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Bacteria biohybrid oral vaccines for colorectal cancer treatment reduce tumor growth and increase immune infiltration. Vaccine 2021; 39:5589-5599. [PMID: 34419301 DOI: 10.1016/j.vaccine.2021.08.028] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 07/14/2021] [Accepted: 08/06/2021] [Indexed: 11/22/2022]
Abstract
Bacteria biohybrid-based vaccine delivery systems, which integrate a vaccine carrier with live non-pathogenic bacteria, are hypothesized to have improved immunostimulating potential. The aim of this study was to develop oral bacteria biohybrid-based vaccines to treat a mouse model of colorectal cancer. E. coli were combined with tumor antigen- and adjuvant-containing emulsions or liposomes. Emulsion and liposome biohybrid vaccines demonstrated in vitro and in vivo therapeutic potential. Bacteria biohybrid vaccines significantly increased the expression of CD40+, CD80+ and CD86+ on murine bone marrow-derived dendritic cells. Mice vaccinated with emulsion biohybrid vaccines had an increased CD8+ T cell infiltration into tumors and developed three-fold smaller tumors compared to the mice that received emulsion vaccine without E. coli.
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Anti-IL-10-mediated Enhancement of Antitumor Efficacy of a Dendritic Cell-targeting MIP3α-gp100 Vaccine in the B16F10 Mouse Melanoma Model Is Dependent on Type I Interferons. J Immunother 2018; 41:181-189. [PMID: 29334492 PMCID: PMC5891382 DOI: 10.1097/cji.0000000000000212] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
The chemokine MIP3α (CCL20) binds to CCR6 on immature dendritic cells. Vaccines fusing MIP3α to gp100 have been shown to be effective in therapeutically reducing melanoma tumor burden and prolonging survival in a mouse model. Other studies have provided evidence that interleukin-10 (IL-10) neutralizing antibodies (αIL-10) enhance immunologic melanoma therapies by modulating the tolerogenic tumor microenvironment. In the current study, we have utilized the B16F10 syngeneic mouse melanoma model to demonstrate for the first time that a therapy neutralizing IL-10 enhances the antitumor efficacy of a MIP3α-gp100 DNA vaccine, leading to significantly smaller tumors, slower growing tumors, and overall increases in mouse survival. The additive effects of αIL-10 were not shown to be correlated to vaccine-specific tumor-infiltrating lymphocytes (TILs), total TILs, or regulatory T cells. However, we discovered an upregulation of IFNα-4 transcripts in tumors and a correlation of increased plasmacytoid dendritic cell numbers with reduced tumor burden in αIL-10-treated mice. Interferon α receptor knockout (IFNαR1) mice received no benefit from αIL-10 treatment, demonstrating that the additional therapeutic value of αIL-10 is primarily mediated by type I IFNs. Efficient targeting of antigen to immature dendritic cells with a chemokine-fusion vaccine provides an effective anticancer therapeutic. Combining this approach with an IL-10 neutralizing antibody therapy enhances the antitumor efficacy of the therapy in a manner dependent upon the activity of type I IFNs. This combination of a vaccine and immunomodulatory agent provides direction for future optimization of a novel cancer vaccine therapy.
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PBMC activation via the ERK and STAT signaling pathways enhances the anti-tumor activity of Staphylococcal enterotoxin A. Mol Cell Biochem 2017; 434:75-87. [DOI: 10.1007/s11010-017-3038-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 04/12/2017] [Indexed: 01/11/2023]
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Zhang G, Xu M, Zhang H, Song Y, Wang J, Zhang C. Up-regulation of granzyme B and perforin by staphylococcal enterotoxin C2 mutant induces enhanced cytotoxicity in Hepa1–6 cells. Toxicol Appl Pharmacol 2016; 313:1-9. [DOI: 10.1016/j.taap.2016.10.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 09/24/2016] [Accepted: 10/10/2016] [Indexed: 11/25/2022]
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Transcytosis, Antitumor Activity and Toxicity of Staphylococcal Enterotoxin C2 as an Oral Administration Protein Drug. Toxins (Basel) 2016; 8:toxins8060185. [PMID: 27322320 PMCID: PMC4926151 DOI: 10.3390/toxins8060185] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Accepted: 06/06/2016] [Indexed: 11/17/2022] Open
Abstract
Staphylococcal enterotoxin C2 (SEC2) is a classical superantigen (SAg), which can tremendously activate T lymphocytes at very low dosage, thus exerting its powerful antitumor activity. As an intravenous protein drug and a bacterial toxin, SEC2 has some limitations including poor patient compliance and toxic side effects. In this research, we devoted our attention to studying the antitumor activity and toxicity of SEC2 as a potential oral administration protein drug. We proved that His-tagged SEC2 (SEC2-His) could undergo facilitated transcytosis on human colon adenocarcinoma (Caco-2) cells and SEC2-His was detected in the blood of rats after oral administration. Furthermore, oral SEC2-His caused massive cytokine release and immune cell enrichment around tumor tissue, leading to inhibition of tumor growth in vivo. Meanwhile, although SEC2-His was dosed up to 32 mg/kg in mice, no significant toxicity was observed. These data showed that SEC2 can cross the intestinal epithelium in an immunologically integral form, maintaining antitumor activity but with reduced systemic toxicity. Therefore, these results may have implications for developing SEC2 as an oral administration protein drug.
