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The results of this investigation indicate that 5 X 10(6) and 5 X 10(8) viable bacillus Calmette-Guerin (BCG) organisms (Mycobacterium bovis strain) can be safely administered in the subconjunctival region of the eye of New Zealand albino rabbits without producing toxic effects locally or within the eye. This study provides a format for testing the applicability of BCG immunotherapy for experimental melanomas.
The present investigation examined the morphological characteristics of epiplexus macrophages following a single intracisternal injection of the antigen, bacillus Calmette-Guerin (BCG). Three days following injection of BCG (0.5 - 4.0 X 10(8) viable microorganisms), mongrel dogs were perfused with buffered aldehydes. The choroid plexus of the lateral and third ventricles was removed and routinely prepared for scanning or transmission electron microscopy. Choroid plexuses from normal animals (no BCG injection) were similarly prepared. Macrophages of normal animals possessed smooth cell surfaces with usually one to three cytoplasmic processes. Following BCG injection, a 10-fold increase in the epiplex macrophage population was observed. Furthermore, the majority of these cells presented an abundance of cell surface microappendages; including blebs, ruffles and microvilli. Cell processes and microvilli frequently mediated contacts between widely separated macrophages. These associations may play a role in the initiation and/or maintenance of the cellular immune response to BCG.
Mongrel dogs were anesthetized intraperitoneally with pentobarbitol. One cc of cerebrospinal fluid was drawn through a needle inserted into the cisterna magna and mixed with 1 cc (4-9 million viable BCG organisms) of freeze-dried bacillus Calmette-Guerin. One minute later this mixture was injected by the same needle into the cisterna magna. At 1 and 12 days postinjection, experimental animals were perfused with buffered aldehydes. Samples of the leptomeninges were post-fixed in OsO4 and routinely prepared for scanning and transmission electron microscopy. Leptomeningeal samples of untreated, control animals were similarly prepared. Scanning and transmission microscopy confirm that free cells resting on the subarachnoid linings and within the subpial connective tissue space of control animals possess the morphology of macrophages (Malloy and Low, '76). Viable BCG in the subarachnoid space produces a 3-fold increase in the free cell population of the leptomeninges in 24 hours and a 10-fold increase in 12 days. These cells tend to form associations varying from loose aggregates to tight clusters. Approximately 80% of these free cells express macrophage morphology, with abundant plasma-lemmal microappendages and cytoplasmic vacuoles. Transmission electron microscopy of the free cell population of BCG-stimulated animals reveals at least two other members of the leukocyte series on the leptomeningeal linings.
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A complete response to BCG is described in a case of recurrent melanoma. In a woman aged 38 years, intracutaneous metastatic deposits confined to the limb of origin had occurred after excision of a malignant melanoma from the ankle, and elective groin dissection had shown two lymph nodes infiltrated with melanoma. BCG vaccine was applied to the buttock, initially by scarification and later by a multiple puncture gun. All metastases slowly regressed, and biopsy of a metastatic site at six months showed no tumour cells. The patient remains free of detectable disease 36 months after the commencement of therapy. It is inferred that BCG may facilitate remission of melanoma, perhaps by reason of antigenic cross-reactivity between BCG and surface components of human melanoma cells.
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Explore the source record for details and available documents.
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The administration of two chemoimmunotherapy programs to 103 consecutive patients with metastatic colorectal cancer resulted in improved survival for patients who achieved either objective tumor regressions or disease stabilization for more than 8 weeks. Objective tumor regression was observed in 47% of patients treated with the Ftorafur-methyl-CCNU-methotrexate-Bacillus Calmette-Guerin (FTOR-MeM-BCG) program and in 34% of patients treated with the 5-fluorouracil-methotrexate-Baker's antifol (FU-M-BAF) +/- Levamisole program. The combinated median duration of survival for patients who achieved objective tumor regression and disease stabilization with FTOR-MeM-BCG was 13 months compared with 6 months for patients who had progression of disease (p = 0.001). The corresponding values for patients treated with FU-M-BAF +/- levamisole were 11 months and seven months, respectively (p = 0.001). While the role of BCG immunotherapy in these results remains speculative, the administration of levamisole immunotherapy did not appear to have influenced results significantly. Patients who presented at diagnosis with Dukes A, B and C lesions, and therefore had longer disease-free intervals, responded more frequently to chemoimmunotherapy and survived longer than patients who presented at diagnosis with Dukes D lesions. Similarly, greater antitumor effect was observed in patients with lower pretreatment plasma CEA levels evaluation of these pretreatment characteristics may have insignificant implications for the design of future clinical trials.
