Preclinical efficacy and safety of the Ty21a vaccine strain for intravesical immunotherapy of non-muscle-invasive bladder cancer

Domingos-Pereira, Sonia; Cesson, Valérie; Chevalier, Mathieu F.; Derré, Laurent; Jichlinski, Patrice; Nardelli-Haefliger, Denise

doi:10.1080/2162402x.2016.1265720

Cited by 20 publications

(23 citation statements)

References 26 publications

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“…No CFU counts were found in the main mycobacteria target organs: liver, lung, and spleen. In contrast, as expected [33][34][35][36][37], SCID mice infected with BCG did not reach the endpoint of the study (105 days). Animals of the BCG group presented with clinical and pathological findings compatible with a severe systemic and multi-organ infection.…”

Section: Discussionsupporting

confidence: 55%

Mycolicibacterium brumae is a Safe and Non-Toxic Immunomodulatory Agent for Cancer Treatment

et al. 2020

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Intravesical Mycobacterium bovis Bacillus Calmette–Guérin (BCG) immunotherapy remains the gold-standard treatment for non-muscle-invasive bladder cancer patients, even though half of the patients develop adverse events to this therapy. On exploring BCG-alternative therapies, Mycolicibacterium brumae, a nontuberculous mycobacterium, has shown outstanding anti-tumor and immunomodulatory capabilities. As no infections due to M. brumae in humans, animals, or plants have been described, the safety and/or toxicity of this mycobacterium have not been previously addressed. In the present study, an analysis was made of M. brumae- and BCG-intravenously-infected severe combined immunodeficient (SCID) mice, M. brumae-intravesically-treated BALB/c mice, and intrahemacoelic-infected-Galleria mellonella larvae. Organs from infected mice and the hemolymph from larvae were processed to count bacterial burden. Blood samples from mice were also taken, and a wide range of hematological and biochemical parameters were analyzed. Finally, histopathological alterations in mouse tissues were evaluated. Our results demonstrate the safety and non-toxic profile of M. brumae. Differences were observed in the biochemical, hematological and histopathological analysis between M. brumae and BCG-infected mice, as well as survival curves rates and colony forming units (CFU) counts in both animal models. M. brumae constitutes a safe therapeutic biological agent, overcoming the safety and toxicity disadvantages presented by BCG in both mice and G. mellonella animal models.

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Section: Discussionsupporting

confidence: 55%

Mycolicibacterium brumae is a Safe and Non-Toxic Immunomodulatory Agent for Cancer Treatment

et al. 2020

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“…Intravesical bladder immunotherapy with BCG or Ty21a is associated with the induction of inflammatory cytokines (7,17). Here, we show a morphological analysis of treated bladders to characterize inflammatory features, including the presence of edema, fibrosis, and immune cell infiltration, as summarized by an inflammatory score (11) (Fig.…”

Section: Characterization Of Bladder Wall Inflammation Upon Intravesimentioning

confidence: 86%

“…To functionally investigate the immune cells involved in the Ty21a-mediated tumorregression, we performed a single Ty21a intravesical instillation (3 x 10 7 CFU) 1 day after MB49 bladder tumor implantation, a treatment protocol that we previously showed to significantly increase mice survival (7). This allowed antibody-mediated immune-cell depletion to be performed without interfering with successive Ty21a treatments.…”

Section: Functional Characterization Of Effector Cells Involvedin Ty2mentioning

confidence: 99%

“…In addition, treatment failure may occur in 30-40% of cases (6), hence the necessity for alternatives. Along this line, we reported that the attenuated Salmonella enterica serovar Typhi Ty21a live vaccine-strain against typhoid fever was effective at inducing regression of established bladder tumors using the immunocompetent orthotopic MB49 bladder-cancer model (7), which closely mimic non-muscle invasive bladder cancer (NMIBC) in mice (8). Beside the excellent safety profile of the oral Ty21a vaccine Vivotif®, as confirmed worldwide in more than 200 million vaccinees over the last 30 years (9), the absence of bacterial survival in the bladder (7) points to it as a viable candidate to test in NMIBC patients.…”

Section: Introductionmentioning

confidence: 99%

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Intravesical Ty21a Vaccine Promotes Dendritic Cells and T Cell–Mediated Tumor Regression in the MB49 Bladder Cancer Model

