Successful immunotherapy with Mycobacterium vaccae in the treatment of adenocarcinoma of the lung.

Immunotherapy with a heat-killed suspension of Mycobacterium vaccae (SRL172), given with chemotherapy, in a phase III trial against non-small-cell-lung cancer showed no improvement in the primary endpoint of survival over chemotherapy alone in the initial published analysis. Compliance was poor, with on average only 53% of patients receiving more than 2 injections in the SRL172 arm of the study. Quality of life was, however, improved in those receiving SRL172. Secondary analyses based on compliance with therapy showed that immunotherapy led to significantly improved survival times of patients with adenocarcinoma but, by contrast, had no beneficial effect on survival times of patients with squamous cell carcinoma. Survival of adenocarcinoma patients receiving SRL172 was increased by a mean of 135 days (p=0.0009, Kaplan-Meier log rank test) and survival after 4 or 5 doses of SRL172 showed a difference of greater than 100 days (p<0.05, Mantel-Hänszel log rank test) in the group receiving SRL172 in addition to chemotherapy. Despite the problems inherent in a secondary analysis, these results encourage further research on the role of killed preparations of adjuvant-rich micro-organisms, including saprophytic mycobacteria such as M. vaccae, and members of related genera in the therapy of a range of cancers.

Immunotherapy of tuberculosis with Mycobacterium vaccae NCTC 11659.

The history of immunotherapy for tuberculosis is briefly reviewed, and the early appreciation of the importance of secreted antigens, common mycobacterial antigens and stress proteins is noted. The methods by which Mycobacterium vaccae strain NCTC 11659 was selected for special attention, and results of some of the pilot studies of its use as an immunotherapeutic for tuberculosis are reviewed. The results suggested that immunotherapy with M. vaccae may be an important step forward in the treatment and eventual control of tuberculosis. Used in combination with modern short course chemotherapy, treatment failures and deaths during treatment can be significantly reduced. Preliminary data suggests that shortened courses of chemotherapy may be possible when combined with immunotherapy, and such treatment may also be effective in patients co-infected with HIV. Studies at several centers show that M. vaccae may have an important part to play in the treatment of multi-drug resistant tuberculosis, especially when resistance is of the primary type. The mechanism by which M. vaccae achieves these results may be through adrenal endocrine influences on immunity, but remains speculative.

Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis in Romania. 1. Newly-diagnosed pulmonary disease.

In this study, 206 previously untreated patients with sputum culture positive pulmonary tuberculosis were randomized to receive an injection of killed Mycobacterium vaccae as immunotherapy, or of saline as placebo, after 1 month of a 6-month chemotherapeutic regime. Not surprisingly in a disease for which there is good chemotherapy, the difference in numbers which were culture negative at the end of treatment was small, and the final outcome at the latest post-treatment follow-up did not reach statistical significance between the two arms of the study. Nonetheless, those receiving immunotherapy showed better progression in every parameter measured, suggesting faster and more complete cure. Whereas seven of 97 patients receiving immunotherapy required a course of re-treatment and five still had active disease after a mean follow-up of 2 yr, 13 of 109 placebo recipients required re-treatment and nine still had active disease at the end of the study. Only one patient receiving M. vaccae plus chemotherapy died of tuberculosis, compared with four of those receiving chemotherapy alone. A degree of drug resistance was shown by the bacilli cultured from 25 of 175 (14%) patients, and seven of them (4.0%) were multi-drug resistant. Fourteen patients received immunotherapy of whom 13 were cured, including all three of those showing multi-drug resistance. Of the 11 patients with drug resistance in the control group, eight were cured, and one patient with multi-drug-resistant disease died of tuberculosis during re-treatment.

Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis in Romania. 2. Chronic or relapsed disease.

