Cancer immunotherapy based on recombinant Salmonella enterica serovar Typhimurium aroA strains secreting prostate-specific antigen and cholera toxin subunit B

Fensterle, Joachim; Bergmann, Birgit; Yone, Clarisse L.R.P.; Hotz, Christian; Meyer, Susanne; Spreng, Simone; Goebel, Werner; Rapp, Ulf R.; Gentschev, Ivaylo

doi:10.1038/sj.cgt.7701109

Cited by 64 publications

(52 citation statements)

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“…Virulent and attenuated strains of ST have been investigated as live vectors for cancer therapy (41,42). Although such studies reveal induction of CD8 + T cells, their long-term protective ability have not been characterized in detail.…”

Section: Discussionmentioning

confidence: 99%

Intracellular Bacterial Vectors That Induce CD8+ T Cells with Similar Cytolytic Abilities but Disparate Memory Phenotypes Provide Contrasting Tumor Protection

2009

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Section: Discussionmentioning

confidence: 99%

Intracellular Bacterial Vectors That Induce CD8+ T Cells with Similar Cytolytic Abilities but Disparate Memory Phenotypes Provide Contrasting Tumor Protection

2009

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“…This is supported by the observation that antitumor efficacies of the dal dat ⌬actA 142 strain and Lm-LLO-PSA were comparable after the administration of similar doses of each immunotherapeutic vector (data not shown). Another live bacterial vaccine, the Salmonella enterica serovar Typhimurium aroA strain expressing PSA, has been shown to confer protection against PSAexpressing tumors (4). However, the therapeutic efficacy for this construct has not been determined.…”

Section: Discussionmentioning

confidence: 99%

Construction and Characterization of an Attenuated Listeria monocytogenes Strain for Clinical Use in Cancer Immunotherapy

Wallecha

Maciag

Rivera

et al. 2009

Clin Vaccine Immunol

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Listeria monocytogenes has been exploited previously as a vaccine vector for the delivery of heterologous proteins such as tumor-specific antigens for active cancer immunotherapy. However, for effective use of live vector in clinics, safety is a major concern. In the present study, we describe an irreversibly attenuated and highly immunogenic L. monocytogenes platform, the L. monocytogenes dal-, dat-, and actA-deleted strain that expresses the human prostate-specific antigen (PSA) using an antibiotic resistance marker-free plasmid (the dal dat ⌬actA 142 strain expressing PSA). Despite limited in vivo survival, the dal dat ⌬actA 142 strain was able to elicit efficient immune responses required for tumor clearance. Our results showed that immunization of mice with the dal dat ⌬actA 142 strain caused the regression of the tumors established by the prostate adenocarcinoma cell line expressing PSA. An evaluation of immunologic potency indicated that the dal dat ⌬actA 142 strain elicits a high frequency of PSA-specific immune responses. Interestingly, immunization with the dal dat ⌬actA 142 strain induced significant infiltration of PSA-specific T cells in the intratumoral milieu. Collectively, our data suggest that the dal dat ⌬actA 142 strain is a safe and potent vector for clinical use and that this platform may be further exploited as a potential candidate to express other single or multiple antigens for cancer immunotherapy.Biological and immunological characteristics of Listeria monocytogenes make this gram-positive bacterium an ideal vaccine vector. L. monocytogenes triggers potent cellular immune responses in an infected host due to its ability to survive in both phagocytic and cytosolic compartments. Several groups have shown recombinant L. monocytogenes to be an effective agent for immunotherapy against infection and cancer (2, 16, 19-21, 24, 27, 28). Currently, there are two methods to genetically modify L. monocytogenes to express heterologous antigens in vivo. These include the insertion of a heterologous gene in the bacterial chromosome either by homologous recombination (7,16) or by phage-specific insertion (13) and the transformation of L. monocytogenes with a plasmid carrying a foreign antigen (7, 26). The plasmid-based strategy has the advantage of multicopy expression but relies on complementation for the maintenance of the plasmid in vivo. To address this, two mechanisms have been described previously for L. monocytogenes. One is based on the complementation of a prfA-deficient L. monocytogenes strain (XFL7) with a copy of episomal prfA (a major gene transcription activator for several virulence genes in L. monocytogenes) (7). This complementation ensures the retention of the plasmid in vivo but requires the presence of antibiotic resistance genes for in vitro selection. The second approach uses complementation with alanine racemase (dal), an enzyme involved in the synthesis of the cell wall component D-alanine (35).In L. monocytogenes, the D-alanine metabolism is regulated by two genes, dal and d...

