Scientific Rationale for Combination Immunotherapy of Hepatocellular Carcinoma with Anti-PD-1/PD-L1 and Anti-CTLA-4 Antibodies

The outcomes of immune checkpoint inhibitor therapies against advanced cancer have greatly exceeded initial expectations since the early clinical studies reported in 2010 [1] and 2012 [2]. It is now evident that immune checkpoint inhibitors are highly effective against multiple solid tumors in addition to malignant melanoma, which was the first malignancy to be studied. Although researchers were initially skeptical about the practical use of conventional cancer immunotherapies that solely enhance immune responses, scientists in both industry and academia are vigorously pursuing the development of anticancer immunotherapies using immune checkpoint inhibitors. In fact, the journal Science designated cancer immunotherapy as the “Breakthrough of the Year” in 2013, and the journal Nature named immune checkpoint blockade in cancer a paradigm shift in cancer treatment. Since then, various industry-academia collaborations have been initiated, and the remarkable strides in this field have been hailed as “the dawn of the new cancer therapy era” [3] and the “renaissance of cancer immunotherapy” [4]. The first immune checkpoint molecule to be described, programmed cell death protein 1 (PD-1), was identified in 1992 by Dr. Tasuku Honjo and colleagues at Kyoto University [5]. Published online: September 27, 2019