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TNF-α produced by SEC2 mutant (SAM-3)-activated human T cells induces apoptosis of HepG2 cells. Appl Microbiol Biotechnol 2015; 100:2677-84. [DOI: 10.1007/s00253-015-7104-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 10/13/2015] [Accepted: 10/14/2015] [Indexed: 10/22/2022]
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7
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Staphylococcal enterotoxin C2 promotes osteogenesis and suppresses osteoclastogenesis of human mesenchymal stem cells. Exp Cell Res 2014; 322:202-7. [DOI: 10.1016/j.yexcr.2013.12.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 11/17/2013] [Accepted: 12/05/2013] [Indexed: 12/20/2022]
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Liu Y, Xu M, Zhang H, Li X, Su Z, Zhang C. SEC2-induced superantigen and antitumor activity is regulated through calcineurin. Appl Microbiol Biotechnol 2013; 97:9695-703. [PMID: 23435984 DOI: 10.1007/s00253-013-4764-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2013] [Revised: 02/04/2013] [Accepted: 02/07/2013] [Indexed: 12/22/2022]
Abstract
Once the TCR-SAg-MHC II ternary complex is established, it triggers a variety of intracellular signal transduction pathways, which provoke extreme responses in the immune system. However, the signaling events that involved in SAg-induced immune activation are not well understood. In this study, we demonstrated that the Ca(2+)/calcineurin (CaN)/nuclear factor of activated T cells (NFAT) signaling pathway was involved in SEC2-induced immune activation, and selective blockade of CaN by its inhibitor cyclosporine A (CsA) can completely inhibited the SEC2-induced T-cell stimulating potency. In addition, we selected an engineered SEC2 mutant named SAM-1 based on a series of biological activity tests, and our further studies on it not only confirmed that the CaN activity and gene transcription of its key substrates were proportional to the SEC2/SAM-1-induced T-cell stimulating potency, but also suggested that intensified Ca(2+)/CaN/NFAT signaling transduction induced by SAM-1 resulted in enhanced T-cell stimulating potency, production of cytokines and cytotoxicity, which finally elicit the improved antitumor activity of SAM-1 in vivo.
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Affiliation(s)
- Yanli Liu
- Institute of Applied of Ecology, Chinese Academy of Sciences, No.72 Wenhua Road Shenhe Dis, P.O. Box 417, 110016, Shenyang, Liaoning, People's Republic of China
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Liu Y, Xu M, Su Z, Cai Y, Zhang G, Zhang H. Increased T-cell stimulating activity by mutated SEC2 correlates with its improved antitumour potency. Lett Appl Microbiol 2012; 55:362-9. [PMID: 22925007 DOI: 10.1111/j.1472-765x.2012.03303.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
AIMS To investigate the improved antitumour activity of SAM-3 compared with recombinant staphylococcal enterotoxins C2 (rSEC2). METHODS AND RESULTS Methylthiazol tetrazolium and flow cytometry assays showed that the antitumour activity of SAM-3 in vivo was improved because of enhanced T-cell stimulating potency, resulting in massive activation of T cells, particularly CD4(+) and CD8(+) T cells, and subsequent cytokine release. Quantitative real-time PCR assay showed that despite similar Vβ specificities induced by rSEC2 and SAM-3, the quantities of activated T cells bearing specific Vβin vitro were different. CONCLUSIONS The results strongly suggested that the increased SAM-3-T-cell receptor (TCR) binding affinity contributed to massive T-cell activation and cytokine release, substantially amplifying antitumour immune response in vivo. SIGNIFICANCE AND IMPACT OF THE STUDY This study provided evidence for the mechanism of SAM-3 antitumour activity improvement compared with rSEC2. Results indicated that SAM-3 could be used as a potent powerful candidate agent for tumour treatment in clinics.