Domingos-Pereira

Sathiyanadan

Rosa

et al. 2019

Cancer Immunology Research

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Preclinical data shows that intravesical instillation of Ty21a/Vivotif®, a commercial vaccine against typhoid fever, is an effective alternative option to standard Bacillus-Calmette-Guérin (BCG) immunotherapy for nonmuscle-invasive bladder cancer (NMIBC). Here we characterized the inflammatory effects of Ty21a on the bladder and investigated the immune mechanisms underlying tumor-regression towards the use of this bacterial vaccine in NMIBC patients. MB49 bladder tumor-bearing mice had significantly improved survival after intravesical instillations of Ty21a doses of 10 6 to 10 8 colony-forming units. By immunohistochemistry and morphology, both BCG and Ty21a instillations were associated with bladder inflammation, which was decreased with the use of low, but ,effective doses of Ty21a. Flow cytometry analysis showed a significant infiltration of T cells, natural killer (NK) cells, and myeloid cells, compared with controls, after a single dose of Ty21a, whereas this was only observed after multiple doses of BCG. The induced myeloid cells were predominantly neutrophils and Ly6C + CD103 + dendritic cells (DC), the latter being significantly more numerous after instillation of Ty21a than BCG. Ex vivo infection of human leukocytes with Ty21a, but not BCG, similarly significantly increased DC frequency. CD4 + and CD8 + T cells, but not NK cells nor neutrophils, were required for effective bladder tumor regression upon Ty21a treatment. Thus, the generation of antitumor adaptive immunity was identified as a key process underlying Ty21a-mediated treatment efficacy. Altogether, these results demonstrate mechanisms behind intravesical Ty21a therapy and suggest its potential as a safe and effective treatment for NMIBC patients.

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“…Salmonella can provide TLR-4 (64) and TLR-9 agonists (65) and may engage TLR-5 through flagellin (66). In a more recent preclinical study the same authors demonstrated that whilst intravesical Ty21a induced tumor cell death and innate and adaptive immune responses in the same therapeutic line as BCG immunotherapy, Ty21a was more effective than BCG for bladder-tumor treatment and thus may be predictive of a higher efficacy in patients (67).…”

Section: Combination Approaches: Personalized Immunomodulation Of a Pmentioning

confidence: 99%

Modifying the Non-muscle Invasive Bladder Cancer Immune Microenvironment for Optimal Therapeutic Response

2020

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It is now well-recognized that the tumor microenvironment (TME) is not only a key regulator of cancer progression but also plays a crucial role in cancer treatment responses. Recently, several high-profile publications have demonstrated the importance of particular immune parameters and cell types that dictate responsiveness to immunotherapies. With this increased understanding of TME-mediated therapy, approaches that increase therapeutic efficacy by remodeling the TME are actively being pursued. A classic example of this, in practice by urologists for over 40 years, is the manipulation of the bladder microenvironment for the treatment of non-muscle invasive bladder cancer (NMIBC) by instillation of intravesical bacillus Calmette-Guerin (BCG). The success of BCG treatment is thought to be due to its ability to induce a massive influx of Th1-polarized inflammatory cells, production of Th1 inflammatory cytokines and the generation of tumor-targeted Th1-mediated cytotoxic responses. Whilst BCG immunotherapy is currently the best treatment for NMIBC, ∼30% of patients show no response to this treatment. Here we present a review highlighting a variety of promising alternative immunotherapies being developed that remodel the bladder tumor microenvironment. These include (1) the use of oncolytic viruses which selectively replicate within cancer cells whilst also modifying the immunological components of the TME, (2) manipulation of the bladder microbiome to augment the response to BCG or other immunotherapies (3) utilizing Toll-like Receptor agonists as anti-tumor agents due to their potent stimulation of innate and adaptive immunity and (4) the growing recognition that immunotherapeutic strategies that will have the largest impact on patients may require multiple therapeutic approaches combined together. The accumulating knowledge on TME remodeling holds promise for providing an alternative therapy for patients with BCG-unresponsive NMIBC.

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Preclinical efficacy and safety of the Ty21a vaccine strain for intravesical immunotherapy of non-muscle-invasive bladder cancer

Cited by 20 publications

References 26 publications

Mycolicibacterium brumae is a Safe and Non-Toxic Immunomodulatory Agent for Cancer Treatment

Mycolicibacterium brumae is a Safe and Non-Toxic Immunomodulatory Agent for Cancer Treatment

Intravesical Ty21a Vaccine Promotes Dendritic Cells and T Cell–Mediated Tumor Regression in the MB49 Bladder Cancer Model

Modifying the Non-muscle Invasive Bladder Cancer Immune Microenvironment for Optimal Therapeutic Response

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