Combination Of BCG Research Articles

BCG and bladder cancer. Forty-eight years after Morales report.

Although BCG use as an anticancer drug was nearly abandoned due to the poor results in most tumors, in 1976 Morales reported a relevant reduction in recurrence with intravesical BCG in few patients affected by NMIBC. Since then BCG was globally accepted as an empirical and effective therapy in treating Tis and preventing recurrence of intermediate and high risk NMIBC. Forty-eight years after Morales' report, although some open questions remain object of debate, we have been able to find answers to many doubts improving BCG activity and toxicity. We better select patients undergoing BCG and many trials have indicated the best dosage and schedule. Moreover, we are able to better identify the patient unresponsive to BCG who might benefit of a timely radical cystectomy. We are also aware of the difficulties and toxicities that can be encountered with BCG use in every-day clinical practice. Research is ongoing to obtain genetically modified BCG to increase its efficacy and reduce toxicity. Moreover, the combination of BCG with other immunotherapeutic drugs given intravesically or systemically, first immune checkpoint inhibitors, is under study to obtain a response in patients unresponsive or intolerant to BCG. Almost 50 years after Morales publication, intravesical BCG remains an inalienable tool against NMIBC.

The Role of Tumor and Host Microbiome on Immunotherapy Response in Urologic Cancers

Introduction & Objective: The role of the microbiome in the development and treatment of genitourinary malignancies is just starting to be appreciated. Accumulating evidence suggests that the microbiome can modulate immunotherapy through signaling in the highly dynamic tumor microenvironment. Nevertheless, much is still unknown about the immuno-oncology-microbiome axis, especially in urologic oncology. The objective of this review is to synthesize our current understanding of the microbiome’s role in modulating and predicting immunotherapy response to genitourinary malignancies. Methods: A literature search for peer-reviewed publications about the microbiome and immunotherapy response in bladder, kidney, and prostate cancer was conducted. All research available in PubMed, Google Scholar, clinicaltrials.gov, and bioRxiv up to September 2023 was analyzed. Results: Significant differences in urinary microbiota composition have been found in patients with genitourinary cancers compared to healthy controls. Lactic acid-producing bacteria, such as Bifidobacterium and Lactobacillus genera, may have value in augmenting BCG responsiveness to bladder cancer. BCG may also be a dynamic regulator of PD-L1. Thus, the combination of BCG and immune checkpoint inhibitors may be an effective strategy for bladder cancer management. In advanced renal cell carcinoma, studies show that recent antibiotic administration negatively impacts survival outcomes in patients undergoing immunotherapy, while administration of CBM588, a live bacterial product, is associated with improved progression-free survival. Specific bacterial taxa, such as Streptococcus salivarius, have been linked with response to pembrolizumab in metastatic castrate-resistant prostate cancer. Fecal microbiota transplant has been shown to overcome resistance and reduce toxicity to immunotherapy; it is currently being investigated for both kidney and prostate cancers. Conclusions: Although the exact mechanism is unclear, several studies identify a symbiotic relationship between microbiota-centered interventions and immunotherapy efficacy. It is possible to improve immunotherapy responsiveness in genitourinary malignancies using the microbiome, but further research with more standardized methodology is warranted.

Novel sequential treatment strategy for patients with muscle-invasive bladder cancer (MIBC): intravesical recombinant BCG, followed by neoadjuvant chemoimmunotherapy, radical cystectomy plus pelvic lymphadenectomy and adjuvant immunotherapy – protocol of a multicentre, single arm phase 2 trial (SAKK 06/19)

IntroductionThe combination of checkpoint inhibition and cisplatin-based chemotherapy is investigated in muscle invasive bladder cancer (MIBC) and results from phase 2 trials have been presented. Intravesical BCG has been used...

