Current Landscape of Adoptive Cell Therapy and Challenge to Develop “Off‐The‐Shelf” Therapy for Hepatocellular Carcinoma

ABSTRACT Adoptive cell therapy (ACT) is a type of immunotherapy in which autologous or allogeneic immune cells, such as tumor‐infiltrating lymphocytes or engineered lymphocytes, are infused into patients with cancer to eliminate malignant cells. Recently, autologous T cells modified to express a chimeric antigen receptor (CAR) targeting CD19 showed a positive response in clinical studies for hematologic malignancies and have begun to be used in clinical practice. This article discusses the current status and promise of ACT research in hepatocellular carcinoma (HCC), focusing on challenges in off‐the‐shelf ACT using primary cells or induced pluripotent stem cells (iPSCs) with or without genetic engineering. Early clinical trials of autologous GPC‐3‐, MUC1‐, or CEA‐targeted CAR‐T cell therapies are underway for HCC. There is a growing demand for the development of off‐the‐shelf therapies due to the high cost and manufacturing issues associated with autologous CAR‐T. The development of ACT from various cell sources, such as NK cells, NKT cells, macrophages, and γδ T cells without MHC restriction other than T cells has been proposed. Advances in genome editing, including HLA gene knockout to avoid GvHD, and strategies to enhance efficacy in overcoming the suppressive tumor microenvironment, are used to create universal ‘off‐the‐shelf’ CAR‐T cells which can be used immediately as therapeutic products from healthy donors or iPSC‐derived immune cells. Despite several limitations, cell‐based immunotherapy is expected to become a key cancer treatment modality for both hematologic malignancies and solid tumors including HCC, thanks to technological advancements overcoming these challenges.