Antitrypsin surrogate, Alphataxin, increases tumor CD4 + T cells and suppresses murine colon cancer

ABSTRACT CD4+ T helper cells are required for CD8+ killer T cells to suppress tumor growth. An orally-available small molecule surrogate of alpha-1 antitrypsin, Alphataxin, was previously demonstrated to elevate the numbers of circulating and tumor-infiltrating CD4+ T cells and to suppress kidney tumor growth in mice. To determine whether Alphataxin might be effective in other T cell-responsive cancers, mice orthotopically implanted with colon tumors were treated using Alphataxin and anti-PD-1 as monotherapies or in combination. Combination therapy significantly suppressed tumor growth (ORR = 37.5%) and increased tumor-infiltrating CD4+ T cells, CD8+ T cells, NK cells, M2 macrophages, and DC2 dendritic cells. Release of IFN-γ by helper T cells in the tumor microenvironment appeared to contribute to the effectiveness of killer T cells in suppressing tumor growth. Toxicology studies in rats revealed no untoward effects. Alphataxin, to our knowledge the first and only drug developed to rapidly and sustainably increase the number of circulating and tumor-infiltrating CD4+ helper T cells, is a powerful therapeutic that provides long-term remission in T cell-responsive cancers in combination with anti-PD-1. Competing Interest Statement CLB and RW report issued patents US 10,413,530 and US 10,709,693. TQG,III declares no potential conflict of interest.