In this study of 102 patients with culture-positive chronic treatment failure or repeatedly relapsed pulmonary tuberculosis receiving chemotherapy, 56 received an injection of killed Mycobacterium vaccae as immunotherapy after 1 month of treatment. At the start of treatment, there was little difference between those receiving immunotherapy and the 46 patients in the control group receiving chemotherapy alone. Thereafter, the two groups diverged so that 1 yr later, 43 of 56 (77%) patients receiving M. vaccae had a successful outcome, in comparison with 24 of 46 (52%) patients receiving chemotherapy alone (P < 0.02). Successful results were obtained from patients infected with drug-resistant bacilli, 20 of 32 (63%) patients compared with 11 of 25 (44%) patients, respectively, as well as from fully drug-sensitive cases (23 of 24 compared with 12 of 21 patients; P = 0.004). At the final follow-up after 22 months, 13 of 56 patients receiving immunotherapy had an unfavourable outcome compared with 26 of 46 members of the control group (P = 0.0006). During the study, 16 patients died of tuberculosis (six after immunotherapy), and 12 were lost to follow-up. Not only was bacteriological success improved by immunotherapy, chest X-ray showed markedly better resolution of cavities and other radiological lesions, recovery of body weight was improved, and the mean erythrocyte sedimentation rate returned almost to normal (P < 0.001) in comparison with those receiving chemotherapy alone. These changes were seen even in those failing bacteriological cure, suggesting that the immunotherapy had been effective, but that bacilli were replicating in an extracellular situation, protecting them from its effects.

Does immunotherapy with heat-killed Mycobacterium vaccae offer hope for the treatment of multi-drug-resistant pulmonary tuberculosis?

The ability of immunotherapy with heat-killed Mycobacterium vaccae (NCTC 11659), as an addition to the available chemotherapy, to improve the outcome in patients with multi-drug-resistant tubercle bacilli (MDRTB) who had not been cured by chemotherapy alone was evaluated in tuberculosis centres in Estonia, Iran, Kuwait, New Zealand, Romania, Vietnam and the U.K. A total of 337 patients in the above countries received intradermal injections of M. vaccae in addition to chemotherapy. Patients were grouped according to the length of their histories of disease: less than or greater than 2 years duration. Initially, single doses of M. vaccae were given but subsequently up to 12 doses at 2-month intervals were given. Chemotherapy varied from isoniazid alone to drugs selected according to susceptibility tests. Most patients had failed to respond to repeated courses of chemotherapy and the majority, were expected to die from their disease. Results were assessed by sputum smear and culture and by clinical observations. Cured patients were followed for 18-24 months to exclude relapse. Eighteen of 22 (82%) patients with disease for less than 2 years were bacteriologically cured by one or two doses of M. vaccae. Among 315 chronic patients, 24 (7.6%) were cured after one dose, 37.9% after seven doses and 41.6% after 12 doses. Sixty-six chronic patients were lost to follow-up, or died, during the multi-dose regimens. Nine of 33 patients (27%) with advanced disease unaffected by several courses of chemotherapy and discharged on isoniazid alone in Vietnam were cured by 3-12 injections of M. vaccae. The data provide preliminary evidence that the addition of immunotherapy with M. vaccae to chemotherapy improves the rate of cure of MDRTB, most effectively in patients with short histories of disease, but multiple dosing can have beneficial effects in chronic patients in whom chemotherapy has failed. A randomized clinical trial of this immunotherapy in MDRTB patients is therefore required.

Environmental echoes.

Allergy, auto immunity and cancer are becoming more prevalent in the developed world. One explanation might be that the immune system required to protect us from such problems is being inadequately trained, perhaps due to our increased separation from the environment which has shaped our mutating genes since we emerged from the primaeval ooze. Those infections which were the essential primers of our immunity are being prevented and action is needed to refocus the immune response without exposing us to the diseases of the past. In this paper we assess our place in relation to the environment and consider ways in which the situation can be redressed. There are considerable similarities between the immune system and human consciousness. Both enter the world in considerable ignorance of the events awaiting them, yet with the genetic ability, endowed by millennia of selection and evolution, to experience the world, to interpret and act on the experiences and to retain memory of the experiences. In both systems, maternal influences and early environmental encounters have profound effects on determining the patterns of subsequent responses. Ideally the 'learned' responses will benefit or protect the individual but inappropriate responses may lead to self damage. As the environment has altered irrevocably, attention must be paid to regulating the balance of immunological responsiveness to that expected of the normal immunological learning process. This should be possible by novel vaccination strategies.

