Enhancing Tumor Immunogenicity and T Cell Subset Function through Intratumoral IL-12 and Anti-CD3 Electroporation

The study explores the effects of intratumorally administered plasmid IL-12, known as tavo, combined with electroporation (EP) on tumor immunogenicity. This treatment, termed IT-tavo-EP, has shown to reduce both local and distant tumors with minimal side effects in prior research. Clinical trials involving melanoma patients have indicated an increase in T cell infiltration and immune activation, with a notable rise in IFN-γ scores for those who benefited from the treatment. The research suggests that the presence of CD3+ tumor-infiltrating lymphocytes (TILs) is crucial for the therapy's effectiveness.

To enhance the T cell response, a plasmid-encoded hybrid antibody targeting CD3 (αCD3) was developed and combined with tavo in a new treatment approach, IT-tavo-αCD3-EP. This treatment was shown to activate CD3+ TILs, leading to increased proliferation and cytotoxicity in a murine model. The study also revealed that the membrane-bound αCD3 can significantly increase the presence of specific T cell types and reduce PD-1 expression on CD8+ T cells. Importantly, it was found that this treatment could activate naive T cells, regulatory T cells, and exhausted T cells, which typically do not have strong anti-tumor responses, to release IFN-γ and granzyme B.

Additionally, the treatment was found to promote T cell proliferation irrespective of the T cells' affinity for their target peptide:MHC complex, suggesting a mechanism that is independent of the T cell receptor. The research also demonstrated that TILs from a melanoma patient with active disease on anti-PD-1 therapy could be restored to functionality with the engagement of membrane-bound αCD3 in the presence of IL-12.

The findings support the potential of IT-tavo-αCD3-EP as a promising treatment for melanoma and other solid tumors, highlighting its ability to mobilize a broad range of T cells and reshape the tumor microenvironment through the production of effector cytokines.