A single dose, BCG-adjuvanted COVID-19 vaccine provides sterilising immunity against SARS-CoV-2 infection

Global control of COVID-19 requires broadly accessible vaccines that are effective against SARS-CoV-2 variants. In this report, we exploit the immunostimulatory properties of bacille Calmette-Guérin (BCG), the existing tuberculosis vaccine, to deliver a vaccination regimen with potent SARS-CoV-2-specific protective immunity. Combination of BCG with a stabilised, trimeric form of SARS-CoV-2 spike antigen promoted rapid development of virus-specific IgG antibodies in the blood of vaccinated mice, that was further augmented by the addition of alum. This vaccine formulation, BCG:CoVac, induced high-titre SARS-CoV-2 neutralising antibodies (NAbs) and Th1-biased cytokine release by vaccine-specific T cells, which correlated with the early emergence of T follicular helper cells in local lymph nodes and heightened levels of antigen-specific plasma B cells after vaccination. Vaccination of K18-hACE2 mice with a single dose of BCG:CoVac almost completely abrogated disease after SARS-CoV-2 challenge, with minimal inflammation and no detectable virus in the lungs of infected animals. Boosting BCG:CoVac-primed mice with a heterologous vaccine further increased SARS-CoV-2-specific antibody responses, which effectively neutralised B.1.1.7 and B.1.351 SARS-CoV-2 variants of concern. These findings demonstrate the potential for BCG-based vaccination to protect against major SARS-CoV-2 variants circulating globally.

Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction.

BackgroundBCG is a prototypal cancer immunotherapeutic factor currently approved of bladder cancer. In attempt to further enhance the effectiveness of immunotherapy of bladder cancer and, potentially, other malignancies, we evaluated the impact of BCG on local production of chemokines attracting the desirable effector CD8+ T cells (CTLs) and undesirable myeloid-derived suppressor cell (MDSCs) and regulatory T(reg) cells, and the ability of bladder cancer tissues to attract CTLs.MethodsFreshly resected bladder cancer tissues were either analyzed immediately or cultured ex vivo in the absence or presence of the tested factors. The expression of chemokine genes, secretion of chemokines and their local sources in freshly harvested and ex vivo-treated tumor explants were analyzed by quantitative PCR (Taqman), ELISAs and immunofluorescence/confocal microscopy. Migration of CTLs was evaluated ex vivo, using 24-transwell plates. Spearman correlation was used for correlative analysis, while paired Students T test or Wilcoxon was used for statistical analysis of the data.ResultsBladder cancer tissues spontaneously expressed high levels of the granulocyte/MDSC-attractant CXCL8 and Treg-attractant CCL22, but only marginal levels of the CTL-attracting chemokines: CCL5, CXCL9 and CXCL10. Baseline CXCL10 showed strong correlation with local expression of CTL markers. Unexpectedly, BCG selectively induced only the undesirable chemokines, CCL22 and CXCL8, but had only marginal impact on CXCL10 production. In sharp contrast, the combination of IFNα and a TLR3 ligand, poly-I:C (but not the combinations of BCG with IFNα or BCG with poly-I:C), induced high levels of intra-tumoral production of CXCL10 and promoted CTL attraction. The combination of BCG with IFNα + poly-I:C regimen did not show additional advantage.ConclusionsThe current data indicate that suboptimal ability of BCG to reprogram cancer-associated chemokine environment may be a factor limiting its therapeutic activity. Our observations that the combination of BCG with (or replacement by) IFNα and poly-I:C allows to reprogram bladder cancer tissues for enhanced CTL entry may provide for new methods of improving the effectiveness of immunotherapy of bladder cancer, helping to extend BCG applications to its more advanced forms, and, potentially, other diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-015-0050-8) contains supplementary material, which is available to authorized users.

Abstract 2697: Enhanced antitumor effect of combination intravesical BCG plus Docetaxel therapy in an orthotopic bladder cancer model

