Alphataxin, a Small-Molecule Drug That Elevates Tumor-Infiltrating CD4 + T Cells, in Combination With Anti-PD-1 Therapy, Suppresses Murine Renal Cancer and Metastasis

• Published in: Frontiers in oncology Vol. 11; p. 739080
• Main Authors: Bristow, Cynthia L, Reeves, Mary Ann B, Winston, Ronald
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 25.11.2021
• Subjects: alpha-1 antitrypsin; alphataxin; cancer; CD4 T cells; elastase; Oncology; PD-1; alpha-1 antitrypsin; elastase; alphataxin; CD4 T cells; cancer; immunodeficiency; PD-1; chemotaxis
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2021.739080

By promoting the cytotoxic function of CD8 T cells, immune checkpoint inhibitor therapy, programmed cell death protein-1 (PD-1), effectively inhibits tumor growth in renal cell carcinoma. Yet, as many as 87% of cancer patients do not respond to immune checkpoint therapy. Importantly, cytotoxic CD8 T cell function crucially relies on CD4 T helper cell cytokines, in particular, tumor necrosis factor beta (TNFβ) and its CD8 T cell receptor (TNFR2) in the opposing manner as immune checkpoints and their receptors. Remarkably, despite advances in immunotherapy, there are no pharmaceutical treatments that increase circulating CD4 T cell counts. Nor has there been much attention given to tumor-infiltrating CD4 T cells. Using data from a clinical trial (NCT01731691), we discovered that the protein alpha-1 proteinase inhibitor (α1PI, alpha-1 antitrypsin) regulates the number of circulating CD4 T cells. The orally available small-molecule drug Alphataxin acts as a surrogate for α1PI in this pathway. We aimed to examine how Alphataxin affected tumor growth in a murine model of renal cell carcinoma. Alphataxin, in combination with anti-PD-1 antibody, significantly elevated the ratio of circulating and tumor-infiltrating CD4 T cells. In one study, following orthotopic implantation of syngeneic renal adenocarcinoma cells, combination treatment resulted in 100% regression of tumor growth. Moreover, in mice implanted orthotopically with one log more tumor cells, doubling Alphataxin dose in combination treatment led to 100% regression in one-third of mice and 81% suppression of tumor growth in the remaining two-thirds of mice. Lung metastasis was present in monotherapy, but significantly reduced in combination-treated mice. Orally available Alphataxin, the first and only drug developed to increase CD4 T cells, in combination with anti-PD-1, is a powerful therapeutic method that provides long-term remission in renal cell carcinoma and potentially other T cell-responsive cancers by increasing the number of CD4 tumor-infiltrating T cells.