Regulatory T cells (Tregs) are an important therapeutic target because they are abundant in the tumor microenvironment of many cancers. Tregs enable the growth and progression of solid tumors by suppressing the host’s antitumor immune response. There have been a variety of attempts to develop cancer treatments aimed at targeting Tregs through their cell surface marker CD25, including the use of daclizumab, a humanized CD25 antibody. However, these therapeutic endeavors have yielded only limited success in inhibiting tumor growth.

Onda et al. (2019) recently explored a new strategy targeting Tregs by injecting a CD25-specific recombinant immunotoxin (RIT) directly into the tumors of mice from three different murine tumor models. This CD25-directed RIT is a chimeric protein composed of the Fv fragment of an anti-CD25 monoclonal antibody, and the enzymatic domain of Pseudomonas exotoxin A. This CD25-specific RIT, known as 2E4-PE38, can specifically target Tregs via its Fv fragment and kill the cell by irreversibly inactivating its ability to synthesize proteins via the toxic activity of Pseudomonas exotoxin A.

The researchers found that 2E4-PE38 treatment led to the regression of both injected and distant, uninjected tumors within the same mouse. They also observed that 2E4-PE38 primed the mouse’s immune system against future tumor growth because even when mice were challenged with an injection of the same type of cancer cells after 50 days, tumors failed to develop. They found that targeting Tregs with 2E4-PE38 led to a systemic and enduring antitumor immunity within the host animal. 2E4-PE38 stimulated an increase in populations of activated CD8 cytotoxic T cells and antigen presenting cells around untreated tumors, suggesting that the mouse’s immune system was activated against the growth of existing tumors and future tumor development. This research work highlights the potential of using recombinant immunotoxins to target Tregs in tumors as an addition to existing cancer therapies.

Onda, M., Kobayashi, K. & Pastan, I. Depletion of regulatory T cells in tumors with an anti-CD25 immunotoxin induces CD8 T cell-mediated systemic antitumor immunity. Proc. Natl. Acad. Sci. 116, 4575 LP-4582 (2019)

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