevance of BCG-induced tuberculin positivity from Dr. Richard Menzies. The original impetus to examine the potential therapeutic and prophylactic effects of BCG in cancer stemmed from case-control studies in Baltimore by Pearl, published in 1929 [1]. He examined patients who had died of malignancies, and matched them to control subjects who were matched for age, sex, and race. He showed that the control group had significantly more active and healed TB than the group with fatal cancers. In general, the incidence of active TB was at least 2-fold higher in the control group, after controlling for race and sex. Conversely, he showed a significantly lower incidence of cancer among patients dying of TB than among similarly matched control subjects. Pearl concluded that some mutual antagonism between TB and cancer existed, the basis for which he was unable to explain. This finding stimulated some Italian investigators to use M. tuberculosis as a cancer chemotherapeutic in an animal model; through the next 40 years, a mycobacterial approach to cancer therapy was considered only sporadically until Zbar et al. [2] in the early 1970s conducted seminal studies at the US National Cancer Institute, which demonstrated the tumor-inhibitory properties of BCG that was injected into animals. Much of what they published in 1971 remains true today and is worth repeating some 25 years later: “The effect of living BCG on tumor growth was evaluated. Complete tumor inhibition was observed when infection with living BCG occurred at the site of tumor inoculation. This inhibition was not attributable to a direct cytotoxic effect of living BCG, but was mediated by a delayed hypersensitivity type (DTH) immunologic response to the infecting organisms. Animals that rejected tumor cells at the site of an infection with BCG showed suppressed tumor growth and DTH reactions to a subsequent challenge of tumor cells. [A certain number of BCG organisms was required, and] optimal suppression of tumor required living BCG, close contact between tumor cells and BCG, and a cell-mediated immune response by the host” [1]. On the basis of the animal work of Zbar et al., Dr. Alvaro Morales of Queen's University in Kingston, Ontario, elected to instill BCG intravesically (i.e., in solution into the urinary bladder via a catheter). His results, published in 1976 (Morales et al. [3]), constituted the first proven cancer immunotherapy. Because we shall be discussing bladder cancer at length, it is worthwhile to describe the current role of BCG in its treatment and prevention. BCG is used for superficial bladder cancer, which encompasses both the flat and spreading carcinoma in situ (CIS), and the frondlike papillary tumours of stages Ta (confined to the bladder mucosa) and T1 (invading the lamina propria but not the underlying muscle layer). The primary treatment of superficial papillary tumors is by surgical resection during transurethral cystoscopic resection. BCG is then instilled intravesically after the removal of these papillary tumors, to prevent or delay recurrence. Thus, the use of BCG in this context is strictly for prophylaxis. However, CIS is not always amenable to complete transurethral resection, because it may not be detectable and may be too extensive. Therefore, intravesical BCG is administered both for therapy and for prophylaxis in CIS patients. A cure of CIS is known as a complete response and is defined as the complete disappearance of any sign of bladder cancer (e.g., on cystoscopy, blind biopsies, and bladder wash cytology) for a defined period of time (e.g., ⩾3 months). Among CIS patients who undergo a complete response, intravesical BCG then also serves the same prophylactic function as among patients with papillary tumors but no CIS. In summary, for patients with papillary tumors and no CIS, the most relevant efficacy outcome measure is time to recurrence; for those with CIS (with or without coexisting papillary tumors), the most relevant efficacy outcome is complete response; and, for those undergoing a complete response, time to recurrence is also relevant. Administered intravesically for the treatment of superficial bladder cancer, Connaught BCG has been studied in 2 large-scale phase III trials conducted by the Southwest Oncology Group (SWOG). The first study, SWOG 8216 [4], compared BCG with intravesical doxorubicin, which was a standard intravesical chemotherapeutic drug. This was followed by a second study, SWOG 8507 [5], in which 2 different treatment regimens of intravesical Connaught BCG were compared: 6 weekly treatments administered over 6 weeks (“induction”) versus 27 treatments over 3 years (“maintenance”). BCG induced a 70% complete response among CIS patients, compared with 34% observed among those treated with doxorubicin. The administration of more BCG was better: using an induction course of “6 + 3” instillations over 14 weeks increased the complete response rate from 73% to 87%. In these 2 studies, in terms of cancer-free survival status at a mean follow-up of 5.5 years, 37% of the patients who received BCG were free of cancer, compared with 17% of the patients who received doxorubicin. In the SWOG 8507 study, at a mean 3 years' follow-up, 80% of maintenance patients were alive and free of cancer, compared with 43% of patients in the induction-only group. These results are displayed in tables 1 and 2. Comparative studies on efficacy of Connaught BCG: treatment regimens and complete response rates. Comparative studies on efficacy of Connaught BCG: no. of patients alive and free of recurrence. Although BCG is clearly the most efficacious current treatment for superficial bladder cancer, it is not without toxicity. Table 3 shows the incidence of common side effects that occurred in the 2 SWOG studies. Although most patients can expect to have some side effects, most of these are not life threatening but are merely uncomfortable and unpleasant. The more BCG administered, the greater the incidence of side effects. There is a small incidence of dangerous side effects, ranging from symptomatic BCG granulomatous prostatitis or epididymitis to serious systemic BCG infection with granulomatous hepatitis and/or miliary pulmonary BCG infection or to life-threatening BCG sepsis. Indeed, 3 deaths have been associated with intravesical Connaught BCG. Maintenance BCG yields far better efficacy results than does induction-only BCG but at the price of greater toxicity. Therefore, the pertinent question is how to maintain or perhaps improve the efficacy of intravesical maintenance BCG while reducing toxicity. To do so may require an understanding of the mechanism of action of BCG in bladder cancer. Incidence of common adverse events associated with any instillation during induction vs. maintenance therapy with Connaught BCG. Figure 3 shows the hypothesized mechanism of action of intravesical BCG against superficial bladder cancer. First, BCG attaches to the bladder mucosa via fibronectin receptors. Then the bacteria are phagocytosed by macrophages and presented to regional lymph nodes. Ensuing activation of regional T lymphocytes and secretion of various cytokines occur. The upregulated expression of HLA-DR (i.e., MHC class II) antigen on tumor cells and adjacent urothelium follows. The killing of tumor cells and adjacent urothelium by cytotoxic T cells, which recognize the coexpression of HLA and BCG antigens, seems to occur. Therefore, the mechanism of action of BCG in bladder cancer is probably specific anti-BCG cell-mediated immunity, which may indeed be the likely mechanism for BCG as an anti-TB vaccine. Hypothesized mechanism of action of intravesical BCG against superficial bladder cancer We thus come full circle in explaining the research interests of the participants in this workshop. Dr. Donald Lamm, the principal investigator on the 3 SWOG studies that established BCG as the treatment of choice for the treatment and prophylaxis of superficial bladder cancer, will review the efficacy and safety of intravesical BCG for this indication. Drs. Elizabeth de Boer and Dennis Schamhart, Stephen Prescott, and Timothy Ratliff will share their research perspectives on the mechanism of action of BCG in bladder cancer. Drs. N. Buu and Erwin Schurr will discuss a murine gene, thought to also exist in humans, which affects susceptibility or resistance to BCG as mediated by macrophages. Perhaps inspired by the previously mentioned Lübeck disaster, Lübeck is well-represented here by Drs. Herbert Flad, S. Brandau, and Andreas Böhle, who will discuss BCG-activated killer cells and the potential role of pentoxifylline, respectively.

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