Safety, feasibility and toxicity profile of a new immunotherapy protocol for metastatic melanoma patients using in vivo salmonella typhimurium vaccination and treatment.

A17

A major obstacle for the development of effective immunotherapy is the ability of tumours to escape the immune system. The possibility to kill tumour cells because they are recognized as infected rather than as malignant, could help to overcome immune-escape mechanisms. Here we report a conceptually new approach of cancer immunotherapy based on in vivo infection of tumours and killing of infected tumour cells. Attenuated but still invasive Salmonella typhimurium (ST) can be successfully exploited to invade melanoma cells that can present antigenic determinants of bacterial origin and become targets for anti-ST specific T cells. Therefore, tumour cells are killed because they are recognized as infected. Preclinical studies on tumour-bearing mice showed that intratumoral ST-infection is able to induce the recruitment of anti-ST specific T-cells elicitated during the vaccination step unto the tumour site for recognition of ST-infected tumour cells. Tumour infection when coupled to anti-ST vaccination leads to 50-100% tumour free mice with a better outcome on larger tumours. This effect is mediated by both CD4 and CD8 T cells as neutralization of these cell types in vivo diminishes the antitumor effect. Invasive ST also exert an indirect toxic effect on tumour cells through the recruitment of inflammatory cells and the cross-presentation of tumour antigens, which allow induction of tumour-specific immune response. This is effective in retarding the growth of untreated established distant tumours and in protecting the mice from subsequent tumour challenges.
 Since may 2006, 8 patients affected by not operable stage III or IV M1a metastatic melanoma where enrolled in the trial, in order to stimuli an autologous immune response using Vivotif® vaccine and ST (Ty21a) as a therapeutic agent. Two steps were foreseen: oral vaccination with Ty21a and intratumoral treatment with Ty21a. Two metastasis were treated and 1 observed in order to evaluate the indirect effect of vaccination. Planned accrual sample size is 43 patients.
 Among the 8 enrolled patients, 1 could not be vaccinated due to the evidence of hepatic metastasis during stadiation, 1 had a rapid worsening of the performance status during vaccination while 2 did not develop adequate anti-ST vaccination titre. Of the remaining 4 patients, only 1 completed the first cycle obtaining a local response, while the other 3 interrupted the treatment due to progressive disease, important hypersensitivity reaction and a worsening of the hepatic function indexes. At injection, all the patients developed a variable degrease of lumbar pain, nausea/vomiting, shivering, fever, hypotension easily controlled by treatment with antihistaminics, antipyretics, antiemetics without the use of cortisones.
 Treated metastases showed all the signs of local inflammation and objective dimensional stabilization or reduction, but systemic disease seem not to be affected by the immunologic treatment.