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Affiliation(s)
- Y Liu
- Microbiology Resources, Institute of Applied Ecology, Chinese Academy of Science, Shenyang, China College of Resource and Environment, Graduate University of Chinese Academy of Sciences, Beijing, China Center for Drug Evaluation and Research, Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - M Xu
- Microbiology Resources, Institute of Applied Ecology, Chinese Academy of Science, Shenyang, China College of Resource and Environment, Graduate University of Chinese Academy of Sciences, Beijing, China Center for Drug Evaluation and Research, Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - Z Su
- Microbiology Resources, Institute of Applied Ecology, Chinese Academy of Science, Shenyang, China College of Resource and Environment, Graduate University of Chinese Academy of Sciences, Beijing, China Center for Drug Evaluation and Research, Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - Y Cai
- Microbiology Resources, Institute of Applied Ecology, Chinese Academy of Science, Shenyang, China College of Resource and Environment, Graduate University of Chinese Academy of Sciences, Beijing, China Center for Drug Evaluation and Research, Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - G Zhang
- Microbiology Resources, Institute of Applied Ecology, Chinese Academy of Science, Shenyang, China College of Resource and Environment, Graduate University of Chinese Academy of Sciences, Beijing, China Center for Drug Evaluation and Research, Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - H Zhang
- Microbiology Resources, Institute of Applied Ecology, Chinese Academy of Science, Shenyang, China College of Resource and Environment, Graduate University of Chinese Academy of Sciences, Beijing, China Center for Drug Evaluation and Research, Tianjin Institute of Pharmaceutical Research, Tianjin, China
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Jia D, Rao W, Wang C, Jin C, Wang S, Chen D, Zhang M, Guo J, Chang Z, Liu J. Inhibition of B16 murine melanoma metastasis and enhancement of immunity by fever-range whole body hyperthermia. Int J Hyperthermia 2011; 27:275-85. [PMID: 21501029 DOI: 10.3109/02656736.2011.559613] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
PURPOSE Whole body hyperthermia (WBH) has been regarded as a promising alternative therapy to cure late stage cancer with metastasis. As the final biological and therapeutic effects are dependent on the specific protocol, the potential of using a microwave-based WBH approach for metastasis inhibition is established and its typical results are discussed. MATERIALS AND METHODS The effectiveness of a 30-min whole body hyperthermia (WH) on animals, raised to a rectal temperature of 40.2° ± 0.3°C for 30 min followed by 84 h observation by 2450 MHz microwave irradiation, were evaluated. In an experimental lung metastasis model by injection of B16-F10 melanoma, lungs were removed from sacrificed mice 16 days after tumour implantation, and the expression of heat shock protein, inter-cellular adhesion molecule 1 (ICAM-1), proliferating cell nuclear antigen (PCNA) and cyclin D(1) was examined. CD4(+), CD8(+) and NK cell subpopulation in peripheral blood were measured by flow cytometry before and after the last treatment. RESULTS The best therapeutic effect was obtained when the mice were treated with WBH in combination with the initial chemotherapy with cis-diaminodichloroplatinum (CDDP) and dacarbazine (DTIC) (p < 0.05). The WBH alone has an advantage of reduced toxicity and lower cost. Heat shock protein (HSP) expression increased in the hyperthermia groups. Reduction of PCNA and cyclin D(1) was observed in the mice treated with WH alone or in combination with chemotherapy. In the hyperthermia groups, CD4(+)/CD8(+) decreased while the NK increased slightly. CONCLUSIONS The whole body hyperthermia protocol described in this work inhibits B16 tumour metastasis by inhibiting cell proliferation, neovascularisation and stimulating favourable immune responses. It demonstrated that WBH treatment benefits therapy of metastasis cancers.
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Affiliation(s)
- Dewei Jia
- Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, P.R. China
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Superantigens increase the survival of mice bearing T cell lymphomas by inducing apoptosis of neoplastic cells. PLoS One 2010; 5:e15694. [PMID: 21203530 PMCID: PMC3008744 DOI: 10.1371/journal.pone.0015694] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2010] [Accepted: 11/23/2010] [Indexed: 11/29/2022] Open
Abstract
Superantigens bind to major histocompatibility complex class II molecules and interact with T cells expressing a particular T cell receptor Vβ inducing a strong proliferation/deletion response of the superantigen-reactive T cells. However, there have been no attempts to investigate the ability of Sags to induce apoptosis in neoplastic T cells by signaling through the Vβ region of their TCR. In the present study we show that bacterial and MMTV-encoded superantigens induce the apoptosis of AKR/J cognate lymphoma T cells both in vitro and in vivo. The Fas-Fas-L pathway was shown to be involved in the apoptosis of lymphoma T cells induced by bacterial superantigens. In vivo exposure to bacterial superantigens was able to improve the survival of lymphoma bearing mice. Moreover, the permanent expression of a retroviral encoded superantigen induced the complete remission of an aggressive lymphoma in a high percentage of mice. The possibility of a therapeutic use of superantigens in lymphoma/leukemia T cell malignancies is discussed.
