Abstract CT123: Immune escape via myeloid-derived suppressor cells in solid tumor cancer patients treated with anchored IL-12? (tolododekin alfa)

Abstract BACKGROUND: Tolododekin alfa (ANK-101) is a first-in-class, aluminum-anchored interleukin-12 (IL-12) engineered for prolonged intratumoral retention. In a Phase 1 trial (NCT06171750), patients with accessible advanced solid tumors received intratumoral injections every 3 weeks and demonstrated acceptable safety and biological activity, with 60% achieving disease control and two patients with an objective partial response1. We showed increased CD8+ T-cell infiltration and PD-L1 expression associated with clinical response to ANK-101 treatment. To better characterize mechanisms of response and resistance to ANK-101 monotherapy, we further evaluated intratumoral changes in total as well as subsets of myeloid-derived suppressor cells (MDSCs). METHODS: Matched baseline (C1D1) and post-treatment (C2D1, day 21) biopsies from 10 patients with melanoma, head and neck squamous cell carcinoma, breast cancer, or bladder cancer were analyzed. FFPE sections underwent immunohistochemistry, multiplex immunofluorescence (CD11b, CD14, CD15, HLA-DR, and CK or S-100), and quantitative pathology to assess CD8⁺ T cells, monocytic MDSCs (M-MDSCs), and polymorphonuclear MDSCs (PMN-MDSCs). Nanostring gene expression analysis was performed on mRNA extracted from paired FFPE tumor biopsies following tumor macro-dissection. RESULTS: Across all samples, CD8⁺ T-cell density increased from 16. 8% at baseline to 28. 7% at C2D1, with more pronounced increases in patients with disease control (13. 25% to 34%). Total MDSCs rose from 69. 9 to 194. 2 cells/mm², driven by expansion of M-MDSCs (37. 6 to 162 cells/mm²), while PMN-MDSCs remained stable (32. 2 to 31. 9 cells/mm²). When stratified by clinical outcome, patients with disease control showed minimal change in total MDSCs (35. 4 to 33 cells/mm²), accompanied by decreased PMN-MDSCs (29. 6 to 9. 8 cells/mm²) and moderate increases in M-MDSCs (5. 6 to 23 cells/mm²). In contrast, patients with progressive disease demonstrated increases in total MDSCs (104. 4 to 355. 4 cells/mm²; p=0. 0625), largely due to marked M-MDSC expansion (69. 6 to 301. 0 cells/mm²). These findings parallel transcriptomic analyses showing higher pro-inflammatory gene expression score (TIS) in responding patients. However, two patients progressed despite high CD8+ T-cell infiltration and inflammatory signaling. These patients lacked disease control and displayed significantly elevated MDSC counts, which likely facilitated immune escape. CONCLUSIONS: Tolododekin alfa promotes intratumoral infiltration of CD8+ T cells, more prominent in patients who achieved disease control with anchored IL-12. Conversely, there is a compensatory recruitment of MDSCs, particularly M-MDSCs, in patients with progressive disease. MDSC expansion as a mechanism of immune escape merits additional mechanistic studies to define drivers of MDSC recruitment and inform rational therapeutic combinations. 1Park J. et al 2025: Nature Communications 16: 8567 Citation Format: Wiem Lassoued, Sailaja Battula, Lisa Sturla, Jong C. Park, Brendan Curti, Marcus O. Butler, John M. Kirkwood, Howard L. Kaufman, James L. Gulley. Immune escape via myeloid-derived suppressor cells in solid tumor cancer patients treated with anchored IL-12? (tolododekin alfa) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT123.