Abstract Introduction and Objective: Little progress in the management of non-muscle invasive bladder cancer (NMIBC) has been made. We explored the combination of intravesical BCG plus Doc in an orthotopic model. Methods: An orthotopic murine bladder cancer model was used. To assess the antitumoral effect of Doc, intravesical Doc therapy was administered at various dose-escalating concentrations: 0 μg (control: PBS), 25 μg, 50 μg and 100 μg (n = 12 for each group; total of 4 groups). Next, a comparative evaluation of tumor growth among the control group, the BCG-alone group, the Doc-alone group, and three combined BCG + Doc groups (a coincident group [CO] and two sequential groups) was performed (n = 12 for each group; total of 6 groups). The sequential combined groups consisted of SA group (SA; Doc administration followed by BCG administration on the next day) and an SB group (SB; BCG administration followed by Doc administration on the next day). Intravesical therapy was administered at 3-day intervals starting on day 5 and was repeated 5 times. To evaluate proliferation, T cell infiltration and apoptosis among the different groups, the tumor cells in the animal model were stained for Ki-67, CD8 and Cleaved caspase 3 after 4 instillations performed every 3 days. Results: In the Doc groups (12 mice each) treated with a dose of 0 μg (survival period: 32.3 ± 9.4 days), 25 μg (36.8 ± 11.4), 50 μg (38.1 ± 11.0) or 100 μg (40.0 ± 12.7), one, two, two and three mice failed to develop tumors and survived, respectively. The survival advantage for intravesical Doc in the 100 μg administration group was statistically significant when compared with that in the control group (p = 0.04). Out of the 12 mice in each group treated with control, Doc-alone, BCG-alone or combined Doc + BCG (CO, SA, SB), 1, 2, 1, 4, 4 and 1 mice failed to develop tumors and survived, respectively. Significant survival advantages were observed in the combined BCG + Doc group (CO: 50.7 ± 9.0, SA: 51.5 ± 6.9) compared with that in the BCG-alone group (33.1 ± 10.4) and the Doc-alone group (38.8 ± 11.5). The Ki-67 index of the cancer cells was significantly lower in the combined group, compared with that in the BCG-alone group (p < 0.0001), the Doc-alone group (p < 0.05) and the control group (p < 0.0001). BCG-alone significantly increased the number of CD8+ T cells (p < 0.05), while Doc-alone reduced the number of CD8+ T cells (p < 0.05), compared with that in the control. Apoptosis was significantly increased when Doc was administrated to the animals irrespective of the presence (p < 0.05) or absence (p < 0.05) of BCG instillation. Conclusions: Our results suggested that the combination of BCG and Doc treatment decreased the tumor appearance rate and improved the survival period. The enhancement in tumor growth inhibition enabled by combination regimens was presumably associated with a reduction in the tumor proliferation rate and might not depend on either CD8+ T cells or apoptosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2697. doi:10.1158/1538-7445.AM2011-2697

521 ENHANCED ANTITUMOR EFFECT OF INTRAVESICAL BCG PLUS DOCETAXEL THERAPY IN AN ORTHOTOPIC BLADDER CANCER MODEL

You have accessJournal of UrologyBladder Cancer: Basic Research1 Apr 2011521 ENHANCED ANTITUMOR EFFECT OF INTRAVESICAL BCG PLUS DOCETAXEL THERAPY IN AN ORTHOTOPIC BLADDER CANCER MODEL Minoru Horinaga, Ryuichi Fukuyama, Masahiro Iida, Masashi Matsushima, Hitoshi Yanaihara, Yoko Nakahira, Munehisa Ueno, and Hirotaka Asakura Minoru HorinagaMinoru Horinaga Saitama, Japan More articles by this author , Ryuichi FukuyamaRyuichi Fukuyama Konan, Japan More articles by this author , Masahiro IidaMasahiro Iida Saitama, Japan More articles by this author , Masashi MatsushimaMasashi Matsushima Saitama, Japan More articles by this author , Hitoshi YanaiharaHitoshi Yanaihara Saitama, Japan More articles by this author , Yoko NakahiraYoko Nakahira Saitama, Japan More articles by this author , Munehisa UenoMunehisa Ueno Saitama, Japan More articles by this author , and Hirotaka AsakuraHirotaka Asakura Saitama, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1217AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Intravesical BCG therapy is currently the most successful adjuvant agent for patients with non-muscle invasive bladder cancer (NMIBC). However, little progress in the management of NMIBC has been made. We explored the combination of intravesical BCG + Docetaxel(Doc) in an orthotopic bladder cancer model. METHODS An orthotopic murine bladder cancer model was used. To assess the antitumoral effect of Doc, intravesical Doc therapy was administered at various dose-escalating concentrations: 0μg (control: PBS), 25μg, 50μg and 100μg (n = 12 for each group; total of 4 groups). Next, a comparative evaluation of tumor growth among the control, the BCG-alone group(100μg), the Doc-alone group, and three combined BCG (100μg) + Doc group (a coincident(CO) and two sequential groups) was performed (n= 12 ; total of 6 groups). The sequential combined groups consisted of SA group (SA; Doc administration followed by BCG administration on the next day) and SB group (SB; BCG administration followed by Doc administration on the next day). Therapy was administered at 3-day intervals starting on day 5 and was repeated 5 times. To evaluate proliferation, T cell infiltration and apoptosis among the different groups, the tumor cells in the animal model were stained for Ki-67, CD8 and Cleaved caspase 3 after 4 instillations performed every 3 days. (n = 5). RESULTS In the Doc groups treated with a dose of 0 μg(survival; 32.3 ± 9.4 days), 25μg (36.8 ± 11.4), 50μg (38.1 ± 11.0) or 100μg (40.0 ± 12.7) one, two, two and three of the mice survived, respectively. Significant survival advantages were observed in the combined BCG + Doc group (CO: 50.7 ± 9.0, SA: 51.5 ± 6.9) compared with that in the BCG-alone group (33.1 ± 10.4) and the Doc-alone group (38.8 ± 11.5). The Ki-67 index of the cancer cells was significantly lower in the combined group, compared with that in the BCG-alone group (p < 0.0001), the Doc-alone group (p < 0.05) and the control(p < 0.0001). BCG-alone significantly increased the number of CD8+ T cells (p < 0.05), while Doc-alone reduced the CD8+ T cells (p < 0.05), compared with that in the control. Apoptosis was significantly increased when Doc was administrated to the animals irrespective of the presence (p < 0.05) or absence (p < 0.05) of BCG instillation. CONCLUSIONS Our results suggested that the combination of BCG + Doc treatment decreased the tumor appearance rate and improved the survival period. The enhancement in tumor growth inhibition enabled by combination regimens was presumably associated with a reduction in the tumor proliferation rate and might not depend on either CD8+ T cells or apoptosis. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e212 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Minoru Horinaga Saitama, Japan More articles by this author Ryuichi Fukuyama Konan, Japan More articles by this author Masahiro Iida Saitama, Japan More articles by this author Masashi Matsushima Saitama, Japan More articles by this author Hitoshi Yanaihara Saitama, Japan More articles by this author Yoko Nakahira Saitama, Japan More articles by this author Munehisa Ueno Saitama, Japan More articles by this author Hirotaka Asakura Saitama, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Subcutaneous boosting with heparin binding haemagglutinin increases BCG-induced protection against tuberculosis

