Practical CAR-T cell therapy for solid tumors based on AI-driven science

Breaking the Wall of "Solid Tumors" with AI-Driven Science: Toward social implementation of next-generation CAR-T cell therapy

Chimeric Antigen Receptor T cell (CAR-T cell) therapy is a treatment in which T-cells, a type of immune cell collected from the patient or a third party, are genetically modified to give them the ability to attack tumors and administered to the patient. This therapy has shown high efficacy, including complete cures, against B-cell-derived hematological malignancies such as acute lymphocytic leukemia, malignant lymphoma, and multiple myeloma. In Japan, five CAR-T cell products are currently on the market.

While research institutions and pharmaceutical companies worldwide are working to apply this high efficacy to other cancers, unfortunately, no CAR-T cell product has yet shown clear efficacy against solid tumors leading to approval. Our research group aims to develop and commercialize CAR-T cell therapies that can bring cures to intractable solid tumors such as brain tumors, pancreatic cancer, breast cancer, and lung cancer.

The difficulty in developing immune cell therapies, including CAR-T, for solid tumors is largely attributed to the unique immunological, physical, and metabolic barriers inherent to the tumor. Such tumor environments inhibit the infiltration, normal cellular function, and long-term persistence of T-cells, which play a crucial role in anti-tumor immune responses, thereby limiting the efficacy of CAR-T cell therapy.

To overcome this, we focused on the transcription factors and nutrient transporters (survival mechanisms) that tumor cells themselves effectively utilize to survive within the tumor microenvironment. By applying these same mechanisms to the enhancement of T-cells, we successfully developed an original CAR-T cell activation platform that enables both activation and long-term persistence simultaneously (left figure).

In an intracranial tumor-bearing model of glioblastoma (GBM), characterized by a severely low-glucose environment, we have confirmed effective activation and enhanced metabolic function of these CAR-T cells, as well as anti-tumor effects including cures and improved survival.

Another characteristic of our research and development lies in CAR design using molecular design technology based on AI-driven science. This utilizes one of the world's largest proprietary databases and algorithms cultivated by our collaborator, MOLCURE Inc.

Conventional CAR design has relied on empirical methods based on existing antibodies. Designing an optimal CAR was not easy due to limitations in target epitope and affinity design, as well as the occurrence of tonic signaling (so-called CAR runaway) caused by unexpected ligand-independent self-aggregation of the CAR.

In this research and development, we aim to design, develop, and commercialize unprecedented high-functional CAR-T cells at high throughput and low cost using this AI-driven CAR design method. To date, we have successfully designed several high-functional CARs targeting mesothelin, expressed in pancreatic cancer and others, and ROR1, expressed in breast and lung cancers.

Moving forward, we will analyze the functional details of these CAR-T cells while formulating clinical trial protocols, preparing for the manufacture of clinical trial products, and conducting non-clinical studies in cooperation with the Department of Experimental Therapeutics at the National Cancer Center Japan (NCCJ).

In this research project, we are advancing development toward regulatory approval and commercialization under a partnership with ARC Therapies Inc., a venture company originating from the NCCJ. While venture-led drug discovery has become a vital modality for new drug development, particularly in the United States, there has unfortunately not yet been a case of a CAR-T cell product from a Japanese venture company receiving approval.

During the R&D, we aim to establish effective CAR-T cell therapy for solid tumors and to become a pioneer for the successful drug discovery by regenerative cell medicine ventures in Japan.