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Wang HR, Jiang H, Hao HJ, Zheng YL, Jie KG, Gu J, Jiang YQ. In vivo and in vitro antitumor effects of a staphylococcal enterotoxin A mutant (SEA-H61D). Cancer Invest 2010; 28:788-96. [PMID: 20504220 DOI: 10.3109/07357900903286982] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
In this study, we evaluated SEA-H61D, a staphylococcal enterotoxin A mutant without emetic activity, as an antitumor agent in vitro and in vivo. It showed that SEA-H61D could significantly inhibit the growth of many cancer cell lines in vitro at very low concentrations by activating human peripheral blood mononuclear cells (PBMCs). CD4+ and CD8+ T lymphocytes could be activated at a dose between 125 and 500 μg/kg. Systemic administration of SEA-H61D in vivo significantly inhibited tumor growth, with the treated group undergoing tumor necrosis and showing a strong infiltration of lymphocytes to the tumor area.
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Affiliation(s)
- Hai-Rong Wang
- State Key Laboratory of Pathogen and Biosecurity, The Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China
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Cheng X, Cao P, Ji X, Lu W, Cai X, Hu C, Wang Z, Zhang S. Antitumour response of a double mutant of staphylococcal enterotoxin C2 with the decreased affinity for MHC class II molecule. Scand J Immunol 2010; 71:169-75. [PMID: 20415782 DOI: 10.1111/j.1365-3083.2009.02359.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Staphylococcal enterotoxin C2 (SEC2) is one of the most potent known activators of human T lymphocytes, and recombinant SEC2 shows promising clinical values, but SEC2 can cause food poisoning and toxic shock syndrome in vivo. In this study, site-directed mutagenesis has been used to introduce alanine substitutions at Phe144 and Leu45 in the molecule. The mutant genes were cloned and expressed, and the corresponding proteins were purified by nickel agarose affinity chromatography. We found that the SEC2 mutant proteins could stimulate the proliferation of human peripheral blood lymphocytes and inhibit the growth of tumour cells as native SEC2. Furthermore, flow cytometry assay showed that mSEC2(F44A, L45A) drastically reduced the ability of the toxin to bind to MHC class II. Physiological parameters revealed that mSEC2(F44A, L45A) reduced significantly rat temperature compared with native SEC2 in vivo. Our results clearly suggest that this genetically modified SEC2 protein is less toxic and justifies its further development as a new, safer antitumour superantigen to prevent SEC2 intoxication.
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Affiliation(s)
- X Cheng
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, Life Sciences College, Nanjing Normal University, Nanjing, Jiangsu, China
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Yu J, Tian R, Xiu B, Yan J, Jia R, Zhang L, Chang AE, Song H, Li Q. Antitumor activity of T cells generated from lymph nodes draining the SEA-expressing murine B16 melanoma and secondarily activated with dendritic cells. Int J Biol Sci 2009; 5:135-46. [PMID: 19173035 PMCID: PMC2631223 DOI: 10.7150/ijbs.5.135] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2009] [Accepted: 01/19/2009] [Indexed: 01/21/2023] Open
Abstract
The successful use of tumor-draining lymph nodes (TDLN) as a source of effector cells for cancer immunotherapy depends largely on the immunogenicity of the tumor drained by the lymph nodes as well as the methods for secondary in vitro T cell activation and expansion. We transferred the bacterial superantigen staphylococcal enterotoxin A (SEA) gene into B16 murine melanoma tumor cells, and used them to induce TDLN (SEA TDLN) in syngeneic hosts. Wild-type (wt) TDLN induced by parental B16 tumor was used as a control. In vitro, SEA TDLN cells proliferated more vigorously, produced more IFNγ and demonstrated higher CTL activity than wt TDLN cells when activated with anti-CD3/anti-CD28/IL-2. In vivo, SEA TDLN cells mediated tumor eradication more effectively than similarly activated wt TDLN cells (p<0.01). Furthermore, use of dendritic cells (DC) plus tumor antigen in vitro in addition to anti-CD3/anti-CD28/IL-2 stimulation further amplified the immune function and therapeutic efficacy of SEA TDLN cells. DC-stimulated SEA TDLN cells eliminated nearly 90% of the pulmonary metastasis in mice bearing established B16 melanoma micrometastases. These results indicate that enforced expression of superantigen SEA in poorly immunogenic tumor cells can enhance their immunogenicity as a vaccine in vivo. The combined use of genetically modified tumor cells as vaccine to induce TDLN followed by secondary stimulation using antigen-presenting cells and tumor antigen in a sequential immunization/activation procedure may represent a unique method to generate more potent effector T cells for adoptive immunotherapy of cancer.
