Tumor-penetrating peptide boosts bispecific T-cell engager antitumor efficacy for the pancreatic cancer

Lu Zou^1,2Jingjing Chen^1,2Xinyuan Bai^1,2Yingxin Wang^1,2Changchang Lu³Wang Qiaoli¹Subiyinuer Tuerhong^1,2Mengzhu Li²Qinghua Zheng²Fanyan Meng^1,2*Juan Du^1,2*

• ¹Nanjing University of Chinese Medicine, Nanjing, China
• ²Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China
• ³Zhejiang University, Hangzhou, China

Background: One of the main hurdles in solid tumors to the limited response of immunotherapy is the lack of sufficient T-cell infiltrate. This study aims to construct an iRGD-modified BiTE-directed T-cell therapeutic approach to enhance the treatment efficacy against KRAS G12V-mutated pancreatic cancer. Methods: We used a novel bispecific T-cell engager (BiTE) targeting the HLA-A2/KRAS G12V complex and CD3 (HLA-A2/KRAS G12V-CD3 BiTE). By modifying with iRGD, we induced BiTE-mediated inward flow of activated effector T cells, specifically targeting the KRAS G12V mutation and improving tumor tissue penetration to address the problem of limited efficacy due to insufficient effector cells infiltration. Results: The results demonstrated that iRGD modification could promote tumor-specific lymphocyte infiltration and accumulation in tumor tissue, significantly inhibit tumor growth, and prolong survival in a xenograft pancreatic tumor model. This dual-action approach enhances T-cell infiltration by promoting transvascular and stromal penetration, greatly enhancing the efficacy of bispecific antibodies in solid tumors, leading to effective tumor eradication. Conclusions: These findings strongly suggest further clinical validation of this iRGD-modified BiTE-directed T-cell therapeutic approach, potentially offering a more effective treatment option for patients with pancreatic cancer and other solid tumors.