Cancer vaccine – astuprotimut-R
Stimulating the immune system by a vaccine to produce a specific T cell response could be an anticancer therapy
If a patient’s immune system can be stimulated by a vaccine to produce a specific T cell response targeting tumour cells, then this could be used as an anticancer therapy. Various different mechanisms are being investigated, and one of these is melanoma associated antigen 3, or MAGE-3. The gene that encodes for the antigen, MAGEA3, is expressed in several different tumours, and not just melanoma, including lung, bladder, breast, oesophageal and gastric cancers, plus leukaemia. GlaxoSmithKline is targeting this mechanism with its therapeutic cancer vaccine astuprotimut-R, which consists of the MAGE-3 epitope fused to part of the Haemophilus influenzae protein D antigen sequence.
Several clinical trials have been carried out. In one Phase I/II trial, 57 patients with MAGE-3 positive metastatic cancers, most of them melanomas, were given escalating doses of the vaccine plus the immunological adjuvant SBAS-2, as four intramuscular injections at intervals of three weeks, then a further two vaccinations at six week intervals in those whose tumour had stabilised or regressed.1 A total of 33 melanoma patients were evaluable for tumour response, with two partial and two mixed responses, and a further patient who had stable disease for 11 months. Time to progression in these patients was between four and 29 months. In another trial, the vaccine was given without the adjuvant, but the clinical and immunological responses were inadequate.2
A randomised, open label Phase II trial was run in 75 patients with MAGE-3 positive cutaneous melanoma were given astuprotimut-R along with either AS15 or AS02B adjuvant.3 Higher specific antibody titres and better T-cell response induction was better with AS15, and toxicity was similar in both groups. A total of 11 patients achieved stable disease for at least 16 weeks, six in the AS15 group and five given AS02B. The gene expression profile in the melanoma correlated with clinical activity induced by the vaccine.
It has also been investigated in patients with non-small cell lung cancer. In a Phase II double blind, placebo controlled, parallel group study, 182 patients with resected MAGE-3 positive NSCLC were given the vaccine either with or without AS02B adjuvant at least six weeks after the resection procedure.4 Subjects were given five injections at three weekly intervals, and then eight injections at three monthly intervals. After a median follow up period of 28 months, the relative improvement in disease free survival was estimated at 27%. Long-term follow up showed that more than 98% of those given the vaccine had an IgG immune response; a CD4+ cell response to the vaccine was seen in 41% of those given the adjuvant, and 14% of the placebo group. Phase III trials are now under way in NSCLC.
References
1. M. Marchand et al. Eur. J. Cancer et al. 2003, 39, 70
2. W.H.J Kruit et al. Int. J. Cancer 2005, 117, 596
3. W.H. Kruit et al. J. Clin. Oncol. 2008, 26 (15, Suppl.), Abst 9065
4. B. Passlick et al. Lung Cancer 2009, 64 (1, Suppl.), Abst 102PD