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Affiliation(s)
- Jiyun Yu
- Institute of Basic Medical Sciences, Academy of Military Medical Sciences, Beijing, China
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15
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Minimally invasive treatment combined with cytokine-induced killer cells therapy lower the short-term recurrence rates of hepatocellular carcinomas. J Immunother 2008; 31:63-71. [PMID: 18157013 DOI: 10.1097/cji.0b013e31815a121b] [Citation(s) in RCA: 120] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The recurrence of hepatocellular carcinoma (HCC) after minimally invasive therapy is frequent. Adoptive immunotherapy is thought to be an effective method to lower recurrence and metastasis rates of malignant tumors. Therefore, 85 HCC patients after transcatheter arterial chemoembolization and radiofrequency ablation therapy were randomized to immunotherapy group and no adjuvant therapy group. Autologous cytokine-induced killer (CIK) cells were transfused via hepatic artery to the patients. The alteration of levels of lymphocyte subsets in peripheral blood of patients was examined by flow cytometry. All patients were screened by computed tomography every 2 months to observe the tumor recurrent conditions. After CIK cell infusions, the percentages of CD3+, CD4+, CD56+, CD3+CD56+ cells, and CD4+/CD8+ ratio increased from 68.6+/-11.0%, 31.1+/-9.0%, 15.6+/-7.9%, 5.2+/-3.1%, and 1.1+/-0.5 to 70.7+/-10.1%, 33.5+/-8.0%, 18.4+/-9.4%, 5.9+/-2.8%, and 1.3+/-0.7, respectively (P<0.05); whereas the percentage of CD8 cells decreased from 31.1+/-7.8% to 28.6+/-8.3% (P<0.05). The 1-year and 18-month recurrence rates of the study group were 8.9% and 15.6%, compared with 30.0% and 40.0% of the control group (both P value<0.05). The data suggest that CIK cell transfusion is an effective treatment. It can boost the immunologic function in HCC patients and plays an important role in reducing the recurrence rate of HCC.
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Sundstedt A, Celander M, Hedlund G. Combining tumor-targeted superantigens with interferon-alpha results in synergistic anti-tumor effects. Int Immunopharmacol 2008; 8:442-52. [DOI: 10.1016/j.intimp.2007.11.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2007] [Revised: 11/07/2007] [Accepted: 11/07/2007] [Indexed: 11/16/2022]
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Shaw DM, Connolly NB, Patel PM, Kilany S, Hedlund G, Nordle O, Forsberg G, Zweit J, Stern PL, Hawkins RE. A phase II study of a 5T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma. Br J Cancer 2007; 96:567-74. [PMID: 17285137 PMCID: PMC2360042 DOI: 10.1038/sj.bjc.6603567] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
In a phase II study, 43 renal cell carcinoma patients were treated with individualised doses of ABR-214936; a fusion of a Fab recognising the antigen 5T4, and Staphylococcal enterotoxin A. Drug was given intravenously on 4 consecutive days, treatment was repeated 1 month later. Treatment was associated with moderate fever and nausea, but well tolerated. Of 40 evaluable patients, 28 had disease control at 2 months, and at 4 months, one patient showed partial response (PR) and 16 patients stable disease. Median survival, with minimum follow-up of 26 months was 19.7 months with 13 patients alive to date. Stratification by the Motzer's prognostic criteria highlights prolonged survival compared to published expectation. Patients receiving higher drug exposure had greater disease control and lived almost twice as long as expected, whereas the low-exposure patients survived as expected. Sustained interleukin-2 (IL-2) production after a repeated injection appears to be a biomarker for clinical effect, as the induced-IL-2 level on the day 2 of treatment correlated with survival. The high degree of disease control and the prolonged survival suggest that this treatment can be effective. These findings will be used in the trial design for the next generation of drug, with reduced antigenicity and toxicity.
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Affiliation(s)
- D M Shaw
- Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK.
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Huang C, Yu H, Wang Q, Yang G, Ma W, Xia D, Chen X, Yi P, Shen F, Zheng H, Cao X. A novel anticancer approach: SEA-anchored tumor cells expressing heat shock protein 70 onto the surface elicit strong anticancer efficacy. Immunol Lett 2005; 101:71-80. [PMID: 15908014 DOI: 10.1016/j.imlet.2005.04.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2005] [Accepted: 04/11/2005] [Indexed: 10/25/2022]
Abstract
Heat shock proteins (HSP) are attractive for their initiation of anticancer specific immunity via a distinct mechanism. To facilitate the induction process, we targeted HSP onto vaccine cell surface genetically. Then, SEA (a typical superantigen) was anchored on the cells by its fusion protein with transmembrane sequence, in order to produce immune-activated microsurrounding for further improvement of specific immunity. Thereby, the dual-modified vaccine, the surface-targeting-HSP70 and SEA-anchored vaccine, was developed successfully. Both in a therapeutic setting and in a pre-immune model, the mice vaccinated with the dual-modified vaccine displayed significant lymphocyte proliferation, higher NK and CTL activity, marked tumor suppression and prolonged survival when compared with those vaccinated with the vaccine modified alone with surface-targeting HSP70 or the SEA-anchored vaccine. Of all the vaccines, the dual-modified vaccine generated the best therapeutic efficacy on melanoma-bearing mice, the strongest protection against melanoma challenge. These results suggested that the dual-modified vaccine could induce more potent anticancer specific immunity while non-specific immunity was augmented.
