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  1. Article ; Online: Immune-priming of the tumor microenvironment by radiotherapy: rationale for combination with immunotherapy to improve anticancer efficacy.

    Shahabi, Vafa / Postow, Michael A / Tuck, David / Wolchok, Jedd D

    American journal of clinical oncology

    2015  Volume 38, Issue 1, Page(s) 90–97

    Abstract: A clear contribution of the immune system to eradication of tumors has been supported by recent developments in the field of immunotherapy. Durable clinical responses obtained after treatment with immunomodulatory agents such as ipilimumab (Yervoy) and ... ...

    Abstract A clear contribution of the immune system to eradication of tumors has been supported by recent developments in the field of immunotherapy. Durable clinical responses obtained after treatment with immunomodulatory agents such as ipilimumab (Yervoy) and anti-PD-1 antibody (BMS-936558), have established that harnessing the immune response against chemoresistant tumors can result in their complete eradication. However, only a subset of patients benefit from these therapeutic approaches. Accumulating evidence suggests that tumors with a preexisting active immune microenvironment might have a better response to immunotherapy. In a number of preclinical and clinical studies, many cytotoxic agents elicit changes within tumors and their microenvironment that may make these malignant cells more sensitive to an efficient immune cell attack. Therefore, it is plausible that combining immunotherapy with standard anticancer therapies such as chemotherapy or radiotherapy will provide synergistic antitumor effects. Despite a large collection of preclinical data, the immune mechanisms that might contribute to the efficacy of conventional cytotoxic therapies and their combinations with immunotherapeutic approaches have not yet been extensively studied in the clinical setting and warrant further investigation. This review will focus on current knowledge of the immunomodulatory effects of one such cytotoxic treatment, radiotherapy, and explore different pathways by which its combination with immunomodulatory antibodies might contribute toward more efficacious antitumor immunity.
    MeSH term(s) Antibodies, Monoclonal/therapeutic use ; Antineoplastic Agents/therapeutic use ; Combined Modality Therapy ; Humans ; Immunotherapy/methods ; Ipilimumab ; Neoplasms/drug therapy ; Neoplasms/immunology ; Neoplasms/radiotherapy ; Radiotherapy/methods ; Tumor Microenvironment/immunology ; Tumor Microenvironment/radiation effects
    Chemical Substances Antibodies, Monoclonal ; Antineoplastic Agents ; Ipilimumab ; nivolumab (31YO63LBSN)
    Language English
    Publishing date 2015-02
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 604536-4
    ISSN 1537-453X ; 0277-3732
    ISSN (online) 1537-453X
    ISSN 0277-3732
    DOI 10.1097/COC.0b013e3182868ec8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Live, attenuated strains of Listeria and Salmonella as vaccine vectors in cancer treatment.

    Shahabi, Vafa / Maciag, Paulo C / Rivera, Sandra / Wallecha, Anu

    Bioengineered bugs

    2010  Volume 1, Issue 4, Page(s) 235–243

    Abstract: Live, attenuated strains of many bacteria that synthesize and secrete foreign antigens are being developed as vaccines for a number of infectious diseases and cancer. Bacterial-based vaccines provide a number of advantages over other antigen delivery ... ...