Pulmonary tuberculosis remains a major health problem. Effective vaccination strategies are urgently needed. It was previously demonstrated that purified Mycobacterium bovis BCG Heparin Binding Haemagglutinin (HBHA) is able to induce in BALB/c mice protection levels against a Mycobacterium tuberculosis infection that are similar to those offered by BCG. Here we developed a heterologous prime/boost immunisation approach using a combination of BCG and HBHA in order to increase the protective immune response. We show that the time period between BCG priming and HBHA boosting strongly influences the efficacy of the boost. The optimized vaccine protocol consisting of a BCG administration followed 8 months later by boosting with HBHA resulted in an increase in the level of protection of up to 0.7 log when compared to BCG alone. These results suggest an immunisation strategy where BCG is administered to neonates and is followed by subcutaneous HBHA boosting in young adults.

Combination of BCG and interferon intravesical immunotherapy: an update

To provide an update on the use of interferon (IFN) in the treatment of non-muscle invasive bladder cancer (NMIBC). A literature review of intravesical IFN was performed. In vitro evidence suggested that IFN combined with BCG may have a synergistic effect on the immune response, and treatment regimens with IFN have used reduced BCG dosage in an attempt to reduce toxicity. IFN combined with BCG may salvage some patients, single-course BCG failures or late relapsers, while those that relapse quickly may be destined to failure. However, based on the results of a recently reported randomized trial, the addition of IFN may not improve efficacy in BCG naïve patients. BCG plus IFN remains an alternative in selected patients with NMIBC who fail intravesical BCG.

Enhanced Protection against Bovine Tuberculosis after Coadministration ofMycobacterium bovisBCG with a Mycobacterial Protein Vaccine-Adjuvant Combination but Not after Coadministration of Adjuvant Alone