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MESH Headings
- Animals
- Cancer Vaccines/administration & dosage
- Cancer Vaccines/biosynthesis
- Cancer Vaccines/genetics
- Cancer Vaccines/immunology
- Cell Line, Tumor
- Cell Membrane/genetics
- Cell Membrane/immunology
- Cell Membrane/metabolism
- Enterotoxins/metabolism
- Female
- HSP70 Heat-Shock Proteins/administration & dosage
- HSP70 Heat-Shock Proteins/biosynthesis
- HSP70 Heat-Shock Proteins/genetics
- HSP70 Heat-Shock Proteins/immunology
- Immunotherapy, Adoptive
- Male
- Melanoma, Experimental/genetics
- Melanoma, Experimental/immunology
- Melanoma, Experimental/metabolism
- Melanoma, Experimental/therapy
- Mice
- Mice, Inbred C57BL
- Transfection
- Vaccines, Synthetic/administration & dosage
- Vaccines, Synthetic/biosynthesis
- Vaccines, Synthetic/genetics
- Vaccines, Synthetic/immunology
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Perabo FGE, Willert PL, Wirger A, Schmidt DH, Wardelmann E, Sitzia M, von Ruecker A, Mueller SC. Preclinical evaluation of superantigen (staphylococcal enterotoxin B) in the intravesical immunotherapy of superficial bladder cancer. Int J Cancer 2005; 115:591-8. [PMID: 15704106 DOI: 10.1002/ijc.20941] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Superantigens are potent activators of T lymphocytes; therefore, their characteristics can be exploited in diseases where immunomodulation is known to be effective. In this study, we evaluated a new approach for the intravesical therapy of superficial bladder cancer. We investigated in coculture experiments if staphylococcal enterotoxin B (SEB)-activated PBMCs are able to induce apoptosis in human transitional cell carcinoma (TCC) cells. Additionally, we tested the toxicity and efficacy of SEB dissolved in NaCl 0.9% administered intravesically once weekly for 6 weeks in a rat bladder cancer model. To validate the coculture in vitro findings, we evaluated tumor stage, grade, apoptotic cells in the urothelium and stroma of the bladder and infiltration of the bladder wall by lymphocytes, macrophages and mononuclear cells. Coculture experiments revealed that SEB-activated PBMCs are able to kill TCC cells by inducing apoptosis. The intravesical toxicity study with a maximum dose of 100 microg/ml SEB demonstrated no side effects. In the intravesically SEB-treated animals (10 microg/ml), only 3 tumors remained vs. 15 persisting tumors in the control group. The remaining tumors of the therapy group showed a significant amount of apoptosis and granulocytes, mainly in the urothelium, whereas no relevant apoptosis or infiltration of the bladder with lymphocytes or macrophages was found in the control group. These preclinical findings suggest that SEB might be an interesting candidate for further clinical evaluation.
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Dermime S, Gilham DE, Shaw DM, Davidson EJ, Meziane EK, Armstrong A, Hawkins RE, Stern PL. Vaccine and antibody-directed T cell tumour immunotherapy. Biochim Biophys Acta Rev Cancer 2004; 1704:11-35. [PMID: 15238242 DOI: 10.1016/j.bbcan.2004.03.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2003] [Revised: 01/22/2004] [Accepted: 03/31/2004] [Indexed: 10/26/2022]
Abstract
Clearer evidence for immune surveillance in malignancy and the identification of many new tumour-associated antigens (TAAs) have driven novel vaccine and antibody-targeted responses for therapy in cancer. The exploitation of active immunisation may be particularly favourable for TAA where tolerance is incomplete but passive immunisation may offer an additional strategy where the immune repertoire is affected by either tolerance or immune suppression. This review will consider how to utilise both active and passive types of therapy delivered by T cells in the context of the failure of tumour-specific immunity by presenting cancer patients. This article will outline the progress, problems and prospects of several different vaccine and antibody-targeted approaches for immunotherapy of cancer where proof of principle pre-clinical studies have been or will soon be translated into the clinic. Two examples of vaccination-based therapies where both T cell- and antibody-mediated anti-tumour responses are likely to be relevant and two examples of oncofoetal antigen-specific antibody-directed T cell therapies are described in the following sections: (1) therapeutic vaccination against human papillomavirus (HPV) antigens in cervical neoplasia; (2) B cell lymphoma vaccines including against immunoglobulin idiotype; (3) oncofoetal antigens as tumour targets for redirecting T cells with antibody strategies.