    Abstract Live, attenuated strains of many bacteria that synthesize and secrete foreign antigens are being developed as vaccines for a number of infectious diseases and cancer. Bacterial-based vaccines provide a number of advantages over other antigen delivery strategies including low cost of production, the absence of animal products, genetic stability and safety. In addition, bacterial vaccines delivering a tumor-associated antigen (TAA) stimulate innate immunity and also activate both arms of the adaptive immune system by which they exert efficacious anti-tumor effects. Listeria monocytogenes and several strains of Salmonella have been most extensively studied for this purpose. A number of attenuated strains have been generated and used to deliver antigens associated with infectious diseases and cancer. Although both bacteria are intracellular, the immune responses invoked by Listeria and Salmonella are different due to their sub-cellular locations. Upon entering antigen-presenting cells by phagocytosis, Listeria is capable of escaping from the phagosomal compartment and thus has direct access to the cell cytosol. Proteins delivered by this vector behave as endogenous antigens, are presented on the cell surface in the context of MHC class I molecules, and generate strong cell-mediated immune responses. In contrast, proteins delivered by Salmonella, which lacks a phagosomal escape mechanism, are treated as exogenous antigens and presented by MHC class II molecules resulting predominantly in Th2 type immune responses. This fundamental disparity between the life cycles of the two vectors accounts for their differential application as antigen delivery vehicles. The present paper includes a review of the most recent advances in the development of these two bacterial vectors for treatment of cancer. Similarities and differences between the two vectors are discussed.
    MeSH term(s) Animals ; Antigen-Presenting Cells/immunology ; Cancer Vaccines/immunology ; Histocompatibility Antigens Class I/immunology ; Histocompatibility Antigens Class I/metabolism ; Humans ; Listeria/immunology ; Listeria/metabolism ; Models, Biological ; Neoplasms/immunology ; Salmonella/immunology ; Salmonella/metabolism
    Chemical Substances Cancer Vaccines ; Histocompatibility Antigens Class I
    Language English
    Publishing date 2010-01-04
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2623145-1
    ISSN 1949-1026 ; 1949-1018
    ISSN (online) 1949-1026
    ISSN 1949-1018
    DOI 10.4161/bbug.1.4.11243
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Listeria-derived ActA is an effective adjuvant for primary and metastatic tumor immunotherapy.

    Wood, Laurence M / Pan, Zhen-Kun / Shahabi, Vafa / Paterson, Yvonne

    Cancer immunology, immunotherapy : CII

    2010  Volume 59, Issue 7, Page(s) 1049–1058

    Abstract: Tumor immunotherapy is currently at the cusp of becoming an important aspect of comprehensive cancer treatment in the clinic. However, the need for improved adjuvants to augment immune responses against tumor antigens is always present. In this paper, we ...

    Abstract Tumor immunotherapy is currently at the cusp of becoming an important aspect of comprehensive cancer treatment in the clinic. However, the need for improved adjuvants to augment immune responses against tumor antigens is always present. In this paper, we characterize the Listeria monocytogenes-derived actin-nucleating protein, ActA, as a novel adjuvant for use in tumor immunotherapy. ActA is a virulence factor that is expressed on the cell surface of L. monocytogenes and facilitates the production of actin tails that propel Listeria throughout the cytosol of an infected host cell. It is believed that this ActA-dependent cytosolic motility allows Listeria to evade adaptive host cell defenses and facilitates its invasion into a proximal uninfected host cell. However, there is evidence that ActA fused to a tumor antigen and delivered by L. monocytogenes can perform a beneficial function in tumor immunotherapy as an adjuvant. Our investigation of this adjuvant activity demonstrates that ActA, either fused to or administered as a mixture with a tumor antigen, can augment anti-tumor immune responses, break immune tolerance and facilitate tumor eradication, which suggests that ActA is not only an effective adjuvant in tumor immunotherapy but can also be applied in a number of therapeutic settings.
    MeSH term(s) Adjuvants, Immunologic/administration & dosage ; Animals ; Antigens, Neoplasm/immunology ; Bacterial Proteins/administration & dosage ; Bacterial Proteins/genetics ; Bacterial Proteins/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cancer Vaccines/administration & dosage ; Cancer Vaccines/immunology ; Cell Line, Tumor ; Female ; Humans ; Immunotherapy/methods ; Male ; Membrane Proteins/administration & dosage ; Membrane Proteins/genetics ; Membrane Proteins/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neoplasm Metastasis ; Neoplasms, Experimental/immunology ; Neoplasms, Experimental/pathology ; Neoplasms, Experimental/therapy ; Papillomavirus E7 Proteins/genetics ; Papillomavirus E7 Proteins/immunology ; Treatment Outcome ; Tumor Burden
    Chemical Substances Adjuvants, Immunologic ; Antigens, Neoplasm ; Bacterial Proteins ; Cancer Vaccines ; Membrane Proteins ; Papillomavirus E7 Proteins ; oncogene protein E7, Human papillomavirus type 16 ; actA protein, Listeria monocytogenes (144430-05-7)
    Language English
    Publishing date 2010-07
    Publishing country Germany
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 195342-4
    ISSN 1432-0851 ; 0340-7004
    ISSN (online) 1432-0851
    ISSN 0340-7004
    DOI 10.1007/s00262-010-0830-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Listeria monocytogenes-derived listeriolysin O has pathogen-associated molecular pattern-like properties independent of its hemolytic ability.