Current efforts are aimed at optimizing the protective efficacy of Mycobacterium bovis BCG by the use of vaccine combinations. We have recently demonstrated that the protection afforded by BCG alone is enhanced by vaccinating cattle with a combination of vaccines comprising BCG and a protein tuberculosis vaccine, namely, culture filtrate proteins (CFPs) from M. bovis plus an adjuvant. In the current study, three different adjuvant systems were compared. The CFP was formulated with a depot adjuvant, dimethyldioctadecyl ammonium bromide (DDA), together with one of three different immunostimulants: monophosphoryl lipid A (MPL), a synthetic mycobacterial phosphatidylinositol mannoside-2 (PIM2), and a synthetic lipopeptide (Pam3Cys-SKKKK [Pam(3)CSK(4)]). Groups of cattle (n = 10/group) were vaccinated with BCG-CFP-DDA-PIM2, BCG-CFP-DDA-MPL, or BCG-CFP-DDA-Pam(3)CSK(4). Two additional groups (n = 10) were vaccinated with BCG alone or BCG-adjuvant (DDA-MPL), and a control group was left unvaccinated. Protection was assessed by challenging the cattle intratracheally with M. bovis. Groups of cattle vaccinated with BCG-CFP-DDA-PIM2, BCG-CFP-DDA-MPL, BCG-CFP-DDA-Pam(3)CSK(4), and BCG alone showed significant reductions in three, three, five, and three pathological and microbiological disease parameters, respectively, compared to the results for the nonvaccinated group. Vaccination with the combination of BCG and the DDA-MPL adjuvant alone abrogated the protection conferred by BCG alone. The profiling of cytokine gene expression following vaccination, prior to challenge, did not illuminate significant differences which could explain the latter result. Vaccination of cattle with a combination of BCG and protein tuberculosis vaccine enhances protection against tuberculosis.

Effects of Combined BCG and DHEA Treatment in Preventing the Development of Asthma

Both BCG and dehydroepiandrosterone (DHEA) induce Th1 immune responses and suppress Th2 allergic reactions. To investigate whether the combination of BCG and DHEA has an additive effect on asthma prevention, BALB/c mice (n = 10 per group) were given an intraperitoneal injection of BCG at the beginning of sensitization, and fed mice chow containing DHEA throughout the study. In female mice, the combined administration of 2 × 104 CFUs BCG and 0.01% DHEA effectively suppressed the ovalbumin-induced increase in airway sensitivity to methacholine (56.5 vs. 8.2 mg/mL, p < 0.01), while BCG (13.9 mg/mL) or DHEA (17.9 mg/mL) alone did not. However, the addition of high dose (0.1%) DHEA decreased the efficacy of high dose (2 × 105 CFUs) BCG in suppressing the airway responsiveness and eosinophilia. In male mice, the treatments with BCG and/or DHEA were less effective, and the interferon-γ / interleukin-4 ratio in the splenocyte supernatant was significantly higher and the ovalbumin-specific IgE concentration in the serum was significantly lower as compared to female mice. In conclusion, the combination of low doses of BCG and DHEA had an additive effect in suppressing the development of airway hypersensitivity. Androgens in males and DHEA overdose might reduce the efficacy of BCG.

Age-specific changes in the female–male mortality ratio related to the pattern of vaccinations: An observational study from rural Gambia

Background According to studies from Guinea-Bissau and Senegal, live vaccines may reduce the female–male mortality ratio (MR) whereas inactivated vaccines increase this ratio. We used data from The Gambia to examine whether similar tendencies could be found in a different setting. Setting Forty villages in the Farafenni area in rural Gambia. Subjects A population of 17,000 was followed with demographic surveillance between 1998 and 2002; 537 children less than 5 years of age died in this period. Methods We used two vaccination surveys and community mortality data to examine, first, the female–male mortality ratio (MR) in the age groups in which DTP and MV are recommended and have a high coverage. Second, using vaccination cards seen post-mortem, we examined the distribution of live or inactivated vaccines as last vaccination in different age groups. Third, we examined the effect of DTP and MV administered simultaneously. Main outcome measures The female–male MR in different age groups and for different vaccines. Results Vaccination coverage was high for BCG, third dose of DTP (DTP3) and MV, reaching a level of 80–90% within a few months of the recommended age of vaccination. First, the female–male MR was 0.93 (0.63–1.38) in the first 2 months of life when children had received no vaccination or the combination of BCG, HBV and OPV. From 2 to 8 months of age, with DTP and HBV being the main vaccinations, the female–male MR was 1.28 (0.86–1.89). Between 9 and 17 months of age, with MV as the main vaccination, this ratio dropped to 0.73 (0.50–1.07), a significant inversion of the female–male MR ( p = 0.045). Second, using information from vaccination cards of dead children, boys who died at 2–4 months of age were more likely to have received live BCG and girls to have received inactivated DTP and HBV as last vaccination ( p < 0.001). At 5–8 months of age, essentially all dead children had received DTP as last vaccination and the female–male MR was 1.68 (0.96–2.93), whereas the MR was 0.70 (0.43–1.15) at 12–17 months of age when nearly all dead children had received MV ( p = 0.022). Third, compared with the general population of children who had received MV, dead children who had received MV were more likely to have received DTP3 simultaneously with MV (relative risk (RR) = 5.59 (2.10–14.8)) or after MV (RR = 2.61 (1.13–6.05)). Conclusion Most children dying at a specific age had received the recommended vaccines. BCG and MV as last vaccination was associated with a low female–male MR, whereas DTP as last vaccination was associated with a high female–male MR. These trends are consistent with observations from other African countries.

