ACM-CpG, a polymersome-delivered TLR9 agonist, elicits rapid and broad immune activation in a phase I trial for advanced solid tumors

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-gamma 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-gamma ELISPOT confirmed a 1.4-3.4-fold increase in antigen-specific IFN-gamma-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.