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Project

Ty21a Salmonella as immunotherapeutic agent against non-muscle-invasive bladder cancer

Funder: Swiss National Science Foundation

Funding period
CHF 372 K
USD 388 K
Funding amount
Abstract
Ty21a Salmonella as immunotherapeutic agent against non-muscle-invasive bladder cancer1. SUMMARY OF THE RESEARCH PLAN Background: Bladder cancer is the second most common urological malignancy. Seventy to 80 % of tumors are diagnosed as non-muscle-invasive and remain confined to the bladder-mucosa. According to specific tumor-stage and grade characteristics, intravesical (IVES) immunotherapy with Bacillus-Calmette-Guerin (BCG) partially limit the high propensity of these tumors to recur and progress after transurethral endoscopic resection. However, repeated BCG instillations are associated with significant toxicity and treatment failure may occur in 30 to 40% of cases, hence the necessity for alternative or complementary immunotherapy. A promising strategy for treating cancer is the use of tumor-associated antigens (TAA) vaccines. With a genital tumor model of cervical cancer, we have shown that local immunstimulation with a synthetic TLR-9 agonist (CpG) after TAA vaccination target the protective vaccine-specific immune response to the tumor site and thus lead to increased genital tumor regression. Interestingly, we have recently shown that live bacteria, such as Salmonella attenuated vaccine strains, are more potent immunostimulants than CpG to recruit vaccine-specific CD8 T cells in the genital mucosa. Our preliminary data show that Salmonella immunostimulation is also effective when applied in the bladder, not only when used in combination with TAA vaccination, but also when used in replacement of IVES BCG treatment in the MB49-orthotopic murine model of non-muscle invasive bladder cancer (NMBIC). In this grant proposal, we will focus on an attenuated Salmonella enterica serovar Typhi strain, Ty21a, which is included in the Vivotif® vaccine against typhoid fever, because of its great safety record after 30 years of use in millions of people, thus enabling fast translation for human use if safety of IVES instillation can be confirmed. Towards this goal, the aims of this research proposal are to thoroughly characterize the effects of Ty21a on the adaptive and the innate immune response in the mouse bladder in two different, but overlapping settings, i.e. after TAA vaccination and as single immunostimulant in the bladder. Activity of Ty21a will also be determined on human cells, including killing and inflammatory responses of bladder tumor cell-lines and immune responses of PBMC and bladder explants toward the design of a phase I trial in NMIBC patients. Working Hypothesis: We hypothesized that Ty21a/Vivotif IVES immunostimulation is highly effective either alone or in combination with TAA vaccination for treating bladder tumors. In line with our data showing a poor infectivity of Ty21a in mouse bladder and in tumor cell lines, we anticipate a higher safety of Vivotif vaccine, as compared to BCG, for treating NMIBC patients.Specific aims:1.Vaccination with TAA-antigens and IVES immunostimulation with Ty21a: Characterize the adaptive immune responses in the bladder and investigate the underlying mechanisms. 2.IVES immunostimulation with Ty21a in bladder tumor models: Investigate infectivity and innate/inflammatory immune responses in comparison to the gold standard BCG. 3.IVES immunostimulation with Vivotif in NMIBC patients: a phase I (safety) trialExperimental Design and Methods: Adjuvanted synthetic polypeptides that include the mouse CTL epitopes E749-57 and Uty246-254 will be used as TC1 and MB49-specific TAA vaccines, respectively. Efficacy and mechanisms of IVES Ty21a will be assessed in WT and in different TLR-KO mice. Chemokines and integrins involved in CD8 T cell recruitment in bladder will be determined by multi-color flow cytometry. Inflammatory, cellular and cytokine/chemokine responses will be determined after IVES Ty21 immunostimulation in murine healthy and MB-49-tumor bearing bladders, as well as after infection of human bladder tumors cell line, blood cells and bladder explants. A Phase I trial with escalating doses of IVES Vivotif will be conducted in NMIBC patients of intermediate risk of tumor progression. Expected Value of the Proposed Project: We are currently testing in NMIBC patients whether TAA-vaccination combined with IVES BCG may induce better vaccine-specific immune responses in bladder (NCT01498172). However, Vivotif turns out to be more effective in murine models and if the mechanisms involved and the safety could be unraveled it would be of great value for optimizing combination protocols not only for bladder cancer but also for other cancer where local immunostimulation could be performed. For NMIBC patients, it would already be a major improvement if the use of Vivotif alone, in replacement of BCG, could result in less adverse events while keeping efficacy. Lately, the use of Salmonella as anti-cancer drug has been put forward and understanding the main facets of its anti-tumor activities may allow further developments.
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System

Categories
  • FOR (ANZSRC)

    1107 Immunology

  • RCDC

    Biotechnology

  • RCDC

    Cancer

  • RCDC

    Clinical Research

  • RCDC

    Immunization

  • RCDC

    Orphan Drug

  • RCDC

    Prevention

  • RCDC

    Rare Diseases

  • RCDC

    Urologic Diseases

  • RCDC

    Vaccine Related

  • HRCS HC

    Infection

  • HRCS HC

    Cancer

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science