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Virus-like particles containing a TLR9 agonist enhance the anti-tumor T cell response
Dissertation   Open access

Virus-like particles containing a TLR9 agonist enhance the anti-tumor T cell response

Travis David Fischer
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2026
DOI: 10.25820/etd.008385
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Virus-Like Particles Containing a TLR9 Agonist Enhance the Anti-Tumor T Cell Response10.61 MBDownloadView
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Abstract

One strategy for enhancing the anti-cancer immune response is to inject tumors with immunostimulatory agents that modify the tumor microenvironment to induce a stronger anti-tumor T cell response, a process known as in situ immunization. In situ immunization with Vidutolimod (Vidu), a virus-like particle containing a CpG-A TLR9 agonist, has demonstrated anti-tumor activity in pre-clinical and early phase clinical studies, however its effect on tumor-specific CD8⁺ T cells remain poorly defined. Using the OT-1 model, we assessed how Vidu impacts activation, cytotoxicity, and anti-tumor activity of tumor-specific CD8⁺ T cells in vitro and in vivo. In vitro, Vidu reduced the proliferation of tumor-specific CD8⁺ T cells but increased their expression of activation and exhaustion markers short-term. Treatment with Vidu induced even greater co-expression of inhibitory markers by chronically stimulated tumor-specific CD8⁺ T cells in long-term cultures, suggesting these cells had developed a deeper state of exhaustion. However, Vidu-treated cells retained robust activation marker expression and had greater recall of inflammatory cytokines and cytotoxicity markers following restimulation. Analysis of genes associated with activation, cytotoxicity, trafficking, and exhaustion demonstrated similar trends seen with protein expression by Vidu-treated tumor-specific CD8⁺ T cells. In vivo, repeated intratumoral Vidu injections induced a transient increase in the percentage of intratumoral tumor-specific CD8⁺ T cells and enhanced anti-tumor activity. The addition of αPD-1 to Vidu therapy led to a persistent increase in intratumoral tumor-specific CD8⁺ T cells and sustained tumor control. Vidu treatment decreased expression of PD-1 on intratumoral tumor-specific CD8⁺ T cells while increasing the frequency of PD-1+LAG3+TIM3+ on these cells. Conversely, intratumoral Vidu injections increased the number of circulating tumor-specific CD8⁺ T cells that expressed higher levels of PD-1, but these cells lacked co-expression of LAG3 and TIM3. Vidu therapy also induced increased CD4⁺ T cell Th1 differentiation in the tumor and circulation. Combination therapy further increased the frequency of Th1 CD4⁺ T cells in both the tumor and circulation. These findings recapitulate previous pre-clinical and clinical evaluations into Vidu therapy. Together, these findings demonstrate the complex and nuanced effects of Vidu treatment on tumor-specific CD8⁺ T cells. In vitro, Vidu induced a more exhausted phenotype by tumor-specific T cells, however, these cells retained strong activation even under chronic stimulation. Notably, Vidu enhanced cytotoxicity of tumor-specific T cells but was limited to T cells that were not chronically stimulated. In vivo, Vidu alone was insufficient for a durable anti-tumor response after cessation of therapy. Combination therapy of Vidu with checkpoint blockade was required for sustain tumor control and enhanced T cell responses. This indicated that checkpoint inhibition synergizes with Vidu to counteract the increased inhibitory receptor expression induced by Vidu treatment. These results revealed important differences between in vitro and in vivo marker expression, highlighting the need for in vivo evaluation for clinical relevance. Overall, in situ immunization with Vidu increases tumor-specific T cell activation and anti-tumor activity and is further enhanced by combination with immune checkpoint blockade therapy.
 Cancer Biology Immuno-oncology TLR Agonists Tumor Microenvironment

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