Cross-trial Analysis of Immunologic and Clinical Data Resulting From Phase I and II Trials of MVA-5T4 (TroVax) in Colorectal, Renal, and Prostate Cancer Patients

Harrop, Richard; Shingler, William; Kelleher, Michelle; Belin, Jackie de; Treasure, Peter

doi:10.1097/cji.0b013e3181f5dac7

Cited by 34 publications

(21 citation statements)

References 22 publications

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“…Immune-engagement with 5T4 was also studied. 5T4-specific antibodies were observed both in MPM patients and healthy donors, with higher levels in patients and similar to levels observed in other solid cancers [17]. In our study, the difference did not reach statistical significance, probably due to the relatively small number of samples and one high healthy responder.…”

Section: Discussionsupporting

confidence: 60%

“…In our study, the difference did not reach statistical significance, probably due to the relatively small number of samples and one high healthy responder. Furthermore, 5T4 antibody levels (without vaccination) had no prognostic value in prostate or colorectal carcinoma [17] and its significance in MPM is also unknown.…”

Section: Discussionmentioning

confidence: 94%

“…It has been tested in 500 patients in Phase I, II and III clinical trials in advanced colorectal, renal and prostate cancer. The vaccine was well tolerated and a positive association was observed between the level of vaccine-induced antibody responses and clinical outcome [17].…”

Section: Introductionmentioning

confidence: 98%

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Overexpression and potential targeting of the oncofoetal antigen 5T4 in malignant pleural mesothelioma

Al-Taei¹,

Salimu²,

Lester³

et al. 2012

Lung Cancer

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Malignant pleural mesothelioma (MPM) is resistant to conventional treatments. Novel, targeted treatments are hampered by the relative lack of MPM-associated tumour antigens. The aim of this study was to evaluate the level of expression and the relevance of 5T4 as a tumour-associated antigen in MPM. 5T4 expression was assessed by Western blotting, flow cytometry, immuno-cytochemistry and -histochemistry in 11 mesothelioma cell lines, 21 tumour biopsies, and ex vivo tumour cells obtained from the pleural fluid (PF) of 10 patients. 5T4 antibody levels were also determined in the plasma of patients and healthy donors. The susceptibility of MPM cells to 5T4-specific T-cell-mediated killing was determined using an HLA-A2(+), CD8(+) T-cell line, developed against the 5T4(17-25) peptide. We report here that cell surface 5T4 expression was detected in all mesothelioma cell lines and PF cell samples. Mesothelin and CD200, a suggested mesothelioma marker, were co-expressed with 5T4 on tumour cells in PF. Immunohistochemistry confirmed overexpression of 5T4, similar to mesothelin, on tumour cells but not on reactive stroma in all tissue sections tested. Median 5T4 antibody levels were 46% higher in patient than in healthy donor plasma, indicating immune recognition. Importantly, 5T4-specific CD8(+) T-cells were able to kill four out of six HLA-A2(+) MPM cell lines but not an HLA-A2(-) cell line, demonstrating immune recognition of MPM-associated 5T4 antigen at the effector T-cell level. We conclude that 5T4 is a potential new antigen for targeted therapies such as immunotherapy in MPM, as it is overexpressed on mesothelioma cells and recognised by 5T4-specific cytotoxic T-cells. Our findings have been translated into a Phase II clinical trial applying 5T4-targeted therapies in MPM patients.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 94%

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Overexpression and potential targeting of the oncofoetal antigen 5T4 in malignant pleural mesothelioma

Al-Taei¹,

Salimu²,

Lester³

et al. 2012

Lung Cancer

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“…However, 5T4 has been most advanced as a target for vaccines. A vaccine consisting of modified vaccinia virus vector encoding human 5T4 (MVA-h5T4, TroVax) has been tested in phase I and II clinical trials and shown to induce cellular and antibody immune responses in patients with advanced prostate, renal and colorectal cancer [16]. However, a randomized phase III trial failed to demonstrate a significant survival advantage in 365 metastatic renal cell carcinoma patients treated with TroVax as compared to 368 placebo control patients [17].…”

Section: Introductionmentioning

confidence: 97%

Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen: implications for immunotherapy

Castro

Al-Muftah

Mulryan

et al. 2011

Cancer Immunol Immunother

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Effective vaccination against tumour-associated antigens (TAA) such as the 5T4 oncofoetal glycoprotein may be limited by the nature of the T cell repertoire and the influence of immunomodulatory factors in particular T regulatory cells (Treg). Here, we identified mouse 5T4-specific T cell epitopes using a 5T4 knock out (5T4KO) mouse and evaluated corresponding wild-type (WT) responses as a model to refine and improve immunogenicity. We have shown that 5T4KO mice vaccinated by replication defective adenovirus encoding mouse 5T4 (Adm5T4) generate potent 5T4-specific IFN-γ CD8 and CD4 T cell responses which mediate significant protection against 5T4 positive tumour challenge. 5T4KO CD8 but not CD4 primed T cells also produced IL-17. By contrast, Adm5T4-immunized WT mice showed no tumour protection consistent with only low avidity CD8 IFN-γ, no IL-17 T cell responses and no detectable CD4 T cell effectors producing IFN-γ or IL-17. Treatment with anti-folate receptor 4 (FR4) antibody significantly reduced the frequency of Tregs in WT mice and enhanced 5T4-specific IFN-γ but reduced IL-10 T cell responses but did not reveal IL-17-producing effectors. This altered balance of effectors by treatment with FR4 antibody after Adm5T4 vaccination provided modest protection against autologous B16m5T4 melanoma challenge. The efficacy of 5T4 and some other TAA vaccines may be limited by the combination of TAA-specific T regs, the deletion and/or alternative differentiation of CD4 T cells as well as the absence of distinct subsets of CD8 T cells.

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Section: Tumour-associated Antigens In MMmentioning

confidence: 99%

The Role of Immunotherapy in the Treatment of Mesothelioma

Al-Taei¹,

Lester²,

Tabi³

2012

Mesotheliomas - Synonyms and Definition, Epidemiology, Etiology, Pathogenesis, Cyto-Histopathological Features, Clinic, Diagnos

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Cross-trial Analysis of Immunologic and Clinical Data Resulting From Phase I and II Trials of MVA-5T4 (TroVax) in Colorectal, Renal, and Prostate Cancer Patients

Cited by 34 publications

References 22 publications

Overexpression and potential targeting of the oncofoetal antigen 5T4 in malignant pleural mesothelioma

Overexpression and potential targeting of the oncofoetal antigen 5T4 in malignant pleural mesothelioma

Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen: implications for immunotherapy

The Role of Immunotherapy in the Treatment of Mesothelioma

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