    Wallecha, Anu / Wood, Laurence / Pan, Zhen-Kun / Maciag, Paulo C / Shahabi, Vafa / Paterson, Yvonne

    Clinical and vaccine immunology : CVI

    2012  Volume 20, Issue 1, Page(s) 77–84

    Abstract: There is a constant need for improved adjuvants to augment the induction of immune responses against tumor-associated antigens (TAA) during immunotherapy. Previous studies have established that listeriolysin O (LLO), a cholesterol-dependent cytolysin ... ...

    Abstract There is a constant need for improved adjuvants to augment the induction of immune responses against tumor-associated antigens (TAA) during immunotherapy. Previous studies have established that listeriolysin O (LLO), a cholesterol-dependent cytolysin derived from Listeria monocytogenes, exhibits multifaceted effects to boost the stimulation of immune responses to a variety of antigens. However, the direct ability of LLO as an adjuvant and whether it acts as a pathogen-associated molecular pattern (PAMP) have not been demonstrated. In this paper, we show that a detoxified, nonhemolytic form of LLO (dtLLO) is an effective adjuvant in tumor immunotherapy and may activate innate and cellular immune responses by acting as a PAMP. Our investigation of the adjuvant activity demonstrates that dtLLO, either fused to or administered as a mixture with a human papillomavirus type 16 (HPV-16) E7 recombinant protein, can augment antitumor immune responses and facilitate tumor eradication. Further mechanistic studies using bone marrow-derived dendritic cells suggest that dtLLO acts as a PAMP by stimulating production of proinflammatory cytokines and inducing maturation of antigen-presenting cells (APC). We propose that dtLLO is an effective adjuvant for tumor immunotherapy, and likely for other therapeutic settings.
    MeSH term(s) Adjuvants, Immunologic/isolation & purification ; Adjuvants, Immunologic/pharmacology ; Animals ; Antigen-Presenting Cells/drug effects ; Antigen-Presenting Cells/immunology ; Bacterial Toxins/isolation & purification ; Bacterial Toxins/pharmacology ; Cancer Vaccines/administration & dosage ; Cancer Vaccines/immunology ; Cytokines/metabolism ; Dendritic Cells/drug effects ; Dendritic Cells/immunology ; Heat-Shock Proteins/isolation & purification ; Heat-Shock Proteins/pharmacology ; Hemolysin Proteins/isolation & purification ; Hemolysin Proteins/pharmacology ; Immunotherapy/methods ; Listeria monocytogenes/chemistry ; Mice ; Mice, Inbred C57BL ; Papillomavirus E7 Proteins/immunology
    Chemical Substances Adjuvants, Immunologic ; Bacterial Toxins ; Cancer Vaccines ; Cytokines ; Heat-Shock Proteins ; Hemolysin Proteins ; Papillomavirus E7 Proteins ; oncogene protein E7, Human papillomavirus type 16 ; hlyA protein, Listeria monocytogenes (R06ZRQ1YX9)
    Language English
    Publishing date 2012-11-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2221082-9
    ISSN 1556-679X ; 1556-6811
    ISSN (online) 1556-679X
    ISSN 1556-6811
    DOI 10.1128/CVI.00488-12
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Multiple effector mechanisms induced by recombinant Listeria monocytogenes anticancer immunotherapeutics.

