Tolododekin alfa (ANK-101) anchored IL-12 drives CD8+ influx—but M-MDSC expansion tracks with progression

Tolododekin alfa (ANK-101) is a first-in-class, aluminum hydroxide–anchored IL-12 cytokine designed for prolonged intratumoral retention after intratumoral injection. In the Phase 1 NCT06171750 correlative cohort with paired biopsies (n=10; melanoma, HNSCC, breast, bladder), CD8+ T-cell density increased overall from 16.8% (C1D1) to 28.7% (C2D1 day 21), with a larger rise in patients with disease control (13.25% to 34%); however, total MDSCs increased from 69.9 to 194.2 cells/mm², driven by M-MDSCs (37.6 to 162) while PMN-MDSCs were stable (32.2 to 31.9). By outcome, disease control associated with minimal total MDSC change (35.4 to 33) plus PMN-MDSC decline (29.6 to 9.8), whereas progressive disease showed marked MDSC expansion (104.4 to 355.4; p=0.0625) largely via M-MDSCs (69.6 to 301.0) and included 2 “inflamed-but-progressing” cases with high CD8+/inflammatory signaling—suggesting MDSCs as an immune-escape pressure that could blunt IL-12 monotherapy even when T-cell trafficking is induced (in early IT immunotherapy monotherapy, clinical benchmarks are typically low—single-digit to low-teens ORR with modest disease-control rates—so this is best viewed as mechanism-first rather than efficacy-defining).