IFN-γ, IL-4, IL-10 and IL-12 gene expression in BCG- Leishmania vaccination of Trypanosoma cruzi-infected mice

We have previously shown that vaccination of BALB/c mice with a combination of BCG plus killed Leishmania promastigotes, applied by the i.p. route 10 and 3 days before Trypanosoma cruzi inoculation, prolonged their survival and decreased their parasitaemia. In the present study we show that the BCG- Leishmania vaccine induced higher levels of circulating IFN-γ in acute and chronic infection of mice [on day 25 and 40 post-infection (p.i.) respectively], in comparison to unvaccinated animals (PBS-treated). Though the IFN-γ mRNA content of spleen cells of vaccinated and infected mice (on day 25 p.i.) was similar to that of unvaccinated animals, the BCG- Leishmania vaccine enhanced significantly the production of IFN-γ by spleen cells stimulated with T. cruzi antigens. This effect was observed to a lower extent in BCG- and Leishmania-treated mice. The BCG- Leishmania vaccine reduced the expression of the IL-10 mRNA of splenocytes as soon as day 12 p.i., before the peak parasitaemia. Such this effect was not observed in BCG- or Leishmania-treated animals. On day 25 p.i., the BCG plus Leishmania- or BCG-treatment of mice abolished the capacity of spleen cells to produce IL-10 in response to T. cruzi antigens. The levels of mIL-4 RNA and protein production were not modified in any group of mice. T. cruzi infection in BCG- Leishmania-vaccined mice stimulated an early and high production of IL-12 transcripts in spleen cells during the acute phase of the infection, that was prolonged during the chronic phase of infection. This effect was weaker or absent in BCG- and Leishmania-treated animals, respectively. These results indicate that the BCG- Leishmania vaccine stimulates the production of IL-12 and IFN-γ, but inhibits that of IL-10 and is without effect on IL-4 when mice are infected with T. cruzi. This highlights the key role of endogenously produced IFN-γ, IL-10 and IL-12 in the control of T. cruzi acute and chronic infection in mice and the favorable modulation of their balance by a vaccination combining BCG and Leishmania.

Vaccination of mice with a combination of BCG and killed Leishmania promastigotes reduces acute Trypanosoma cruzi infection by promoting an IFN- γ response

The combination of BCG with killed Leishmania promastigotes, demonstrated to be efficient in the cure of patients suffering American cutaneous leishmaniasis and in the induction of a long-term immune response in healthy vaccinated volunteers, was tested in BALB/c mice infected with Trypanosoma cruzi, in comparison to BCG or Leishmania alone, and a vehicle (PBS) control. BCG– Leishmania vaccination, applied intra-peritoneally 10 and 3 days before T. cruzi trypomastigote inoculation, prolonged the survival, and reduced blood parasitaemia of infected animals. Proliferation studies indicated that splenocytes of mice vaccinated with BCG– Leishmania and harvested in the acute phase of T. cruzi infection displayed stimulation indices higher than cells from PBS-treated mice when stimulated with PHA mitogen, PPD, Leishmania or T. cruzi antigens. Injections of a monoclonal antibody able to neutralise IFN- γ into BCG– Leishmania vaccinated mice increased parasitaemia to levels similar to those of control animals (treated with PBS) and reversed the beneficial effect of vaccination on the proliferative response to T. cruzi antigen. These results show that vaccination of mice with BCG plus killed Leishmania promastigotes delayed acute T. cruzi infection, stimulated a T-cell response to T. cruzi antigen and promoted IFN- γ production.

Effect of different doses of BCG on an allogeneic cell-mediated antitumor response in mice.