The use of mycobacterial adjuvant-based agents for immunotherapy of cancer.

A heat-killed preparation of Mycobacterium vaccae (SRL172) has been shown, in recent studies, to be effective in the treatment of adenocarcinoma of the lung and renal cell cancer. It is postulated that the mechanisms of this form of immunotherapy is, at least in part, due to immune regulation, reflected in the selective enhancement of Th1 and down-regulation of Th2 T cell activity. These beneficial effects are attributed to the ability of adjuvants in the bacterial cell walls to modify and optimise the response to antigens shared by the bacteria and stressed host tissues, resulting in the destruction of cancer cells by programmed cell death or apoptosis. The M. vaccae-induced apoptosis appears to be most effective against carcinomas, perhaps especially those of glandular tissue, in contrast to pyrexia-induced necrosis which is most effective against tumours of mesodermal origin. In view of the great range of adjuvants, especially in the genus Mycobacterium and related genera, it may prove possible to develop a range of immunotherapeutic agents with useful activity against a wide range of cancers.

Childhood atopy and allergic disease and skin test responses to environmental mycobacteria in rural Crete: a cross-sectional survey.

BACKGROUND: Through its powerful immunoregulatory effects, infection with atypical mycobacteria may exert a protective effect on the development of childhood allergic disease. OBJECTIVE: To examine the relationship between childhood atopy or allergic disease and previous infection with four species of atypical mycobacteria. METHODS: Eight hundred and six children aged 8-18 years and living in rural Crete--most of whom had had previous BCG immunization--underwent skin prick testing with 10 aeroallergens; their parents completed a standardized questionnaire relating to allergic disease. No less than 8 weeks later each child underwent intradermal skin tests with 0.1 mL solutions of four selected mycobacterial reagents (Aviumin C, Gordonin, Chelonin and Ranin I). RESULTS: Twenty-three percent of children were atopic on skin prick testing; far fewer had symptoms of asthma (5%) or hayfever in conjunction with a positive prick test to pollens (2%). Eighty percent of children had positive skin responses to one or more mycobacterial species. Among all children--and those with a BCG scar--there was no association between atopy or allergic symptoms and mycobacterial skin responses; among the few children without a BCG scar however those with positive mycobacterial responses were less likely to be atopic or to report allergic symptoms; these differences were not statistically significant. CONCLUSIONS: Our findings, in a population of BCG-immunized children, do not lend support to the suggestion that infection with atypical mycobacteria is protective against childhood allergic disease.

Vaccination against leprosy at Ben San Leprosy Centre, Ho Chi Minh City, Vietnam.

Three vaccines, BCG alone, BCG + 10(7) killed Mycobacterium vaccae and 10(8) killed M. vaccae alone, were studied in children living in close contact with leprosy. In the year before vaccination, 14/446 (3.1%) children had developed leprosy. Among those who were not vaccinated, 9/74 (12.2%) developed the disease in the first 4 years of the study and 5/65 (7.7%) developed the disease in the second 4 years. In comparison with this, among those vaccinated, 20/343 (5.8%) developed leprosy in the first 4 years and 5/323 (1.5%) developed leprosy in the second 4 years. This represents 52.5% protection in the first 4 years and 80.5% in the second 4 years. There were no significant differences in protection afforded by each of the three vaccines but the success of the killed preparation of M. vaccae is an important finding.

Skin test studies on close contacts of leprosy patients in India.

