Thymosin Alpha 1 From Bench to Bedside

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).