    Wallecha, Anu / Carroll, Kyla Driscoll / Maciag, Paulo Cesar / Rivera, Sandra / Shahabi, Vafa / Paterson, Yvonne

    Advances in applied microbiology

    2009  Volume 66, Page(s) 1–27

    Abstract: Listeria monocytogenes is a facultative intracellular gram-positive bacterium that naturally infects professional antigen presenting cells (APC) to target antigens to both class I and class II antigen processing pathways. This infection process results ... ...

    Abstract Listeria monocytogenes is a facultative intracellular gram-positive bacterium that naturally infects professional antigen presenting cells (APC) to target antigens to both class I and class II antigen processing pathways. This infection process results in the stimulation of strong innate and adaptive immune responses, which make it an ideal candidate for a vaccine vector to deliver heterologous antigens. This ability of L. monocytogenes has been exploited by several researchers over the past decade to specifically deliver tumor-associated antigens that are poorly immunogenic such as self-antigens. This review describes the preclinical studies that have elucidated the multiple immune responses elicited by this bacterium that direct its ability to influence tumor growth.
    MeSH term(s) Antigen-Presenting Cells/immunology ; Cancer Vaccines/immunology ; Cancer Vaccines/therapeutic use ; Humans ; Listeria monocytogenes/genetics ; Listeria monocytogenes/immunology ; Listeria monocytogenes/pathogenicity ; Listeriosis/immunology ; Listeriosis/microbiology ; Neoplasms/immunology ; Neoplasms/therapy ; T-Lymphocytes, Regulatory/immunology ; Vaccines, Synthetic/immunology ; Vaccines, Synthetic/therapeutic use ; Virulence ; Virulence Factors/genetics ; Virulence Factors/immunology
    Chemical Substances Cancer Vaccines ; Vaccines, Synthetic ; Virulence Factors
    Language English
    Publishing date 2009
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 160-0
    ISSN 0065-2164
    ISSN 0065-2164
    DOI 10.1016/S0065-2164(08)00801-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-related gastrointestinal adverse events.

    Shahabi, Vafa / Berman, David / Chasalow, Scott D / Wang, Lisu / Tsuchihashi, Zenta / Hu, Beihong / Panting, Lisa / Jure-Kunkel, Maria / Ji, Rui-Ru

    Journal of translational medicine

    2013  Volume 11, Page(s) 75

    Abstract: Background: Treatment with ipilimumab, a fully human anti-CTLA-4 antibody approved for the treatment of advanced melanoma, is associated with some immune-related adverse events (irAEs) such as colitis (gastrointestinal irAE, or GI irAE) and skin rash, ... ...