Skin-test studies with a series of tuberculins have been carried out in close contacts of multibacillary (MB) leprosy patients around three leprosy centers in India, and casual contacts of the disease around two centers. The results show that the rate of acquisition of leprosin A positivity is associated with age and the closeness of contact with MB leprosy. At the age of 15 years, the differences between the two types of contact were highly significant (p less than 0.00001). Many responses to leprosin A are directed toward the group iv species-specific, antigens of the leprosy bacillus, and the significance of positivity is discussed in relation to protective immunity from leprosy. The differences from Iran show that positivity to leprosin A is not solely the effect of the degree of contact with the disease, but must also have a genetic or environmental element, the latter being favored. The results from Miraj show that the high levels of tuberculin, scrofulin, and vaccin positivity seen in Fathimanagar, and to a lesser extent in Karigiri, are not a consequence of contact with leprosy. BCG vaccination made little difference to the leprosin A positivity of close contacts of leprosy patients, although it significantly enhanced positivity among casual contacts around Miraj (p less than 0.002). BCG vaccination significantly increased tuberculin positivity in Miraj and Karigri, and in those under 11 years of age in Fathimanagar. It made no difference to the already high level of positivity found in older persons around Fathimanagar.(ABSTRACT TRUNCATED AT 250 WORDS)

Vaccination and skin test studies on the children of leprosy patients.

In an attempt to achieve maximal skin-test positivity to leprosin A in children of leprosy patients living in Baba Baghi Leprosy Sanatorium in Iranian Azerbaijan, two new vaccines have been employed. Children without scars of previous BCG and without response to leprosin A were given a vaccine containing 10(8) viable units of BCG Glaxo plus 10(7) killed Mycobacterium vaccae per dose (vaccine B). Children with BCG Pasteur (Teheran) scars but without response to leprosin A were given a vaccine containing 10(8) killed M. vaccae alone (vaccine D). Eight years later skin testing was repeated, and both new vaccines were found to have significantly increased the numbers of children responding to leprosin A above the level that would have been expected had they received BCG Pasteur alone. This increase was due in large part to increases in the proportions of individuals responding to group i (common mycobacterial) antigens, and known as category 1 responders. The use of suspensions of killed M. vaccae in conjunction with BCG may represent a considerable advance in inducing protection from multibacillary leprosy in close contacts of leprosy patients if leprosin A positivity is truly a correlate of protective immunity. A comparison, using the same criteria, with the other proposed vaccines for leprosy would be very interesting.

Vaccination and skin test studies on children living in villages with differing endemicity for leprosy and tuberculosis.

The purpose of this study carried out in Iranian Azerbaijan was to determine the pattern of skin-test positivity to mycobacterial antigens in children living in the valley, and to assess the effect on this of a series of vaccines against mycobacterial disease. Set up in 1978, 1707 tuberculin-negative children without scars of previous BCG vaccination were vaccinated with BCG Glaxo alone (vaccine A) or with the addition of a suspension of killed Mycobacterium vaccae (vaccine B). One hundred children were vaccinated with BCG Glaxo plus a suspension of M. leprae (vaccine C). Eight to 10 years later about half of the children were found for follow up. At this time further children were skin tested, and the results obtained were related to whether or not they had scars of vaccination with BCG Pasteur (Teheran) given by the local health authorities. Between setting up the study and the first follow up, cases of leprosy or tuberculosis had occurred in some of the villages, although not among those we had vaccinated. Differences between the effects of the vaccines were only found in villages with cases of leprosy. In these villages positivity to leprosin A was significantly greater after vaccine B (49%) than after vaccine A (36%; p less than 0.04). The results for scrofulin and vaccine were the same after both vaccines, and significantly lower than in the villages without cases of leprosy. The general reduction in skin-test positivity in the villages with leprosy cases was mainly due to a loss of category 1 responders to group i, common mycobacterial, antigens. It was concluded that where casual contact with cases of leprosy occurs the combination of BCG with killed M. vaccae is likely to be a better vaccine for leprosy than is BCG alone. Although few children received the combination with M. leprae, the results obtained were not particularly promising.