PO.CT01.01 · 临床试验
经锚定IL-12（tolododekin alfa）治疗的实体瘤癌症患者中通过髓源性抑制细胞发生的免疫逃逸
Immune escape via myeloid-derived suppressor cells in solid tumor cancer patients treated with anchored IL-12? (tolododekin alfa)
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：Tolododekin alfa（ANK-101）是一种首创的铝锚定白细胞介素-12（IL-12），经工程化设计以实现瘤内长时间滞留。在一项1期试验（NCT06171750）中，可及晚期实体瘤患者每3周接受一次瘤内注射，展现出可接受的安全性和生物学活性，60%的患者实现疾病控制，2例患者达到客观部分缓解¹。我们显示CD8+ T细胞浸润和PD-L1表达增加与ANK-101治疗的临床应答相关。为了更好地表征对ANK-101单药治疗的应答和耐药机制，我们进一步评估了髓源性抑制细胞（MDSC）总量及亚群的瘤内变化。方法：分析了10例黑色素瘤、头颈部鳞状细胞癌、乳腺癌或膀胱癌患者的配对基线（C1D1）和治疗后（C2D1，第21天）活检样本。对FFPE切片进行免疫组织化学、多重免疫荧光（CD11b、CD14、CD15、HLA-DR以及CK或S-100）和定量病理学分析，以评估CD8⁺ T细胞、单核细胞型MDSC（M-MDSC）和多形核MDSC（PMN-MDSC）。在肿瘤宏观切割后，对从配对FFPE肿瘤活检样本提取的mRNA进行Nanostring基因表达分析。结果：在所有样本中，CD8⁺ T细胞密度从基线的16.8%增加至C2D1的28.7%，在实现疾病控制的患者中增加更为明显（13.25%至34%）。总MDSC从69.9增加至194.2个细胞/mm²，由M-MDSC的扩增所驱动（37.6至162个细胞/mm²），而PMN-MDSC保持稳定（32.2至31.9个细胞/mm²）。按临床结局分层时，实现疾病控制的患者总MDSC变化极小（35.4至33个细胞/mm²），伴随PMN-MDSC减少（29.6至9.8个细胞/mm²）和M-MDSC的适度增加（5.6至23个细胞/mm²）。相比之下，疾病进展的患者总MDSC增加（104.4至355.4个细胞/mm²；p=0.0625），主要由于M-MDSC的显著扩增（69.6至301.0个细胞/mm²）。这些发现与转录组分析相符，后者显示应答患者具有更高的促炎基因表达评分（TIS）。然而，有2例患者尽管CD8+ T细胞浸润和炎性信号较高但仍进展。这些患者未获得疾病控制，并显示出显著升高的MDSC计数，这可能促成了免疫逃逸。结论：Tolododekin alfa促进CD8+ T细胞的瘤内浸润，在通过锚定IL-12实现疾病控制的患者中更为突出。相反，在疾病进展的患者中存在MDSC（尤其是M-MDSC）的代偿性募集。MDSC扩增作为免疫逃逸机制值得进一步的机制研究，以明确MDSC募集的驱动因素并为合理的治疗联合提供依据。¹ Park J.等 2025：Nature Communications 16: 8567
查看英文原文 English 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
利益披露 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.