As described above, there have been continuous attempts to develop immunotherapy for ovarian cancer, and recently, clinical efficacy has been shown in some instances. However, despite a long history of immunotherapy against solid cancers, the effect of cancer immunotherapy has been limited because there are several problems in its development. Every time new knowledge of tumor immunity was discovered in the basic fields, the new idea of immunotherapy was usually evaluated in preclinical trials with animal experiments similar to the process of evaluating other anticancer reagents. In this step, in vivo mouse models play an important role as an immunotherapy model, but there is inherent problem with the use of mouse models as the evaluation system. The use of established cancer cell lines along with pure mouse strains is thought to mimic the immune reaction of human immunity. This experimental system has been established using cancer cell lines from a wide variety of organs. The effect of the immunotherapies is validated in animal models as the preclinical phase and is eventually administered to actual cancer patients in clinical trials. However, in most cases, only a small percentage of the patients show efficacy despite a marked effect in the animal experiments. One of the reasons is that the immune reaction is a highly complex biological phenomenon compared to chemotherapy agents. In the case of chemotherapy agents, a mouse model system using transplanted tumor has much in common with human cancers, and the effectiveness of a therapy in animal experiments may predict clinical efficacy. In contrast, animal models of cancer immunotherapy are only a simplified model of the true complex tumor immunity in humans, and there is a large gap between them. For example, an established murine cell line often grows rapidly in vivo, but human cancers can maintain a state of dormancy for years. Such differences may influence the evaluation of tumor immunity.

Second, the evaluation method in clinical trials is also challenging regarding the clinical efficacy of immunotherapy. With chemotherapy agents, evaluating the tumor size may be associated with long-term efficacy. However, in case of immunotherapy, an initial antitumor effect does not necessarily correspond to the final clinical efficacy. Compared to conventional chemotherapies, immunotherapy requires a longer time interval to elicit an antitumor effect. However, we are unaware of the exact signaling mechanisms in the immune system, and we do not have a reliable method to predict the final effect of immunotherapy. Similar to other molecularly targeted drugs, it is important to develop effective predictive biomarkers in order to efficiently implement immunotherapy.

Several years ago, a novel immunotherapy attracted a great deal of attention. A therapy using an anti-PD-1 antibody, which inhibits the binding of PD-L1 to PD-1, was used for malignant melanoma, renal cancer, and lung cancer. The first trial showed that the antibody had a high antitumor effect not only in melanoma and renal cancer (which have high immunogenicity) but also in lung cancer, which is not considered to be immunogenic [21, 22].