Effector CD4 T cells convert transient responses to KRAS targeted therapy into long term durable remissions in pancreatic cancer

Direct inhibitors of KRAS are clinically promising although acquired resistance is common. Interleukin-21 is a plieotropic cytokine with potential to augment anti-tumor immunity.

Using AI-assisted computational design, we developed a de novo IL-21 mimic, 21h10, which displays augmented stability and high signaling potency in both humans and mice. We modeled KRAS inhibitor response and relapse in mice with orthotopic PDAC and show that - unlike chemotherapy or checkpoint blockade combinations - combination of 21h10 with KRASi is curative. Efficacy of 21h10 in PDAC is not dependent on CD8 T cells or MHC class I expression by the tumor.