Hong Kai Teo, Shuting Han, Thamizhanban Manoharan, Yi Ren, Cyrus Zai Ming Cheng, Soon Chai Loo, Zhewang Lin, Jiaqi Li, Who-Whong Wang, Si‐Lin Koo, Malini Rethnam, Choon Kong Yap, Bei-En Siew, Gwyneth Shook-Ting Soon, Wai‐Kit Cheong, Kai-Yin Lee, Ian Jse-Wei Tan, Bettina Lieske, Ker‐Kan Tan, Han Chong Toh, I L Tan, Gloryn Chia
T cells, emphasizing the critical need for comprehensive functional validation before patient vaccination. Here, we provide a direct comparison of neoantigen-specific T cell responses between vaccinated patients with cancer and HLA-matched healthy donors. Despite vaccination, patient-derived T cells recognized only a small fraction of predicted neoantigens, whereas healthy donor T cells consistently exhibited broader and more robust neoantigen reactivity. Furthermore, we successfully expanded neoantigen-specific T cells from allogeneic donors, revealing that their T cell receptors (TCRs) can recognize targets that the patient's own T cells fail to engage with, partly due to poor T cell fitness. Collectively, these results indicate that cancer vaccines may be insufficient to overcome intrinsic defects in patient-derived T cell responses, supporting the use of healthy donor-derived TCRs as a complementary approach.