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Affiliation(s)
- Said Dermime
- Immunology, Cancer Research UK Groups, Paterson Institute for Cancer Research and University of Manchester, Christie Hospital NHS Trust, Manchester M20 4BX, UK
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Huang C, Yu H, Wang Q, Ma W, Xia D, Yi P, Zhang L, Cao X. Potent antitumor effect elicited by superantigen-linked tumor cells transduced with heat shock protein 70 gene. Cancer Sci 2004; 95:160-167. [PMID: 14965367 PMCID: PMC11159597 DOI: 10.1111/j.1349-7006.2004.tb03198.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2003] [Revised: 11/27/2003] [Accepted: 11/28/2003] [Indexed: 11/26/2022] Open
Abstract
Heat shock proteins (HSP) induce antitumor-specific immunity via a unique mechanism, but HSP alone fails to produce a satisfactory antitumor efficacy. We considered that the potent immune-activation of superantigen (SAg) might assist HSP to elicit a strong tumor-antigen-specific immunity. We initially prepared B16 melanoma cells linked to SAg SEA via a fusion protein with a transmembrane sequence (TM), and demonstrated that SEA thus anchored on the tumor cell surface could elicit strong antitumor immunity. We then prepared cells transduced with an inducible heat shock protein 70 (HSP70) gene, and bearing SEA-TM fusion protein on the cell surface, and used these cells as a dual-modified vaccine. In this study, either in a therapeutic setting or in a pre-immune model, the SEA-anchored vaccine or the HSP70 gene-modified vaccine induced marked tumor suppression, prolonged survival, augmented lymphocyte proliferation and higher NK and CTL activity in C57BL/6 mice compared with their controls (P < 0.01), though they were less effective than the dual-modified vaccine. Among these vaccines, the dual-modified vaccine showed the best therapeutic efficacy in B16 melanoma-bearing mice and gave the greatest protection against wild-type B16 melanoma challenge. The results indicated that the dual-modified vaccine could induce a potent tumor-antigen-specific immune response in addition to an increase of non-specific immunity. This study offers a novel approach to bridging specific and non-specific immunity for cancer therapy.
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Affiliation(s)
- Changxin Huang
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, P. R. China
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22
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Kaplan MJ, Lewis EE, Shelden EA, Somers E, Pavlic R, McCune WJ, Richardson BC. The apoptotic ligands TRAIL, TWEAK, and Fas ligand mediate monocyte death induced by autologous lupus T cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2002; 169:6020-9. [PMID: 12421989 DOI: 10.4049/jimmunol.169.10.6020] [Citation(s) in RCA: 139] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Individuals with systemic lupus erythematosus show evidence of a significant increase in monocyte apoptosis. This process is mediated, at least in part, by an autoreactive T cell subset that kills autologous monocytes in the absence of nominal Ag. We have investigated the apoptotic pathways involved in this T cell-mediated process. Expression of the apoptotic ligands TRAIL, TNF-like weak inducer of apoptosis (TWEAK), and Fas ligand on lupus T cells was determined, and the role of these molecules in the monocyte apoptotic response was examined. We report that these apoptotic ligands mediate the autologous monocyte death induced by lupus T cells and that this cytotoxicity is associated with increased expression of these molecules on activated T cells, rather than with an increased susceptibility of lupus monocytes to apoptosis induced by these ligands. These results define novel mechanisms that contribute to increased monocyte apoptosis characterizing patients with lupus. We propose that this mechanism could provide a source of potentially antigenic material for the autoimmune response and interfere with normal clearing mechanisms.
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Affiliation(s)
- Mariana J Kaplan
- Department of Internal Medicine, University of Michigan, 1150 West Medical Center Drive, 5220 Medical Science Research Building I, Ann Arbor, MI 48109, USA.
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Mondal TK, Bhatta D, Ray PK, Pal P. Synergistic immunopotentiating effects induced by T-cell and B-cell superantigen in mice. Immunol Invest 2001; 30:169-80. [PMID: 11570638 DOI: 10.1081/imm-100105062] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Staphylococcal Enterotoxin-A(SEA), a 27kDa monomeric protein, produced by some strains of Staphylococcus aureus, is a prototype T-cell superantigen which causes proliferation of cytotoxic T-lymphocytes and produces cytokines like TNF-alpha and IFN-gamma. Recently Protein A (PA), a 42 kDa membrane protein of the Staphylococcus aureus Cowan-I strain, has been termed a B-cell super antigen. It has been shown to cause multiple immunological responses. In the present study we examined the effect of these two superantigens used separately as well as combination in a normal mouse system. It has been shown that combination treatment of PA and SEA is more effective than that of each individual one. FACS analyses of cell cycles showed that a finely turned cellular collaboration occurred in various phases of cell growth and proliferative response compared with controls (P<0.01). It has also been shown that the percentage of various cell types bearing different clusters of differentiation markers, e.g., CD8+, CD34+ increases considerably due to the combined effect of PA and SEA. We also observed that co-administration of both the elicits different soluble mediators like cytokines (TNF-alpha, INF-gamma, IL-1beta). No apoptotic phenomenon was observed (from the cell cycle analysis) for the dose of PA and SEA, used for the experiments, suggesting that these doses of PA and SEA should be non-toxic.
