piggyBac transposon-mediated CAR-T cell therapy
Pioneering CAR-T Cell Therapy for a Promising Future
Since our team first announced the development of CAR-T cells using the PB method in 2009,
we have dedicated ourselves to refining this cutting-edge technology.
CAR-T cell therapy has made significant strides in the treatment of B-cell tumors, a subset of hematologic tumors, and has gained clinical approval.
However, the progress in CAR-T cell therapy for other hematologic and solid malignancies has been hindered by challenges such as transient clinical effects and potential on-target toxicity.
Clinical application of CAR-T cell therapy
Overcoming Challenges through Innovative Strategies
In the pursuit of advancing CAR-T cell therapy, we recognize the crucial role of product quality
in determining clinical efficacy. One of the current challenges lies in the treatment of hematologic tumors, where stem cell memory T-cells within CAR-T cells play a vital role in achieving sustainable efficacy. Consequently, generating CAR-T cells with memory T-cell characteristics
has become a focal point in the field.
The quality of CAR-T cells determines the function
Unlocking the Potential: CAR-T Cells with Enhanced Effectiveness
Through our research, we have discovered that CAR-T cells generated using the PB method exhibit
notable advantages over traditional CAR-T cells. Our PB-generated CAR-T cells are less prone to immune exhaustion, a common issue faced by conventional CAR-T cells, which can compromise drug efficacy.
This can be attributed to the dominant integration of the CAR gene into memory T cells
facilitated by the PB method.
Moreover, our unique cell amplification technology allows for the preferential amplification of
memory T cells with the CAR gene, leading to reduced differentiation and diminished immune exhaustion.
As a result, we can produce CAR-T cells with ideal characteristics, ensuring sustained drug efficacy.
PB-mediated CAR-T cells exhibited memory phenotype
The Power of piggyBac: CAR-T Cells with Stem Cell Memory-like Properties
In contrast to the viral vector method predominantly used in CAR-T cell manufacturing today,
our employment of piggyBac transposon technology provides distinct advantages.
Traditional methods often activate T cells, leading to undesirable differentiation and immune exhaustion. Our technology addresses these concerns, enabling us to produce high-quality CAR-T cells
with sustained drug efficacy.
Additionally, our simplified manufacturing process and reduced costs improve
patient accessibility to CAR-T cell therapy.
PB-mediated CAR-T manufacturing
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Suematsu M, Yagyu S*, Nakazawa Y, et al. Targeting FLT3-specific chimeric antigen receptor T cells for acute lymphoblastic leukemia with KMT2A rearrangement. Cancer Immunol Immunother. 10. doi: 10.1007/s00262-022-03303-4. 2022
Suematsu M, Yagyu S*, Nakazawa Y, et al. PiggyBac Transposon-Mediated CD19 Chimeric Antigen Receptor-T Cells Derived From CD45RA-Positive Peripheral Blood Mononuclear Cells Possess Potent and Sustained Antileukemic Function. Front. Immunol. 13:770132. doi: 10.3389/fimmu.2022.770132, 2022
Tomida A, Yagyu S*, Nakazawa Y, et al. Inhibition of MEK pathway enhances the antitumor efficacy of chimeric antigen receptor T cells against neuroblastoma. Cancer Sci. Oct;112(10):4026-4036. 2021
Yagyu S*, Nakazawa Y*. Lymphodepleted non-human primate model for the assessment of acute on-target and off-target toxicity of human CAR-T cells. Clin Transl Immunol 10(6):e1291, 2021
Hasegawa A, Yagyu S, Nakazawa Y*, et al. Mutated GM-CSF-based CAR T-cells targeting CD116/CD131 complexes exhibit enhanced anti-tumor effects against AML. Clin Transl Immunol 10(5):e1282, 2021
Kubo H, Yagyu S*, Nakazawa Y, et al. Development of non-viral, ligand-dependent, EPHB4-specific chimeric antigen receptor T cells for treatment of rhabdomyosarcoma. Mol Ther Oncolytics 20:646-658, 2021
Morokawa H, Yagyu S*, Nakazawa Y*, et al. Autologous non-human primate model for safety assessment of piggyBac transposon-mediated chimeric antigen receptor T cells on granulocyte-macrophage colony-stimulating factor receptor. Clin Transl Immunol. 22;9(11):e1207, 2020
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Nakazawa Y*, et al. Evaluation of long-term transgene expression in piggyBac-modified human T lymphocytes. J Immunother. 36:3-10, 2013
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Nakazawa Y*, et al. PiggyBac-mediated cancer immunotherapy using EBV-specific cytotoxic T-cells expressing HER2-specific chimeric antigen receptor. Mol Ther. 19:2133-43, 2011
Huye LE, Nakazawa Y, et al. Combining mTor inhibitors with rapamycin-resistant T cells: A two-pronged approach to tumor elimination. Mol Ther. 19:2239-48, 2011
Manuri PV, Nakazawa Y, et al. piggyBac transposon/transposase system to generate CD19-specific T cells for treatment of B-lineage malignancies. Hum Gene Ther. 21:427-37, 2010
Galvan DL, Nakazawa Y, et al. Genome-wide mapping of PiggyBac transposon integrations in primary human T cells. J Immunother. 32:837-44, 2009
Nakazawa Y*, et al. Optimization of the PiggyBac transposon system for the sustained genetic modification of human T lymphocytes. J Immunother. 32:826-36, 2009