Three distinct types of free cell contours are recognizable in scanning electron microscopy (SEM) on the leptomeningeal sheaths of dogs twelve days after an intrathecal injection of bacillus of dogs twelve days after an intrathecal injection of bacillus Calmette-Guerin (BCG). Macrophages posses abundant plasmalemnal blebs which are shown in transmission electron microscopy (TEM) to be composed of large membrane-bound vacuoles. Smooth surfaced lymphoblasts exhibit many basal microvilli that rest upon and often indent the plasmalemma of an underlying pial cell. Neutrophils display many microvilli over their rounded, chrysanthemum-like surfaces. The consistency with which these external features are expressed suggests that each cell type possesses characteristic surface topography, at least under these conditions of challenge.
The data reported here demonstrate that a preparation extracted from nonpathogenic mycobacteria such as Mycobacterium smegmatis and hereafter referred to as interphase material protected mice against Ehrlich ascitic carcinoma, L-1210 leukemia, and another syngeneic lymphoid leukemia. Furthermore, mice treated by this preparation were much less susceptible to endotoxins than when stimulated by BCG (bacillus Calmette-Guerin) or M. smegmatis cells. Moreover, guinea pigs treated by interphase material administered in Freund's incomplete adjuvant showed an increased immune response, yet their sensitivity to tuberculin was much weaker than that of controls sensitized with Freund's complete adjuvant. Finally, resistance to Columbia SK virus infection could be demonstrated when interphase material was administered to mice prior to virus challenge.
Specific immunity developed by mice against protozoan (Toxoplasma gondii and Besnoitia jellisoni) and bacterial (Listeria monocytogenes) infections was compared with nonspecific protection conferred by prior infections. The results indicated that homologous immunity protected mice from more than 10-5 LD50 of T. gondii or B. jellisoni, but from only 10-2 LD50 of L. monocytogenes. Heterospecific protection among these organisms was for 10-0.4 minus 10-1.2 LD50. In studies in hamsters specific immunity to protozoan (T. gondii and B. jellisoni) and viral (equine Herpesvirus type 1 and Oriboca virus) infections was compared with nonspecific protection conferred by prior infections with several heterospecific agents: T. gondii; B. jellison; equine Herpesvirus type 1; Oriboca, Ossa, vesicular stomatitis, yellow fever, and Newcastle disease viruses; L. monocytogenes; and the bacillus Calmette-Guerin strain of Mycobacterium tuberculosis. The results indicated that homologous immunity in hamsters was effective against 10-6 minus 10-7 LD50 of T. gondii, B. jellisoni, equine Herpesvirus type 1, or Oriboca virus. Prior infection with Newcastle disease virus protected (probably by interferon induction) against 10-3 LD50 of equine Herpesvirus type 1. Heterospecific protection among other agents was for less than 10 LD50. This insignificant heterospecific protection in infections in which cellular immunity plays a role suggests that both the induction phase and the expression phase are specific.
The effect of preimmunization with Bacillus Calmette-Guerin cell walls (BCGcw) on tumor growth was studied with the use of transplantable Morris Hepatoma 3924a in inbred ACl rats. There was an increase in tumor incidence, an increase in the i.m. tumor growth rate, and an increase in the average i.m. tumor mass in animals that were preimmunized with BCGcw. The BCGcw-induced enhancement in tumor growth was dependent upon the amount of tumor present at the time of BCGcw immunization. No enhancement occurred in animals immunized with BCGcw 12 days after the inoculation of tumor cells.
