Talactoferrin Alfa, a novel immunomodulatory agent with anti-cancer activity in phase II clinical trials.

Proc Amer Assoc Cancer Res, Volume 47, 2006 5579 Clinical Background: Talactoferrin alfa (talactoferrin) is a novel, orally administered immunomodulatory agent that appears to be safe and well tolerated and has anti-cancer activity in human clinical trials. Talactoferrin met its primary efficacy endpoints in multi-center Phase II clinical trials in RCC and NSCLC. In a 44-patient RCC trial, patients receiving talactoferrin monotherapy had an apparent increase in their median PFS. In a 110-patient placebo-controlled, multi-center Phase II trial in patients with advanced NSCLC, addition of oral talactoferrin to carboplatin/paclitaxel in first-line NSCLC substantially enhanced both response rate and PFS. Confirmed BOR in the 110 ITT patients increased from 27% to 42% (15% absolute increase, 56% relative increase; p=0.08). Confirmed RR in the 100 prospectively defined evaluable patients increased from 29% to 47% (18% absolute improvement, 62% relative improvement; p=0.05). Median PFS increased by 2.8 months from 4.2 months to 7 months (61% improvement). Talactoferrin will soon be entering Phase III trials. . Immunomodulatory Mechanism: Talactoferrin is an orally active protein that acts at the gut and the Gut Associated Lymphoid Tissue (GALT) through a novel mechanism involving chemokine and cytokine modulation. Talactoferrin binds enterocyte receptors and immune cells in the Peyer's patches, and initiates an immunostimulatory cascade in the GALT. This results in an increase in key cytokines including IFN-g and IL-18, and activation of both innate and adaptive immunity. In animal experiments, we see increased numbers of NK-T cells and CD8+ T-lymphocytes in small intestinal Peyer's patches, a systemic increase in Natural Killer (NK) and Cytotoxic T-lymphocyte (CTL) activity, and cellular infiltration of distant tumors. The essential role of IFN-g and immune effector cells in talactoferrin's anti-cancer activity has been demonstrated in knockout and depletion experiments. Talactoferrin induced increases in NK-T cells and CD8+ lymphocytes in Peyer's patches was abolished in IFN-g knockout mice, as was talactoferrin's anti-cancer activity. Talactoferrin activity was also lost in animals lacking NK-T or CD8+ cells. . Conclusion: Talactoferrin is a first-in-class molecule with promising Phase II anti-cancer activity, and a novel immunomodulatory mechanism.