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“…Antigens have also been linked to bacterial toxins that are highly immunogenic to sensitize the immune system against cancer cell antigens [10,40]. Again, this approach harnesses the ability of S. Typhimurium to deliver immune sensitizing compounds at the tumor site to alert circulating immune cells, while at the same time the bacteria target the more difficult to reach anoxic regions of the tumor.…”

Section: Using Salmonella To Deliver Anti Cancer Compoundsmentioning

confidence: 99%

“…Other approaches employ S. Typhimurium to deliver cytokines to the tumor site in an attempt to activate immune cells or elicit an immune response against the tumor [8,10,35,36,37,38,39]. Antigens have also been linked to bacterial toxins that are highly immunogenic to sensitize the immune system against cancer cell antigens [10,40].…”

Section: Using Salmonella To Deliver Anti Cancer Compoundsmentioning

confidence: 99%

“…Bacterial toxins that are highly immunogenic have also been manipulated by linking them to tumor antigens in an attempt to elicit an immune response to tumors and sensitize the immune system to tumor presence [9,10]. Furthermore, bacteria such as S. Typhimurium have an innate advantage as a chemotherapeutic considering they are attracted to cancer cells by compounds released by necrotic or quiescent cells within the tumor, thereby they can be used to either infect cells or deliver compounds directly to the tumor site [8,11,12,13].…”

Section: The Benefits Of Bacterial Cancer Therapymentioning

confidence: 99%

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Targeting Tumors with Salmonella Typhimurium - Potential for Therapy

2010

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AbstrAct:When one considers the organism Salmonella enterica serotype Typhimurium (S. Typhimurium), one usually thinks of the Gram-negative enteric pathogen that causes the severe food borne illness, gastroentertitis. In this context, the idea of Salmonella being exploited as a cancer therapeutic seems pretty remote. However, there has been an escalating interest in the development of tumor-therapeutic bacteria for use in the treatment of a variety of cancers. This strategy takes advantage of the remarkable ability of certain bacteria to preferentially replicate and accumulate within tumors. In the case of S. Typhimurium, this organism infects and selectively grows within implanted tumors, achieving tumor/normal tissue ratios of approximately 1,000:1. Salmonella also has some attractive properties well suited for the design of a chemotherapeutic agent. In particular, this pathogen can easily be manipulated to carry foreign genes, and since this species is a facultative anaerobe, it is able to survival in both oxygenated and hypoxic conditions, implying this organism could colonize both small metastatic lesions as well as larger tumors. These observations are the impetus to a burgeoning field focused on the development of Salmonella as a clinically useful anti-cancer agent. We will discuss three cutting edge technologies employing Salmonella to target tumors.

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Cancer immunotherapy based on recombinant Salmonella enterica serovar Typhimurium aroA strains secreting prostate-specific antigen and cholera toxin subunit B

Cited by 64 publications

References 52 publications

Intracellular Bacterial Vectors That Induce CD8+ T Cells with Similar Cytolytic Abilities but Disparate Memory Phenotypes Provide Contrasting Tumor Protection

Intracellular Bacterial Vectors That Induce CD8+ T Cells with Similar Cytolytic Abilities but Disparate Memory Phenotypes Provide Contrasting Tumor Protection

Construction and Characterization of an Attenuated Listeria monocytogenes Strain for Clinical Use in Cancer Immunotherapy

Targeting Tumors with Salmonella Typhimurium - Potential for Therapy

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