Abstract Background: ACM-CpG is a novel innate immune activator comprising of TLR9 agonist CpG7909 encapsulated within polymer vesicles (“polymersomes”). This formulation enhances in vivo immune activation compared with free CpG. In preclinical animal models, ACM-CpG induced tumor regression, durable antitumor immune memory, and growth inhibition of distal, non-injected tumors. Intramuscular administration also achieved tumor control on abscopal subcutaneous tumors. Based on these findings, a Phase I clinical trial (NCT06587295) was initiated at the National Cancer Centre Singapore to evaluate the safety and early efficacy signals of intramuscular ACM-CpG monotherapy in patients with advanced solid malignancies. Methods: This is a 3+3 dose-escalation study of ACM-CpG administered intramuscularly as monotherapy. Eligible patients had advanced cancers with prior clinical response to immune checkpoint inhibitors, either alone or in combination with chemotherapy. A total of 8 patients have been treated to date in the monotherapy arm. Subsequent study arms will assess ACM-CpG in combination with immune checkpoint inhibitors or cancer peptide vaccines. Immune responses were profiled using CyTOF, multiplex cytokine assays (Luminex/Olink), IFN-γ ELISPOT, and single-cell RNA/TCR sequencing. Results: Pharmacodynamic data covering the first treatment cycle of all patients shows that ACM-CpG triggered rapid and coordinated activation across multiple innate and adaptive compartments within 24 hours post-injection. Immune profiling showed expansion of myeloid populations with upregulation of activation markers CD86, CD38, and CD40, accompanied by transient expansion of MDSCs and pDCs, indicating strong antigen-presenting activity. Adaptive immune activation was demonstrated by proliferation and activation of NK cells and CD4+/CD8+ T cells expressing CD69, along with PD-1 upregulation in some patients, consistent with T-cell priming. Cytokine profiling revealed 5-30-fold elevations of MCP-1, MCP-2, CXCL10, and CXCL11, reflecting potent TLR9-driven pro-inflammatory signaling. IFN-γ ELISPOT confirmed a 1.4-3.4-fold increase in antigen-specific IFN-γ-secreting T cells. Single-cell transcriptomics identified strong type I interferon signatures and upregulation of innate and adaptive immune effectors. CpG7909 was rapidly cleared within 24 hours, with no systemic accumulation observed. ACM-CpG was well tolerated with no dose-limiting toxicities observed. Conclusions: ACM-CpG induces rapid, broad-spectrum immune activation, engaging both innate and adaptive compartments and enhancing cytokine and T-cell responses with a favorable safety profile. These early clinical findings support continued development of ACM-CpG as a potent monotherapy and a versatile immunologic amplifier for combination immunotherapy. Citation Format: Amit Jain, Aaron C. Tan, Andrea Budiman, Nan Jiang, Kim Peng Tan, Jackwee Lim, Loo Ser Yue, Jian Hang Lam, Yan Jun Lee, Teck Wan Chia, Katherine Schultheis, Madhavan Nallani, Daniel Sw Tan. ACM-CpG, a polymersome-delivered TLR9 agonist, elicits rapid and broad immune activation in a phase I trial for advanced solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7789.
Jain et al. (Fri,) studied this question.