Abstract
Background:
Personalized cancer vaccines targeting tumor-specific neoantigens (nAgs) are an emerging therapeutic strategy, particularly effective in early-stage disease before immune suppression is established. Immune checkpoint inhibitors have demonstrated benefit in the adjuvant setting (postsurgery), and recent evidence suggests neoadjuvant administration (before surgery) may further enhance antitumor immunity. This study evaluated the efficacy of a multiepitope nAg vaccine in a preclinical melanoma model resistant to checkpoint inhibition, comparing neoadjuvant and adjuvant treatment, alone or in combination with anti-programmed cell death protein 1 (PD1) therapy.
Methods:
A viral vector nAg vaccine was developed and administered in the B16F10 murine melanoma model. Mice received the vaccine either before (neoadjuvant) or after (adjuvant) tumor resection alone or in combination with anti-PD1. Tumor recurrence and survival were assessed. Immune profiling was performed to evaluate T cell phenotypes, and CD8+ T cell depletion experiments were conducted to assess the role of this population. Protection against tumor rechallenge was considered to evaluate long-term immunity.
Results:
Neoadjuvant vaccination alone provided approximately 70% protection against tumor recurrence. When combined with anti-PD1, protection increased to 90%. Notably, anti-PD1 alone conferred 60% protection when used in a neoadjuvant setting. In contrast, adjuvant vaccination was ineffective as monotherapy and required combination with anti-PD1 to prevent relapse. The efficacy of neoadjuvant vaccination was dependent on CD8+ T cells and associated with robust effector memory T cell responses. Long-term protection against tumor rechallenge was superior in the neoadjuvant vaccine group compared with anti-PD1 alone.
Conclusions:
Neoadjuvant nAg vaccination elicits potent CD8+ T cell-mediated immunity and offers superior protection against tumor recurrence and rechallenge compared with adjuvant approaches or checkpoint blockade alone. These findings support the clinical evaluation of neoadjuvant cancer vaccines, particularly in settings where tumors are resistant to conventional immunotherapy.