Temsirolimus, an mTOR inhibitor, enhances anti-tumour effects of heat shock protein cancer vaccines

BACKGROUND: Temsirolimus is a mammalian target of rapamycin (mTOR) inhibitor and rapamycin analogue that is approved for treating advanced renal cell carcinoma (RCC). It is being actively evaluated in clinical trials for melanoma. The mTOR inhibitors are also immunosuppressants and are used clinically to prevent rejection following solid-organ transplant. Novel immunotherapies are being actively developed for immunoresponsive tumours, such as RCC and melanoma. METHODS: Immune-modulating effects of temsirolimus were characterised when used in combination with cancer vaccines targeting RCC (RENCA) and melanoma (B16). Cancer vaccines were recombinant tumour-specific proteins (CA9 or gp100), and recombinant heat shock protein (HSP; hsp110) served as the immune adjuvant. RESULTS: In murine models, temsirolimus enhanced the anti-tumour activity of cancer vaccines used to treat established RENCA and B16 tumours. A tumour prevention model established that the enhanced anti-tumour activity associated with temsirolimus was immune mediated. In mice treated with an HSP-based anti-tumour vaccine, temsirolimus-treated CD8 T cells had greater interferon-g and cytotoxic T-cell responses when compared with mice treated with vaccine alone. Temsirolimus also enhanced the formation of CD8 memory cells following administration of HSP-based cancer vaccine. CONCLUSION: These results provide a rationale for combining mTOR inhibitor with immunotherapy when treating immunoresponsive tumours. British Journal of Cancer (2011) 104, 643-652. doi:10.1038/bjc.2011.15 www.bjcancer.com Published online 1 February 2011 (C) 2011 Cancer Research UK