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Affiliation(s)
- T K Mondal
- Immunotechnology Section, Bose Institute, Calcutta, India
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Wang Q, Yu H, Ju DW, He L, Pan JP, Xia DJ, Zhang LH, Cao X. Intratumoral IL-18 gene transfer improves therapeutic efficacy of antibody-targeted superantigen in established murine melanoma. Gene Ther 2001; 8:542-50. [PMID: 11319621 DOI: 10.1038/sj.gt.3301428] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2000] [Accepted: 01/15/2001] [Indexed: 01/12/2023]
Abstract
Antibody-targeted superantigen C215Fab-SEA is a fusion protein of staphylococcal enterotoxin A (SEA) and the Fab region of the tumor-reactive C215 mAb. It can trigger CTL against C215 antigen-positive tumor cells and induce tumor-suppressive cytokines. However, the antitumor effect of C215Fab-SEA is not satisfactory because of suboptimal production of Th1 cytokines after repeated administration. Interleukin 18 (IL-18) is a novel cytokine with profound effects on Th1 cellular response. In this study, we showed that adenovirus-mediated intratumoral IL-18 gene transfer strongly improved the therapeutic efficacy of C215Fab-SEA in the pre-established C215 antigen-expressing B16 melanoma murine model. More significant tumor inhibition and prolonged survival time were observed in tumor-bearing mice received combined therapy of C215Fab-SEA and Ad IL-18 than those of mice treated with C215Fab-SEA or AdIL-18 alone. Combination therapy augmented NK and CTL activities of tumor-bearing mice more markedly. The production of IL-2 and IFN-gamma also increased more significantly. More potent antitumor effect of combined therapy was observed in IL-10 KO mice with enhanced Th1 response. Our data demonstrated that the antitumor effect of C215Fab-SEA immunotherapy could be potentiated significantly by combination with intratumoral IL-18 gene transfer through more efficient activation of Th1 immune responses.
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Affiliation(s)
- Q Wang
- Institute of Immunology, Zhejiang University, 353 Yan'an Road, Hangzhou, 310031, PR China
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Yang LJ, Sui YF, Chen ZN. Preparation and activity of conjugate of monoclonal antibody HAb18 against hepatoma F(ab')(2) fragment and staphylococcal enterotoxin A. World J Gastroenterol 2001; 7:216-21. [PMID: 11819763 PMCID: PMC4723525 DOI: 10.3748/wjg.v7.i2.216] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2000] [Revised: 11/28/2000] [Accepted: 11/30/2000] [Indexed: 02/06/2023] Open
Abstract
AIM To prepare the conjugate of staphylococcal enterotoxin A (SEA) protein which is a bacterial SAg and the F(ab')(2) fragment of mAb HAb18 against human hepatocellular carcinoma (HCC), and identify its activity in order to use SAg in the targeting therapy of HCC. METHODS MAb HAb18 was extracted from the abdominal dropsy of Balb/c mice, and was purified through chromatography column SP 40HR with Fast protein liquid chromatography (FPLC) system. The F(ab')(2) fragment of mAb HAb18 was prepared by papainic digestion method. The conjugate of mAb HAb18 F(ab')(2) fragment and SEA was prepared with chemical conjugating reagent N succinimidyl 3 (2-pyridyldithio) propionate (SPDP) and purified through chromatography column Superose 12 with FPLC system. The molecular mass and purity of each collected peak were identified with SDS-PAGE assay. The protein content was assayed by Lowry's method. The antibody activity of HAb18 F(ab')(2) against HCC in the conjugate was identified by indirect immunocytochemical ABC method, and the activity of SEA in the conjugate to activate peripheral blood mononuclear cells (PBMC) was identified with MTT assay. RESULTS The IgG mAb HAb18 was extracted, and purified successfully. Immunocytochemical staining demonstrated that it reacted with most of HHCC cells of human HCC cell line. There were two peaks in the process of purification of the prepared HAb18 F(ab')(2) SEA conjugate. SDS-PAGE assay demonstrated that the molecular mass of the first peak was about 130 ku, and the second peak was the mixture of about 45 ku and a little 100 ku proteins. The immunocytochemical staining was similar in HAb18 F(ab') (2) SEA conjugate and HAb18 F(ab') (2), i.e.the cytoplasm and/or cell membranes of most HHCC cells were positively stained. The MTT assay showed that the optical absorbance (A) value at 490 nm of HAb18 F(ab') (2) SEA conjugate was 0.182 +/- 0.012, that of negative control was 0.033 +/- 0.009, and there was significant difference between them (P < 0.05). CONCLUSION SPDP is a good protein conjugating reagent and can be used in preparing protein conjugate. The conjugate of mAb HAb18 F(ab') (2) fragment and SEA protein was prepared successfully in present study and can be used in the experimental study of HCC targeting therapy with the conjugate of SAg and anti HCC mAbs or their fragments.
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Affiliation(s)
- L J Yang
- Department of Pathology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province,China.
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