Combining T-Cell Engagers with a Tumor-Targeted IL-2 × IL-10 Immunocytokine: A Mechanistic Strategy to Address Toxicity, Potency, Objective Response, and Durability
Jacob C. McCright¹, Jeffery D. Smith1, David Boclair1, Pavel Khrimian1, Christopher Yaen1, John B. Mumm2*
1Deka Biosciences, Germantown, MD/USA
21080 O'Brien Dr. Suite B, Menlo Park, CA 94025
T-cell engagers (TCEs) have transformed the therapeutic landscape for hematological malignancies and are advancing rapidly into solid tumors, yet their clinical utility is constrained by four interrelated limitations: (1) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), (2) suboptimal potency in cold tumors, (3) modest objective response rates outside select indications, and (4) limited durability driven by T-cell exhaustion. Recent preclinical and first-in-human data on DK210 (EGFR), a tumor-anchored IL-2 × IL-10 immunocytokine, provides the mechanistic foundation for combining such a molecule with TCEs. IL-10 selectively abrogates IL-2- and IFN-γ-driven inflammatory cytokine cascades while sparing CD8+ effector activation, restores oxidative metabolism in tumor-infiltrating lymphocytes, and limits regulatory T-cell expansion. IL-2 delivered focally to the tumor synapse augments TCR-driven activation without requiring lymphodepletion. In a Phase 1 dose-escalation study, DK210 (EGFR) showed dose-proportional IFN-γ induction without CRS-associated IL-6, TNF-α or IL-1β elevation at therapeutic doses. We argue that combining a tumor-anchored IL-2 × IL-10 immunocytokine with a TCE simultaneously addresses each of the four canonical TCE liabilities and represents a tractable, near-term clinical strategy.
DOI: 10.29245/2578-2967/2026/1.1212 View / Download Pdf