Abstract
mRNA based vaccines utilizing lipid-based delivery systems have been used for cancer therapy with some success targeting tumor associated antigens (TAA) or neoantigens. However, in many patients, T cell exhaustion or tumor suppression impedes the induction of a protective anti-tumor T cell response, which suggests that additional activation signals are required to reduce antagonistic tumor effects and reinvigorate the T cells. Here we sought to evaluate novel ionizable lipids for lipid nanoparticle (LNP)-formulations containing a tumor antigen mRNA as a therapeutic treatment for solid tumors and identify key immunogenic features of successful ionizable lipid candidates. Focusing on the induction of a tissue destructive immune response became the ideal in vivo screening to compare two novel ionizable lipids, INTENT-1 and INTENT-2. Both LNPs carrying the same mRNA encoded antigen induced good CD8+ T cell responses but only INTENT-2.1 LNP could cause tissue destruction. Mechanism of action studies revealed that INTENT-2.1 but not INTENT-1.1 LNP induced type I interferons, independently of the mRNA, to enhance anti-tissue CD8+ T cell responses. These results demonstrate efficacy of INTENT-2.1 LNP for cancer vaccines, shed light into its mechanism of action, and support its use in clinical trials to treat solid tumors.
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