Immune escape via myeloid-derived suppressor cells in solid tumor cancer patients treated with anchored IL-12? (tolododekin alfa)
Presenter: Wiem Lassoued, PhD Session: Phase 0 and First-in-Human Phase I Clinical Trials Time: 4/20/2026 2:00:00 PM → 4/20/2026 5:00:00 PM
Authors
Wiem Lassoued 1 , Sailaja Battula 2 , Lisa Sturla 2 , Jong C. Park 3 , Brendan Curti 4 , Marcus O. Butler 5 , John M. Kirkwood 6 , Howard L. Kaufman 2 , James L. Gulley 1 1 NIH, Bethesda, MD, 2 Ankyra Therapeutics, Cambridge, MA, 3 Massachusetts General Hospital, Boston, MA, 4 Providence Portland Medical Center, Portland, OR, 5 Princess Margaret Cancer Centre, Toronto, ON, Canada, 6 University of Pittsburgh, Pittsburgh, PA
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 response 1 . 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. 1 Park J. et al 2025: Nature Communications 16: 8567
Disclosure
W. Lassoued, None. S. Battula, Ankyra therapeutics Employment. L. Sturla, Ankyra therapeutics Employment. J. C. Park, Alx olcology ). Ankyra therapeutics ). Inhibrx. ). B. Curti, Merck Advisory role. Astra-Zeneca Honorarium. Bristol-Myers Squibb ). Astra-Zeneca ). Ankyra therapeutics ). M. O. Butler, Adaptimmune, EMD Serono, Genzyme, Glaxosmithkline, IDEAYA Biosciences, Immunocore, Immunovaccine, InstilBio, Iovance Biotherapeutics, LaRoche Posay, Medison, Novartis, Pfizer, Regen Advisory role. Bristol-Myers Squibb, Merck, Novartis, Roche, and Sanofi Honorarium. Merck ). Merck and Novartis. expert testimony. J. M. Kirkwood, Ankyra Therapeutics, AXIO Research, Boxer Capital, Bristol-Myers Squibb, Cytomx Therapeutics, Daiichi Sankyo Inc., DermTech, Health Media, GE Healthcare Inc., IQVIA, Istari Oncology, Lumira Ca Advisor role. Ankyra Therapeutics, Bristol-Myers Squibb, Checkmate Pharmaceuticals, Harbour BioMed, Immunocore, Immvira, Iovance Biotherapeutics, Lion Biotechnologies, Lytix Biophara AS, Merck, Novartis, Regeneron ). Bristol-Myers Squibb, Mural Oncology, and Regeneron. Travel. H. L. Kaufman, Ankyra therapeutics Employment. Cryton Biosciences and Marengo Therapeutics serves on the boards. ImmVira, PrimeVax, Tatum Biosciences, and Virogin. Advisor role. J. L. Gulley, None.
Cited in
Control: 10416 · Presentation Id: 12048 · Meeting 21436