The s.c.-propagated murine glioma, GL-26, was established in tissue culture. The tissue culture line, with a doubling time of 36 hr, was used as the common source for all tumor cells. Suspensions of the tumor cells were transplanted intracerebrally in mice to produce an anaplastic ependymoblastoma. In vitro 51-Cr cytotoxicity assays did not detect any cellular immunity against GL-26 tumor cells in animals bearing either s.c. or i.c. tumors, indicating that the tumor itself is not highly immunogenic. Howeveer,significant cellular cytotoxicity was elicited in non-tumor-bearing animals by immunization with Vibrio cholerae neuramini-animals by immunization with Vibrio cholerae neuraminidase and mitomycin C-treated tumor cells plus complete Freund's adjuvant. In vivo therapy studies revealed significant increases in survival of animals preimmunized with V. cholerae neuraminidase- and mitomycin C-treated cells plus complete Freund's adjuvant. 1(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea, when given i.p. on Day 3 or 12 after tumor challenge, also resulted in significant increases in survival. Furthermore, the effects of 1-(2-chloroethyl)- 3-cyclohexyl-1-nitrosourea and preimmunization were additive, with significanchloroethyl)-3-cyclohexyl-1-nitrosourea. In contrast to results reported for several extracranial tumor systems, immunotherapy, using either V.cholerae neuraminidase- and mitomycin-treated tumor cells, Bacillus Calmette-Guerin, or both, beginning 3 0r 4 days after tumor challenge, did not produce any significant increases in survival.
Sixty-two patients with transitional cell carcinoma have been admitted to a double-blind randomized control study with levamisole as an immune adjuvant, in addition to standard therapy for noninvasive and invasive bladder cancer. Levamisole has been shown to be easily administered and is well-tolerated, especially when compared to other immune adjuvants such as bacillus Calmette-Guerin or Corynebacterium parvum. To date, there is no significant difference in the disease-free interval in the levamisole-treated group compared to the placebo group. Initial dinitrochlorobenzene (DNCB) reactivity may be an important prognostic indicator with regard to tumor recurrence. Tumor recurrence seems to be rare in those patients who are initially DNCB-positive. Total monocyte count, T lymphocyte, FC receptor cells, and PHA response showed no improvement with levamisole therapy. Monocyte chemotaxis remains the only immune function study to improve with levamisole, but the clinical significance of this test is yet to be explained.
Among 53 patients with documented Crohn's disease, 30% manifested a defect in delayed hypersensitivity demonstrated by negative DNCB skin tests and significant (p less than 0.01) T-lymphocyte hyporeactivity. A double-blind controlled trial was conducted to evaluate oral Bacillus Calmette-Guerin (BCG) therapy in nine of these patients with Crohn's disease and deficient cellular immunity. All patients had a Crohn's Disease Activity Index (CDAI) greater than 150 (at least moderate activity) upon randomization to BCG (five patients) or placebo (four patients) treatment for six to 12 months. No significicant differences between BCG and placebo treatment were found in the CDAI, laboratory tests and gastrointestinal roentgenograms. We conclude that the disturbance in cell-mediated immunity in patients with Crohn's disease probably is a manifestation of the disease rather than an etiological factor and that immunostimulation with oral BCG is not effective therapy.
Patients with stage III and IV melanoma were randomly assigned to receive procarbazine (100 mg/m2, Days 1--10), vinblastine (5 mg/m2, Days 1 and 8), and actinomycin D (0.5 mg/m2, Days 1 and 8) with or without methanol-extracted residue (MER) of bacillus Calmette-Guerin (200 micrograms in five sites). In patients with measurable disease, 20% (eight of 40 patients) responded with only the combination chemotherapy while 15% (six of 39 patients) responded with the MER added. Toxicity was tolerable except for some instances of severe, gastrointestinal toxicity associated with procarbazine. MER as given in this study, failed to either increase the response rate or prolong survival.