mRNA Vaccines Enhance Tumor Control and Synergize with 4-1BB Costimulatory Therapy

Introduction/Rationale: Although mRNA–lipid nanoparticle (mRNA-LNP) vaccines are being explored as cancer immunotherapies, their clinical application is constrained by the need for personalized identification of tumor neoantigens and time-consuming vaccine design. Here, we investigated whether an off-the-shelf, antigen-mismatched mRNA-LNP vaccine could elicit bystander anti-tumoral effects without the need to express any tumor antigen.

Methods: C57BL/6 mice were challenged subcutaneously with 1x10^6 B16 melanoma cells, and five days later, they were immunized intratumorally with an mRNA-LNP encoding an irrelevant antigen, ovalbumin (mRNA-OVA), either alone or in combination with a tolerable dose of 4-1BB agonistic antibodies (50 μg of clone 3H3, administered intraperitoneally).

Results: Remarkably, mRNA-OVA vaccination alone resulted in robust tumor control despite the absence of any tumor antigen. Notably, mice mounting the strongest OVA-specific CD8 T cell responses exhibited the greatest tumor control, suggesting a role for bystander CD8 T cell activation in potentiating anti-tumoral activity. Importantly, the anti-tumoral efficacy of mRNA-LNP vaccination was further enhanced when combined with a low dose of costimulatory anti-4-1BB antibodies. This costimulatory anti-4-1BB regimen was well tolerated and did not result in elevated liver enzyme levels in mice. Mechanistically, mRNA vaccination induced potent type I interferon (IFN-I) responses, which increased the expression of costimulatory molecules, rendering tumors more responsive to costimulatory triggering.

Conclusion: Together, these findings demonstrate that mRNA-LNP vaccines promote anti-tumor immunity and can synergize with 4-1BB costimulation to enhance tumor control, providing a mechanistic rationale for combining mRNA vaccines with costimulatory immunotherapies.