    Abstract Background: Treatment with ipilimumab, a fully human anti-CTLA-4 antibody approved for the treatment of advanced melanoma, is associated with some immune-related adverse events (irAEs) such as colitis (gastrointestinal irAE, or GI irAE) and skin rash, which are managed by treatment guidelines. Nevertheless, predictive biomarkers that can help identify patients more likely to develop these irAEs could enhance the management of these toxicities.
    Methods: To identify candidate predictive biomarkers associated with GI irAEs, gene expression profiling was performed on whole blood samples from 162 advanced melanoma patients at baseline, 3 and 11 weeks after the start of ipilimumab treatment in two phase II clinical trials (CA184004 and CA184007). Overall, 49 patients developed Grade 2 or higher (grade 2+) GI irAEs during the course of treatment. A repeated measures analysis of variance (ANOVA) was used to evaluate the differences in mean expression levels between the GI irAE and No-GI irAE groups of patients at the three time points.
    Results: In baseline samples, 27 probe sets showed differential mean expression (≥ 1.5 fold, P ≤ 0.05) between the GI irAE and No-GI irAE groups. Most of these probe sets belonged to three functional categories: immune system, cell cycle, and intracellular trafficking. Changes in gene expression over time were also characterized. In the GI irAE group, 58 and 247 probe sets had a ≥ 1.5 fold change in expression from baseline to 3 and 11 weeks after first ipilimumab dose, respectively. In particular, on-treatment expression increases of CD177 and CEACAM1, two neutrophil-activation markers, were closely associated with GI irAEs, suggesting a possible role of neutrophils in ipilimumab-associated GI irAEs. In addition, the expression of several immunoglobulin genes increased over time, with greater increases in patients with grade 2+ GI irAEs.
    Conclusions: Gene expression profiling of peripheral blood, sampled before or early in the course of treatment with ipilimumab, resulted in the identification of a set of potential biomarkers that were associated with occurrence of GI irAEs. However, because of the low sensitivity of these biomarkers, they cannot be used alone to predict which patients will develop GI irAEs. Further investigation of these biomarkers in a larger patient cohort is warranted.
    MeSH term(s) Antibodies, Monoclonal/adverse effects ; Antibodies, Monoclonal/therapeutic use ; Biomarkers, Tumor/blood ; GPI-Linked Proteins/metabolism ; Gastrointestinal Tract/drug effects ; Gastrointestinal Tract/pathology ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Immune System/drug effects ; Immune System/metabolism ; Immunoglobulins/genetics ; Immunoglobulins/metabolism ; Ipilimumab ; Isoantigens/metabolism ; Leukocyte Count ; Melanoma/blood ; Melanoma/drug therapy ; Melanoma/genetics ; Neutrophils/metabolism ; ROC Curve ; Receptors, Cell Surface/metabolism ; Reproducibility of Results ; Signal Transduction/drug effects ; Signal Transduction/genetics
    Chemical Substances Antibodies, Monoclonal ; Biomarkers, Tumor ; CD177 protein, human ; GPI-Linked Proteins ; Immunoglobulins ; Ipilimumab ; Isoantigens ; Receptors, Cell Surface
    Keywords covid19
    Language English
    Publishing date 2013-03-22
    Publishing country England
    Document type Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
    ISSN 1479-5876
    ISSN (online) 1479-5876
    DOI 10.1186/1479-5876-11-75
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Listeria-derived ActA is an effective adjuvant for primary and metastatic tumor immunotherapy

    Wood, Laurence M / Pan, Zhen-Kun / Shahabi, Vafa / Paterson, Yvonne

    Cancer immunology, immunotherapy. 2010 July, v. 59, no. 7

    2010  

    Abstract: Tumor immunotherapy is currently at the cusp of becoming an important aspect of comprehensive cancer treatment in the clinic. However, the need for improved adjuvants to augment immune responses against tumor antigens is always present. In this paper, we ...

    Abstract Tumor immunotherapy is currently at the cusp of becoming an important aspect of comprehensive cancer treatment in the clinic. However, the need for improved adjuvants to augment immune responses against tumor antigens is always present. In this paper, we characterize the Listeria monocytogenes-derived actin-nucleating protein, ActA, as a novel adjuvant for use in tumor immunotherapy. ActA is a virulence factor that is expressed on the cell surface of L. monocytogenes and facilitates the production of actin tails that propel Listeria throughout the cytosol of an infected host cell. It is believed that this ActA-dependent cytosolic motility allows Listeria to evade adaptive host cell defenses and facilitates its invasion into a proximal uninfected host cell. However, there is evidence that ActA fused to a tumor antigen and delivered by L. monocytogenes can perform a beneficial function in tumor immunotherapy as an adjuvant. Our investigation of this adjuvant activity demonstrates that ActA, either fused to or administered as a mixture with a tumor antigen, can augment anti-tumor immune responses, break immune tolerance and facilitate tumor eradication, which suggests that ActA is not only an effective adjuvant in tumor immunotherapy but can also be applied in a number of therapeutic settings.
    Keywords neoplasms ; Listeria monocytogenes ; immunotherapy
    Language English
    Dates of publication 2010-07
    Size p. 1049-1058.
    Publisher Springer-Verlag
    Publishing place Berlin/Heidelberg
    Document type Article
    ZDB-ID 195342-4
    ISSN 1432-0851 ; 0340-7004
    ISSN (online) 1432-0851
    ISSN 0340-7004
    DOI 10.1007/s00262-010-0830-4
    Database NAL-Catalogue (AGRICOLA)

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  8. Article ; Online: Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab.