The effect of BCG on the development of cell-mediated cytotoxicity (CMC) in the spleens of allogeneic tumor-bearing (C57BL/6 X A)F1 mice was studied. BCG-treated tumor-bearing animals elicited a stronger CMC response than did the untreated tumor-bearing animals. Furthermore, the degree of activation was dependent on different doses of BCG, so that if the BCG was administered at doses above or below the optimum dose, a less marked stimulation of the CMC resulted. The combination of BCG given before the tumor implant plus an intratumor inoculation resulted in a significantly higher CMC than did either treatment alone.

Active immunotherapy of L1210 leukemia with neuraminidase-treated, drug-resistant L1210 sublines

The effectiveness of neuraminidase-treated, drug-resistant L1210 sublines in active immunotherapy of L1210 leukemia was evaluated. Optimal conditions for the establishment of in vitro, drug-resistant cells included (a) proper drug concentration, (b) the use of logarithmic-phase cultures in fresh medium, containing 5 or 10% serum, and (c) continual exposure to drug. Active immunotherapy, after tumor burden was reduced with chemotherapy, with neuraminidase-treated cells alone was either effective or deleterious, depending upon the drug-resistant subline used for immunization. The combination of BCG and neuraminidase-treated cells was superior to treatment with chemotherapy only. Optimal response was observed with the use of parental L1210 cells, combined with BCG, in immunotherapy of parental L1210 tumor. The results emphasize that an important prerequisite to successful immunotherapy is that tumor vaccines must elicit immunologic products which are cytotoxic for residual tumor.

Intermittent chemotherapy and immunotherapy with BCG in remission maintenance of children with acute lymphocytic leukemia: Effects upon immunological function

Twelve children with acute lymphocytic leukemia who had been in complete remission on continuous chemotherapy for at least 12 months, were treated with intermittent courses of chemotherapy alternating with BCG inoculation during the drug-free intervals. Measurements were made of leukocyte populations in blood and bone marrow leukemic blastogenic responses of blood lymphoid cells to phytohemmagglutinin and soluble leukemic blast cell membrane antigen. Antibody titers to a soluble leukemic blast-cell membrane-derived antigen were determined. Comparison was made with similar measurements during a second phase of intermittent chemotherapy without BCG inoculation (phase II). Two children showed bone-marrow relapse and two developed central nervous system leukemia during the study. Rises in blood and bone-marrow lymphoid cell numbers were found during both phases of the study. Blastogenic responses to phytohemagglutinin, depressed at the start of the study following at least 12 months of continuous chemotherapy, rose during intermittent chemotherapy and BCG and remained within normal ranges during phase II. Antibody titers and blastogenic responses to leukemia blast-cell membrane antigens increased in eight of twelve and six of seven children respectively during the BCG phase and were maintained during phase II. Only one child showed further increases in phase II. The combination of BCG and intermittent chemotherapy may increase leukemia-associated immunity in some patients with acute lymphocytic leukemia in remission. The separate contributions of either BCG or intermittent chemotherapy in producing this effect cannot be determined by this study.

Chemoimmunotherapy for cancer of the head and neck

Summary A total of thirty-two patients with squamous cell carcinoma of the head and neck and three with cancer of the parotid gland have received a combination of BCG, isoniazid, and methotrexate. Twenty of the squamous cell carcinomas responded with greater than 50 per cent regression with a mean duration of 322+ days as of April 1, 1973. A patient with acinic cell carcinoma of the parotid gland remains in greater than 90 per cent regression and is asymptomatic and working full time after 956+ days of treatment. The value of BCG and isoniazid as adjuvants in cancer chemotherapy has not been proved conclusively by this study. However, the results are impressive and suggest the need for further investigation of these two agents.

Effects of active specific and non-specific immunotherapy on E♂G 2 leukaemia according to the route of administration and combination of immunological stimulants

The effects of active immunotherapy, specific, using AkR leukaemic cells, and non-specific with BCG, on E♂G2 leukaemia injected intraperitoneally into (DBA/ 2 × C 57B 1/6) F 1 recipients have been examined. The routes of administration intraperitoneally and intravenously, and the combination of these treatments have been studied. Under these conditions the intraperitoneal route appears to be more efficient than the intravenous injection. The combination of BCG and AkR cells can be more effective than either of these treatments given alone (i.e. BCG and AkR cells intravenously), but they can be less effective (i.e. BCG i.p. is more effective if given alone than in combination of AkR cells i.v. or i.p.). The mortality curves of the treated animals showed a change after a period of time; initially they were very similar to the untreated animals, then the curve became a plateau, the treated animals are either little or unaffected, or cured. These different points are discussed.