A phase I study of a mutant KRAS-targeted long peptide vaccine in patients at high risk of developing pancreatic cancer.

Abstract

TPS758 Background: KRAS mutations are identified in the majority of premalignant lesions that precede pancreatic ductal adenocarcinoma (PDAC). Arising during tumorigenesis, mutant KRAS (mKRAS) neoantigens are less susceptible to central tolerance mechanisms and serve as ideal vaccine targets. Indeed, targeting mKRAS neoantigens with vaccines has shown promising anti-tumor activity in the preclinical setting. For instance, our group previously demonstrated that a Listeria-based vaccine targeting mKRAS G12D combined with Treg-depleting agents can prevent the progression of early pancreatic intraepithelial neoplasia to overt PDAC in a mouse model (Keenan et al, 2014). Building upon this work, the current study aims to determine the safety and immunogenicity of a pooled synthetic long peptide (SLP) mKRAS vaccine in patients identified as high risk for developing PDAC based on family history and germline mutation testing. Methods: This is a single-arm, open-label phase I trial evaluating a pooled SLP mKRAS vaccine in patients at high risk of developing PDAC ( n = 20). The vaccine consists of poly-ICLC adjuvant admixed with SLPs corresponding to six common mKRAS subtypes: G12D, G12R, G12V, G12A, G12C, and G13D. A four-dose series of the mKRAS vaccine is administered on weeks 1, 3, 4, and 17. Following completion of the treatment phase, all patients have the option to continue annual follow-up visits until study closure. Eligible patients must have radiographic evidence of a premalignant pancreatic lesion and fall under at least one of the following three high-risk groups: 1) ≥ 2 familial pancreatic cancer relatives, 2) germline mutation carriers with ≥ 10% lifetime PDAC risk and 3) germline mutation carriers with ~5% lifetime PDAC risk. The co-primary endpoints of this study are safety and T cell response. Safety will be assessed by the frequency and grading of adverse events per NCI CTCAE v5.0. T cell response will be determined by the maximal percent change in IFNγ-producing mKRAS-specific T cell density within 16 weeks post-vaccination compared to baseline. Correlative studies will explore vaccine-associated changes in T cell quality (e.g., memory, exhaustion, poly-functionality, and activation) using mass cytometry analysis of peripheral blood samples. Patient accrual began in April 2022 and is currently ongoing. Clinical trial information: NCT05013216 .

Current and future immunotherapeutic approaches in pancreatic cancer treatment

“…As our understanding of the complex interplay between the immune system and pancreatic cancer continues to evolve, the field of pancreatic cancer immunotherapy is positioned at the forefront of cutting-edge research. These groundbreaking domains of research, such as machine learning and artificial intelligence [ 547 ], mutant KRAS peptide-driven vaccines and personalized RNA neo-antigen vaccines [ 401 , 548 ], single-cell multi-omics-oriented approaches [ 546 , 549 ], and CRISPR/Cas-based RNA editing [ 550 ], are of utmost importance as they define the active research areas of the future, paving the way for gaining better clinical outcomes. Given the role of artificial intelligence in cancer research, researchers used machine learning to analyze complex tumor molecular data from pancreatic cancer patients and found that anti-CD40 therapy reduced T-cell exhaustion in the TME.…”