    Shahabi, Vafa / Whitney, Gena / Hamid, Omid / Schmidt, Henrik / Chasalow, Scott D / Alaparthy, Suresh / Jackson, Jeffrey R

    Cancer immunology, immunotherapy : CII

    2012  Volume 61, Issue 5, Page(s) 733–737

    Abstract: Ipilimumab, a fully human monoclonal antibody against cytotoxic T lymphocyte antigen-4, has demonstrated significant improvement in overall survival in previously treated advanced melanoma patients. The BRAF inhibitor, vemurafenib, has shown up to 78% ... ...

    Abstract Ipilimumab, a fully human monoclonal antibody against cytotoxic T lymphocyte antigen-4, has demonstrated significant improvement in overall survival in previously treated advanced melanoma patients. The BRAF inhibitor, vemurafenib, has shown up to 78% objective response rates in melanoma patients harboring the BRAF-V600E mutation but not in patients lacking the mutation. As an immune potentiator, the mechanism of action of ipilimumab may not be dependent of the activity of the BRAF pathway. To test this, we investigated whether the clinical activity of ipilimumab would be affected by the BRAF-V600E mutation status of the tumors. Thus, this retrospective analysis was carried using a set of tumor biopsies from a completed phase II clinical trial. CA184004 was a randomized, double-blind, multicenter trial of 82 previously treated or untreated patients with unresectable stage III/IV melanoma. Patients received ipilimumab 3 or 10 mg/kg every 3 weeks for four doses followed by maintenance dosing in eligible patients. The BRAF-V600E mutation status for 80 patients was determined in tumor biopsies by PCR-based assays. Data on disease control were available for 69 patients with evaluated BRAF-V600E mutation status. Rates of objective responses and stable disease in patients with BRAF-V600E mutation positive tumors (30%) were comparable to those in patients with the wild-type gene (~33%). Eleven patients displayed Durable Disease Control (DDC) of which 55% had BRAF-V600E mutation positive tumors and 45% did not. In the 48 patients showing no DDC, the mutation frequency was 50%. In this study, no association between BRAF-V600E mutation status of melanoma tumors and DDC after treatment with ipilimumab was detected.
    MeSH term(s) Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/therapeutic use ; Clinical Trials, Phase II as Topic ; Double-Blind Method ; Humans ; Ipilimumab ; Melanoma/drug therapy ; Melanoma/genetics ; Mutation ; Proto-Oncogene Proteins B-raf/genetics ; Retrospective Studies ; Treatment Outcome
    Chemical Substances Antibodies, Monoclonal ; Ipilimumab ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
    Language English
    Publishing date 2012-03-01
    Publishing country Germany
    Document type Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
    ZDB-ID 195342-4
    ISSN 1432-0851 ; 0340-7004
    ISSN (online) 1432-0851
    ISSN 0340-7004
    DOI 10.1007/s00262-012-1227-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Construction and characterization of an attenuated Listeria monocytogenes strain for clinical use in cancer immunotherapy.

    Wallecha, Anu / Maciag, Paulo Cesar / Rivera, Sandra / Paterson, Yvonne / Shahabi, Vafa

    Clinical and vaccine immunology : CVI

    2008  Volume 16, Issue 1, Page(s) 96–103

    Abstract: 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 ... ...

    Abstract 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 DeltaactA 142 strain expressing PSA). Despite limited in vivo survival, the dal dat DeltaactA 142 strain was able to elicit efficient immune responses required for tumor clearance. Our results showed that immunization of mice with the dal dat DeltaactA 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 DeltaactA 142 strain elicits a high frequency of PSA-specific immune responses. Interestingly, immunization with the dal dat DeltaactA 142 strain induced significant infiltration of PSA-specific T cells in the intratumoral milieu. Collectively, our data suggest that the dal dat DeltaactA 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.
    MeSH term(s) Adenocarcinoma/immunology ; Adenocarcinoma/pathology ; Adenocarcinoma/prevention & control ; Animals ; Cancer Vaccines/genetics ; Cancer Vaccines/immunology ; Gene Deletion ; Genes, Bacterial ; Immunotherapy/methods ; Listeria monocytogenes/genetics ; Listeria monocytogenes/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplasms/therapy ; Plasmids ; Prostate-Specific Antigen/genetics ; Prostate-Specific Antigen/immunology ; Survival Analysis ; Vaccines, Attenuated/genetics ; Vaccines, Attenuated/immunology
    Chemical Substances Cancer Vaccines ; Vaccines, Attenuated ; Prostate-Specific Antigen (EC 3.4.21.77)
    Language English
    Publishing date 2008-11-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2221082-9
    ISSN 1556-679X ; 1556-6811
    ISSN (online) 1556-679X
    ISSN 1556-6811
    DOI 10.1128/CVI.00274-08
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Development of a Listeria monocytogenes based vaccine against prostate cancer.

