4231 Background: Tumor specific neoantigens are peptides carrying somatic mutations presented by HLA molecules and recognized by T cells, which subsequently induce specific immune response (IR). The IR could be further boosted when in combination with PD-1/L1 inhibitor. RGL-270 is a lipid nanoparticle (LNP)-encapsulated, mRNA-based PCV, encoding tumor specific neoantigens screened via a proprietary algorithm to induce patient specific IR. This investigator-initiated, open-label, dose escalation and expansion clinical trial was conducted in China, to evaluate the safety, efficacy and immunogenicity of RGL-270 in combination with adebrelimab (anti-PD-L1 mAb) in patients with resectable PDAC. Methods: PDAC patients with R0/R1 surgical margins were enrolled. After surgery, RGL-270 was administrated up to 9 cycles, in combination with adebrelimab and followed by modified FOLFIRINOX chemotherapy. The key endpoints included safety, efficacy assessment with recurrence-free survival (RFS), overall survival (OS), 18-month RFS rate, and PCV specific IR evaluation by ELISpot. Results: As of 01/15/2026, 16 patients in the dose escalation (n = 7) and expansion (n = 9 at expansion dose level) stage received RGL-270 combo with adebrelimab therapy. Up to date, all dose levels were safe and well tolerated. The most common treatment-related adverse events (TRAEs) were fever, influenza-like illness and injection-site reactions. All TRAEs were CTCAE grade 1~2 and no treatment-related SAE or DLT was reported. Currently, the median follow-up is 18.0 months, with median RFS and OS not reached yet, and the 18-month RFS rate is 100%.The PCV-specific IR positive rate was 100%. Interestingly, IR was also detected in patients who had undergone prior splenectomy (5/16). The primary IR emerged as early as 2 cycles after the first PCV administration, with the best of response (BoR) observed 2~4 cycles post-baseline and, in most cases, persisting until cycle 9, the booster cycle. To date, no dose-dependent manner for IR has been observed. Additionally, concordance between the predicted and immunogenic neoantigens was analyzed, and the resulting insights were fed back to improve the neoantigen screening algorithm. Furthermore, bulk T-cell receptor sequencing was performed to further characterize the PCV specific IR. Conclusions: Based on proprietary LNP delivery systems, algorithms for neoantigen identification and immunogenicity prediction, the combination treatment of RGL-270 and adebrelimab demonstrated a favorable safety profile, promising efficacy, and robust immunogenicity. This preliminary result guarantees the further development of PCV-based anti-tumor therapy in the adjuvant setting for PDAC. Clinical trial information: NCT06156267 .
Shi et al. (Wed,) studied this question.