An invited review following the Soujinkai Fujiu Memorial Award: Development of the Novel Immunotherapies Based on the Analyses of Suppressive Immunity in Gastrointestinal Cancer

Surgical resection is the most effective treatment for gastrointestinal cancer; however, a novel treatment is needed for unresectable cases. We have developed an immunotherapy for gastrointestinal cancers. In 1990, we devised a combination immunotherapy for hepatocellular carcinoma using interleukin-2, OK-432, Adriamycin, cyclophosphamide, and famotidine, which resulted in complete response in 4 out of 24 patients. Subsequently, we developed immune cell therapies for gastrointestinal cancers. Tumor antigen-specific immunity was first reported in 1991. We administered cancer vaccines using epitope peptides derived from oncoantigens for colorectal and pancreatic cancers. As a result, antigen-specific immunity was induced at a high frequency, and cases showing long-term antitumor effects were observed, whereas cases that were ineffective were also observed; therefore, we searched for the cause. A comprehensive analysis of lymphocytes, serum, and tumor tissues revealed the presence of many immunosuppressive factors. Therefore, we developed an immune adjuvant that induces cytotoxic T lymphocytes without fatigue markers and tumor antigen-specific peptides. This vaccine was administered preoperatively in 20 cases of hepatocellular carcinoma; 12 cases showed significant lymphocyte invasion into tumors and tumor necrosis in 6 cases, and these results suggested that hepatocellular carcinoma changed into a hot tumor. This immunotherapy is expected to be useful in combination with checkpoint inhibitors.