    Shahabi, Vafa / Reyes-Reyes, Mariela / Wallecha, Anu / Rivera, Sandra / Paterson, Yvonne / Maciag, Paulo

    Cancer immunology, immunotherapy : CII

    2008  Volume 57, Issue 9, Page(s) 1301–1313

    Abstract: Prostate specific antigen (PSA) is a likely immunotherapeutic target antigen for prostate cancer, the second leading cause of cancer-related death in American men. Previously, we demonstrated that attenuated strains of Listeria monocytogenes (Lm) can be ... ...

    Abstract Prostate specific antigen (PSA) is a likely immunotherapeutic target antigen for prostate cancer, the second leading cause of cancer-related death in American men. Previously, we demonstrated that attenuated strains of Listeria monocytogenes (Lm) can be used as effective vaccine vectors for delivery of tumor antigens causing regression of established tumors accompanied by strong immune responses toward these antigens in murine models of cancer. In the present study, we have developed and characterized a recombinant live attenuated L. monocytogenes/PSA (Lm-LLO-PSA) vaccine with potential use for the treatment of pCa. Human PSA gene was cloned into and expressed by an attenuated Lm strain. This recombinant bacterial vaccine, Lm-LLO-PSA was tested for stability, virulence, immunogenicity and anti-tumor effects in a murine model for pCa. Immunization with Lm-LLO-PSA was shown to lower the number of tumor infiltrating T regulatory cells and cause complete regression of over 80% of tumors formed by an implanted genetically modified mouse prostate adenocarcinoma cell line, which expressed human PSA. Lm-LLO-PSA was immunogenic in C57BL/6 mice and splenocytes from mice immunized with Lm-LLO-PSA showed significantly higher number of IFN-gamma secreting cells over that of the naïve animals in response to a PSA H2Db-specific peptide, as measured by both, ELISpot and intracellular cytokine staining. In addition, using a CTL assay we show that the T cells specific for PSA were able to recognize and lyse PSA-peptide pulsed target cells in vitro. In a comparison study with two other PSA-based vaccines (a pDNA and a vaccinia vaccine), Lm-LLO-PSA was shown to be more efficacious in regressing established tumors when used in a homologues prime/boost regimen. Together, these results indicate that Lm-LLO-PSA is a potential candidate for pCa immunotherapy and should be further developed.
    MeSH term(s) Animals ; Antigens, Neoplasm/chemistry ; Antineoplastic Agents/pharmacology ; Bacterial Toxins/chemistry ; Cancer Vaccines ; Heat-Shock Proteins/chemistry ; Hemolysin Proteins/chemistry ; Humans ; Immune System ; Immunotherapy/methods ; Listeria monocytogenes/metabolism ; Macrophages/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/therapy ; Virulence
    Chemical Substances Antigens, Neoplasm ; Antineoplastic Agents ; Bacterial Toxins ; Cancer Vaccines ; Heat-Shock Proteins ; Hemolysin Proteins ; hlyA protein, Listeria monocytogenes (R06ZRQ1YX9)
    Language English
    Publishing date 2008-02-14
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 195342-4
    ISSN 1432-0851 ; 0340-7004
    ISSN (online) 1432-0851
    ISSN 0340-7004
    DOI 10.1007/s00262-008-0463-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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