by
ENRICO GARACI
ABSTRACT: After the initial dramatic effects, observed in a Lewis lung
carcinoma animal model, using a combination of thymosin alpha 1 (T1)
and interferon (IFN) after cyclophosphamide, a number of other preclinical
models in mice (Friend erythroleukemia and B16 melanoma) and
in rats (DHD/K12 colorectal cancer liver metastasis) have confirmed
the efficacy of the combination therapy with T1 and either IFN or
IL-2 plus chemotherapy. These results provided the scientific foundation
for the first clinical trials using T1 in combination with BRMs
and/or chemotherapy. Pivotal trials in advanced non-small cell lung
cancer (NSCLC) and melanoma with T1 and IFN- low doses after
cis-platinum or dacarbazine produced the first evidence of the high potentiality
of this approach in the treatment of human cancer. The combination
of T1 and IFN- was also used in patients affected by chronic
B and C hepatitis including IFN-nonresponders and infected by precore
mutants or genotype 1b. Further studies demonstrated additional biological
activities clarifying the mechanism of action of T1, partially
explaining the synergism with IFN. It has been shown the capacity of activating
infected dendritic cells through Toll-like receptor signaling, thus
influencing the inflammation balance, and of increasing the expression
of tumor, viral, and major histocompatibility complex (MHC) I antigens.
Dose–response studies suggested the possibility of improving the efficacy
of this molecule reducing the overall toxic. Based on these information
two clinical trials are ongoing: a large phase II on advanced melanoma
patients treated with T1 at different doses after dacarbazine and a
phase III one, on IFN-resistant hepatitis C virus (HCV) patients treated
with a triple combination (IFN, ribavirin, and T1).
