1. Autologous HER2 CAR-T cell therapy for advanced sarcoma and gynecological tumors
  2. Durable anti-tumor effects mediated more easily and safely through non-viral gene transfer

1. CAR-T Structure and mechanism of action

A chimeric antigen receptor (CAR) is a synthetic chimeric protein that is introduced into a T cell to redirect antigenic specificity and enhance cellular anti-tumor functionality. The receptor is engineered into T cells that are extracted from a patient.  A viral or non-viral vector is used to transfer the gene encoding CAR into T cells.

A CAR typically consists of an extracellular antigen-binding domain from an antibody and an intracellular T-cell activation and signaling domain.

The antigen-recognizing domain of a CAR is formed by variable regions of heavy (VH) and light (VL) chains, which are derived from a tumor antigen-specific monoclonal antibody and connected in the form of a single chain(scFv). The receptor enables CAR-T cells to target via the antigen-binding site and to lyse cancer cells by providing both activation and costimulatory signals to the CAR-engineered T cells via the signal transmitting domain and releasing cytotoxic proteins such as perforin and granzymes.



2. How CAR-T cell therapy works

A patient’s T cells are extracted and reprogrammed with CAR outside of the body to recognize and fight cancer cells expressing a specific antigen.

(1) Extract white blood cells, including T cells, from a patient
(2) Transfect CAR-encoding genes into T cells
(3) Expand the CAR-T cell population in culture
(4) Infuse CAR-T cells into the patient’s blood
(5) CAR-T cells proliferate in the patient's body and attack cancer cells


3. Characteristics of BP2301

BP2301 targets the HER2 antigen and uses a non-viral vector (PiggyBac transposon) to transfer the gene encoding HER2 CAR into T cells, which leads to high proliferative capacity and long-term persistence of CAR-T cells.

Most CAR-T therapies use viral vectors for CAR gene transfer, which leads to limited engraftment and a response duration lasting from a few days to a few weeks. This could cause a potential limitation of CAR-T cell efficacy in solid tumors that have an immunosuppressive tumor environment where long-term persistence of anti-tumor effects is required. To overcome this, BP2301 uses a non-viral gene transfer method established by Professor Yozo Nakazawa’s team and the newly developed CAR-T cell culture method (patent applied jointly with BrightPath). The BP2301 T cell subset is largely comprised of young memory T cells (TSCM, TCM) that have stem cell-like properties and differentiate into effector cells under antigenic stimulation. Such a cell population rich in young memory T cells exhibits high proliferative capacity and achieves long-term persistence of anti-tumor effects, which is expected lead to better clinical efficacy.

T cell subset and differentiation

TSCM:Stem Cell Memory T cell
TCM: Central Memory T cell
TEM: Effector Memory T cell
TEFF: Effector T cell
Figure: T cell subset and differentiation

BP2301 was created by Dr. Yozo Nakazawa, Professor and Chairman at Department of Pediatrics, Shinshu University School of

Medicine, and Dr. Shigeki Yagyu, Assistant Professor at Department of Pediatrics, Kyoto Prefectural University of Medicine.

An investigator initiated clinical trial of BP2301 for solid tumors (osteosarcoma) is expected to start in fiscal 2020.

BP2301 T cell subset

Figure: BP2301 T cell subset

While viral vectors serve as a tool for efficiently transferring genes into host cells, the clinical use of viral vector requires high-standard production facilities and extensive safety testing. On the contrary, the non-viral gene transfer method established by Professor Nakazawa has the advantage of easy operation with simplified facilities without impeding the anti-tumor effects of output products.

Development of piggyBac transposonmediated HER2-CAR-T cells for the treatment of solid tumors.
AACR 2022