Novel lipid nanoparticle in a mRNA cancer vaccine drives tumor control via type I IFNs and effector CD8+ T cells.

mRNA based vaccines utilizing lipid-based delivery systems have been used for cancer therapy with some success targeting tumor-associated antigens (TAAs) 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 similar CD8+ T cell responses, but only INTENT-2.1 LNPs 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 the efficacy of INTENT-2.1 LNP for cancer vaccines, shed light on its mechanism of action, and support its use in clinical trials to treat solid tumors.