Targeted Immunotherapies in Gastrointestinal Cancer: From Molecular Mechanisms to Implications

Abstract

Gastrointestinal cancer is a leading cause of cancer-related mortality and remains a major challenge for cancer treatment. Despite the combined administration of modern surgical techniques and chemoradiotherapy (CRT), the overall 5-year survival rate of gastrointestinal cancer patients in advanced stage disease is less than 15%, due to rapid disease progression, metastasis, and CRT resistance. A better understanding of the mechanisms underlying cancer progression and optimized treatment strategies for gastrointestinal cancer are urgently needed. With increasing evidence highlighting the protective role of immune responses in cancer initiation and progression, immunotherapy has become a hot research topic in the integrative management of gastrointestinal cancer. Here, an overview of the molecular understanding of colorectal cancer, esophageal cancer and gastric cancer is provided. Subsequently, recently developed immunotherapy strategies, including immune checkpoint inhibitors, chimeric antigen receptor T cell therapies, tumor vaccines and therapies targeting other immune cells, have been described. Finally, the underlying mechanisms, fundamental research and clinical trials of each agent are discussed. Overall, this review summarizes recent advances and future directions for immunotherapy for patients with gastrointestinal malignancies.

Cancer Stem Cells in Tumor Microenvironment of Adenocarcinoma of the Stomach, Colon, and Rectum

“…Checkpoint inhibitors, such as the CTLA-4 and PD-1 inhibitors tremelimumab, and nivolumab, have presented limited activity. In addition, the Check-Mate-142 trial (Phase II) evaluated nivolumab and nivolumab plus ipimumab in patients with metastatic CRC with MSI-H/dMMR or MSS/pMMR status, showing improvement in patient survival [ 130 ]. Moreover, the FDA-approved nivolumab (Opdivo) combined with chemotherapy for initial treatment of patients with advanced or metastatic GC due to improvement in survival compared with placebo [ 131 ].…”

“…Coadjuvant therapy with FOLFOX and PD-1/PD-L1 inhibitors achieved an objective response rate (ORR) of up to 50% and increased survival. In MSI-H/dMMR CRC, checkpoint inhibitors should be used after therapy with first-line drugs such as fluoropyrimidine, oxaliplatin, and irinotecan [ 130 ].…”

Colorectal cancer vaccines: The current scenario and future prospects

“…DCs are matured in culture with cytokines and pulsed with exogenous peptide or tumor lysate to be prepared for infusion into patients. DC vaccines, indicating ideal effects in clinical trials of melanoma and prostate cancer ( 52 ), are commonly studied in CRC as well.…”

Implication of gut microbiome in immunotherapy for colorectal cancer

“…Tumor microenvironment (TME) includes multiple types of cells, such as fibroblasts, immune cells, endothelial and stromal cells[ 66 ]. TME demonstrates a significant role in immune responses, particularly in CRC, and constitutes as a therapeutic target for many anti-cancer agents[ 67 ].…”