Harnessing the Immune System: The Potential of RTX-212 in Cancer Therapy

Rubius Therapeutics has engineered a red cell therapeutic, RTX-212, designed to express both 4-1BBL and an IL-15/IL-15Rα fusion protein (IL-15TP) to enhance T and NK cell activation and expansion. This approach aims to overcome the limitations of recombinant agonists by presenting native ligands through cell-cell contact, potentially reducing off-tissue toxicity due to the vascular system's restricted biodistribution.

In vitro studies have shown that RTX-212 can significantly expand memory CD8 T cells and NK cells without TCR stimulation and induce substantial proliferation of CD8 and CD4 T cells with increased IFNγ secretion in the presence of TCR stimulation. The combination of 4-1BBL and IL-15TP on RTX-212 provides synergistic effects, with each molecule offering complementary functions that broaden its activity.

To assess in vivo immune responses, anti-tumor activity, and safety, a mouse surrogate therapeutic, mRBC-212, was created. This surrogate demonstrated a significant decrease in lung metastases and an increase in NK cell infiltration in C57Bl6 mice injected with B16F10 melanoma cells. In a CT26 tumor model, mRBC-212 treatment resulted in tumor growth inhibition and an increase in tumor infiltration of proliferating and cytotoxic CD8 T cells. Importantly, mRBC-212 showed no liver toxicity, unlike agonistic 4-1BB antibodies.

The data suggest that RTX-212 could offer an effective therapy with an improved safety profile over existing 4-1BB agonist antibodies and IL-15 agonists, warranting its further clinical development.