This study evaluates the therapeutic efficacy of neoantigen-screened tumor infiltrating lymphocytes (TIL) in patients with advanced gastrointestinal (GI) cancers, particularly demonstrating significantly improved response rates when combined with the PD-1 inhibitor pembrolizumab. This personalized cellular therapy strategy offers new hope for patients who do not respond to conventional immunotherapy.
Literature Overview
This article, titled 'Neoantigen-specific tumor infiltrating lymphocytes in gastrointestinal cancers: a phase 2 trial', published in the journal Nature Medicine, reviews and summarizes a non-randomized, single-center phase 2 clinical trial assessing the efficacy of neoantigen-specific selected tumor infiltrating lymphocytes (SEL-TIL) in advanced gastrointestinal (GI) cancers, and explores the impact of combining with the PD-1 inhibitor pembrolizumab (SEL-TIL + P) on treatment response. The study included 91 patients with refractory, mismatch repair-proficient metastatic GI cancers. The results showed no clinical response with unselected TIL therapy, while among 39 patients treated with SEL-TIL, 3 achieved partial response (7.7%), and in the SEL-TIL + P group of 34 patients, 8 achieved objective response (23.5%). Additionally, some patients showed significant tumor shrinkage even without meeting RECIST criteria, highlighting the potential of personalized immunotherapy in addressing tumor heterogeneity.Background Knowledge
Gastrointestinal cancers, including colorectal, pancreatic, and bile duct cancers, generally show low response rates to conventional immunotherapy, particularly in patients with proficient mismatch repair, who typically do not respond to immune checkpoint inhibitors like pembrolizumab. Although high tumor mutation burden (TMB) correlates with TIL therapy response in melanoma and non-small cell lung cancer, GI cancers often have lower TMB, and the presence of numerous non-specific bystander T cells in TIL limits therapeutic efficacy. This study aims to overcome T cell exhaustion and bystander effects by selecting TIL with clear neoantigen reactivity and combining with PD-1 inhibitors in some patients, thereby enhancing therapeutic outcomes. Transcriptomic analysis revealed enrichment of inflammatory pathways in the tumor microenvironment of responders, while activation of translational pathways was observed in non-responders, suggesting that specific molecular features may predict treatment response. Furthermore, the study highlights the critical role of CD4+ TIL in tumor response, providing a theoretical basis for optimizing adoptive cell transfer (ACT) therapy strategies in the future.
Research Methods and Experiments
The study enrolled 227 patients with metastatic GI cancers, of which 73 received neoantigen-specific TIL therapy. During the screening process, tumor mutations were identified through whole-exome and RNA sequencing, followed by synthesis of candidate neoantigen peptides or minigenes. TIL cultures were co-cultured with autologous dendritic cells to evaluate whether they exhibited specific T cell receptor activation. The final selected TIL products underwent functional testing prior to infusion to ensure their reactivity to neoantigens. Additionally, some patients received pembrolizumab after TIL infusion to further enhance anti-tumor immune responses. Safety was assessed based on adverse event data, and exploratory analyses were conducted to identify clinical and laboratory features associated with treatment response.Key Conclusions and Perspectives
Research Significance and Prospects
The study demonstrates that significant anti-tumor immune responses can be induced in GI cancers with low TMB by selecting TIL with neoantigen reactivity. Future research will focus on optimizing TIL selection strategies, such as selecting CD8+ TIL based on stem-like phenotypes or employing in vitro sensitization (IVS) techniques to improve response rates. Additionally, researchers are exploring predictive biomarkers based on transcriptomic features to guide patient selection and individualized treatment decisions. This study provides clinical evidence supporting the application of ACT in upper GI, hepatobiliary, and colorectal cancers, and emphasizes the importance of personalized immunotherapy in overcoming tumor heterogeneity.
Conclusion
This study demonstrates the potential of neoantigen-specific TIL therapy in treating advanced GI cancers, particularly the marked improvement in response rates when combined with PD-1 inhibitors. Although all patients experienced severe chemotherapy-related toxicity, the treatment-related mortality was low, and no long-term severe side effects were observed. The study also revealed the key role of CD4+ T cells in tumor response and the association between specific transcriptomic features and treatment outcomes. These findings lay the foundation for further development of personalized immunotherapy in GI cancers and provide new directions for treatment strategies in other cancers with low mutation burden. Although the current selection process is complex and time-consuming, future improvements through optimized screening techniques, AI-assisted analysis, or specific surface marker sorting are expected to enhance both the feasibility and efficacy of TIL-based therapies.
