Journal article
Cytokine-modified Mycobacterium smegmatis as a novel anticancer immunotherapy
International journal of cancer, Vol.112(4), pp.653-660
2004
DOI: 10.1002/ijc.20442
PMID: 15382047
Abstract
Intravesical administration of live M. bovis BCG organisms for carcinoma in situ of the urinary bladder is the most successful immunotherapy for solid malignancy. Nevertheless BCG-therapy is associated with significant toxicity and is ineffective in 30-40% of cases. Recently it has been proposed that cytokine-modified mycobacteria may give greater efficacy. As any immunotherapy involving administration of live BCG organisms (wild-type or recombinant) is likely to have associated toxicity (notably in the immunocompromised), we examined the anti-tumour potential of the closely related nonpathogenic organism, Mycobacterium smegmatis, and a TNFα gene-modified recombinant M. smegmatis. When wild-type M. smegmatis were delivered to immunocompetent C57BI/6 mice bearing the transplantable MB49 bladder tumour, efficacy comparable to live BCG was observed with 10-20% long-term survival. However, this effect was lost in both Nude and Beige mice, lacking functional T and NK cells, respectively. Recombinant M. smegmatis secreting TNFα, however, gave a 70% durable tumour-free survival. Lymphocytes from draining lymph-nodes and spleens of these mice exhibited pronounced IFNγ production to mycobacterial-antigen and tumour-lysate, indicating a bias towards cell-mediated immunity. This was further supported by histopathological examination of the tumour site, which revealed significantly increased numbers of CD3+ lymphocytes in animals receiving the recombinant vaccine, but not in those receiving wild-type bacteria. Importantly, tumour rejection following M. smegmatis/TNFα was independent of T lymphocytes, as athymic Nude mice efficiently eradicated MB49 tumours. In contrast, the therapeutic efficacy of M. smegmatis/TNFα was reduced in animals deficient in NK cytolytic function, suggesting a role for NK-cells in initial tumour destruction. Furthermore the absence of NK-function in Beige mice did not prevent the establishment of tumour-protective memory. No toxicity was observed with wild-type or recombinant M. smegmatis in immunocompetent, T-deficient or NK-deficient models. We demonstrate for the first time that recombinant mycobacteria expressing mammalian cytokines have markedly increased anti-tumour properties. The lack of toxicity suggests that M. smegmatis is a "safe" vehicle for use in immunocompromised patients. © 2004 Wiley-Liss, Inc.
Details
- Title: Subtitle
- Cytokine-modified Mycobacterium smegmatis as a novel anticancer immunotherapy
- Creators
- Sarah L Young - St James's University HospitalMichael Murphy - St James's University HospitalXing Wu Zhu - St James's University HospitalPatricia Harnden - St James's University HospitalMichael A O'DONNELL - University of IowaKeith James - University of EdinburghPoulam M Patel - St James's University HospitalPeter J Selby - St James's University HospitalAndrew M Jackson - St James's University Hospital
- Resource Type
- Journal article
- Publication Details
- International journal of cancer, Vol.112(4), pp.653-660
- Publisher
- Wiley-Liss
- DOI
- 10.1002/ijc.20442
- PMID
- 15382047
- ISSN
- 0020-7136
- eISSN
- 1097-0215
- Language
- English
- Date published
- 2004
- Academic Unit
- Urology
- Record Identifier
- 9984320070102771
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