WT1-targeted immunotherapy of leukaemia

Xue, Sa; Gao, Liquan; Gillmore, Roopinder; Bendle, Gavin; Holler, Angelika; Downs, Anne-Marie; Tsallios, A; Ramı́rez, Francisco; Ghani, Yasmeen; Hart, D.; Alcock, Sally; Tranter, Amy; Stauss, Hans J.; Morris, Emma

doi:10.1016/j.bcmd.2004.08.018

Cited by 19 publications

(13 citation statements)

References 28 publications

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“…Furthermore, as the full-length cDNA of the Ag is expressed in the bacteria, the vaccine is unlikely to be restricted to a specific HLA haplotype in humans. Current work in our laboratory in the context of tumor Ags that are self Ags has demonstrated that vaccination with recombinant E. coli LLO expressing the Wilm's tumor 1 Ag (WT-1) (45,46) led to a significant control of WT-1-expressing tumors in C57BL/6J mice, correlated to specific CTL responses and Treg functional defect (J. Nitcheu-Tefit, M. S. Dai, and G. Vassaux, unpublished observations). Based on these results, it is possible to envisage the use of this system in humans.…”

Section: Discussionmentioning

confidence: 99%

Listeriolysin O Expressed in a Bacterial Vaccine Suppresses CD4+CD25high Regulatory T Cell Function In Vivo

Nitcheu-Tefit

Dai

Critchley-Thorne

et al. 2007

The Journal of Immunology

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CD4+CD25high regulatory T cells (Treg) protect the host from autoimmune diseases but are also obstacles against cancer therapies. An ideal cancer vaccine would stimulate specific cytotoxic responses and reduce/suppress Treg function. In this study, we showed that Escherichia coli expressing listeriolysin O and OVA (E. coli LLO/OVA) demonstrated remarkable levels of protection against OVA-expressing tumor cells. By contrast, E. coli expressing OVA only (E. coli OVA) showed poor protection. High-avidity OVA-specific CTL were induced in E. coli LLO/OVA-vaccinated mice, and CD8+ depletion—but not NK cell depletion, abolished the antitumor activity of the E. coli LLO/OVA vaccine. Phenotypic analysis of T cells following vaccination with either vaccine revealed preferential generation of CD44highCD62Llow CD8+ effector memory T cells over CD44highCD62Lhigh central memory T cells. Unexpectedly, CD4+ depletion turned E. coli OVA into a vaccine as effective as E. coli LLO/OVA suggesting that a subset of CD4+ cells suppressed the CD8+ T cell-mediated antitumor response. Further depletion experiments demonstrated that these suppressive cells consisted of CD4+CD25high regulatory T cells. We therefore assessed these vaccines for Treg function and found that although CD4+CD25high expansion and Foxp3 expression within this population was similar in all groups of mice, Treg cells from E. coli LLO/OVA-vaccinated animals were unable to suppress conventional T cells proliferation. These findings provide the first evidence that LLO expression affects Treg cell function and may have important implications for enhancing antitumor vaccination strategies in humans.

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Section: Discussionmentioning

confidence: 99%

Listeriolysin O Expressed in a Bacterial Vaccine Suppresses CD4+CD25high Regulatory T Cell Function In Vivo

Nitcheu-Tefit

Dai

Critchley-Thorne

et al. 2007

The Journal of Immunology

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“…With the confirmed expression of WT1-derived peptides on malignant cell surfaces and the recognition of these peptides by cellular and humoral immune responses, several studies suggest that WT1 may be a promising potential target antigen in immunotherapeutic trials. 13,14,[27][28][29][30][31] As far as mucinous breast carcinoma is concerned, WT1 immunotherapy appears to be an attractive targeted therapy as these tumors occur predominantly in the elderly population, where the choice of safe chemotherapeutic regimen is rather limited. However, it is still not clear if these patients with relatively indolent tumor type might benefit.…”

Section: Discussionmentioning

confidence: 99%

WT1 immunoreactivity in breast carcinoma: selective expression in pure and mixed mucinous subtypes

et al. 2008

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Current literature suggests that strong WT1 expression in a carcinoma of unknown origin virtually excludes a breast primary. Our previous pilot study on WT1 expression in breast carcinomas has shown WT1 expression in approximately 10% of carcinomas that show mixed micropapillary and mucinous morphology (Mod Pathol 2007;20(Suppl 2):38A). To definitively assess as to what subtype of breast carcinoma might express WT1 protein, we examined 153 cases of invasive breast carcinomas. These consisted of 63 consecutive carcinomas (contained 1 mucinous tumor), 20 cases with micropapillary morphology (12 pure and 8 mixed), 6 micropapillary 'mimics' (ductal no special type carcinomas with retraction artifacts), 33 pure mucinous carcinomas and 31 mixed mucinous carcinomas (mucinous mixed with other morphologic types). Overall, WT1 expression was identified in 33 carcinomas, that is, 22 of 34 (65%) pure mucinous carcinomas and in 11 of 33 (33%) mixed mucinous carcinomas. The non-mucinous component in these 11 mixed mucinous carcinomas was either a ductal no special type carcinoma (8 cases) or a micropapillary component (3 cases). WT1 expression level was similar in both the mucinous and the non-mucinous components. The degree of WT1 expression was generally weak to moderate (490% cases) and rarely strong (o10% cases). None of the breast carcinoma subtype unassociated with mucinous component showed WT1 expression.

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“…[1][2][3][4] Recently, we and other investigators have succeeded in generating CD8 ϩ cytotoxic T lymphocytes (CTLs) that recognize WT1-derived peptides in vitro. [5][6][7][8][9] These WT1-specific CTLs efficiently lysed leukemia cells and solid tumor cells, but not normal cells, in an HLA class I-restricted manner.…”

Section: Introductionmentioning

confidence: 99%

Direct recognition and lysis of leukemia cells by WT1-specific CD4+ T lymphocytes in an HLA class II-restricted manner

Guo

Niiya

Azuma

et al. 2005

Blood

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WT1-targeted immunotherapy of leukaemia

Cited by 19 publications

References 28 publications

Listeriolysin O Expressed in a Bacterial Vaccine Suppresses CD4+CD25high Regulatory T Cell Function In Vivo

Listeriolysin O Expressed in a Bacterial Vaccine Suppresses CD4+CD25high Regulatory T Cell Function In Vivo

WT1 immunoreactivity in breast carcinoma: selective expression in pure and mixed mucinous subtypes

Direct recognition and lysis of leukemia cells by WT1-specific CD4+ T lymphocytes in an HLA class II-restricted manner

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