Gene Therapy

We are currently advancing the clinical developments of the following gene therapies and anti-cancer therapy with the aim of commercialization.

What is Gene Therapy?

Oncolytic virus HF10 project

Oncolytic virus HF10 Takara Bio acquired the HF10 business from M's Science Corporation in November 2010, and owns 100 percent of the worldwide rights to HF10.

HF10 is an attenuated, replication-competent mutant strain of Herpes Simplex Virus type 1 (HSV1). HF10 a spontaneously occurring mutant of HSV1 newly established by Professor Yukihiro Nishiyama, Nagoya University, School of Medicine, and it does not contain any foreign DNA. Live viruses such as HSV infect human cells, replicate, and destroy the infected cells. Using this property of viruses, the new approach to cancer therapy termed "oncolytic virotherapy" has been developed and investigated. HF10 is one of the promising new strains for oncolytic virotherapy. HF10 shows a strong killing effect against tumor cells because of its high replication competence in these cells. Moreover, administration of HF10 also induces a strong immune response which is expected to further enhance the anti-tumor activity. The virulence of HF10 is significantly reduced compared to wild-type HSV1 because it carries mutations in genes controlling virulence.

Three investigator-initiated clinical studies with HF10 were conducted in the hospital of Nagoya University, Japan. These clinical studies demonstrated oncolytic activity and tolerability of HF10 in cancer patients. In February 2012, Mie University Hospital began a clinical study on solid tumors. Further, in April 2013, Nagoya University School of Medicine commenced a clinical study with patients suffering from non-resectable pancreatic cancer for the treatment in combination of HF10 with existing anticancer drugs. In the U.S., Phase I clinical trial targeting solid cancers was completed and Phase II clinical trials targeting malignant melanoma are now underway.

Information of the HF10 clinical trial (ClinicalTrials.gov Identifier:NCT02272855):
A Study of Combination Treatment With HF10 and Ipilimumab in Patients With Unresectable or Metastatic Melanomas

TCR gene therapy project

TCR gene therapy project T-cell receptor (TCR) gene therapy, is one of the new adoptive immunotherapies, which get attention as "tailor-made therapy" against cancers. In this gene therapy, the T-cell receptor genes which recognize cancer antigens are transduced into lymphocytes of a cancer patient for treatment. During this process, it is important to transduce the genes with high efficiency into lymphocytes, and RetroNectin® is used for this purpose. The gene-modified lymphocytes are cultured in a large scale, and infused back into the patient. The lymphocytes express the T-cell receptors on the surface, and these receptors recognize the peptides derived from the cancer antigens. So the gene-modified lymphocytes can specifically attack tumor cells expressing the cancer antigens and kill them finally.

TCR gene therapy has lots of advantages compared with the vaccine therapy using peptides of the cancer antigens. This gene therapy does not require the induction of lymphocytes which specifically recognize the tumor cells expressing the cancer antigens inside the body, and enables to prepare the lymphocytes already having cytotoxicity against tumor cells specific for the cancer antigens ex vivo. Also it is possible to determine the effective doses of infused cells, and also to control the patient's immune background in a different way and so on.

Concerning this type of gene therapy, we are providing RetroNectin® for Dr. Steven Rosenberg at the National Cancer Institute in the U.S. He is one of the pioneers in the development of the adoptive immunotherapy and currently conducting the clinical trials of the TCR gene therapy for metastatic malignant melanoma. His group transduces the T-cell receptor genes which recognize melanoma cancer antigens, MART-1, gp100 or NY-ESO-1, into the patient-derived lymphocytes for the trial.

In Japan, Mie University Hospital, in collaboration with Takara Bio Inc., is conducting clinical research on TCR gene therapy targeting esophageal cancer. Also, Mie University Hospital, Ehime University Hospital, Nagoya University Hospital, and Fujita Health University Hospital are conducting clinical research on TCR gene therapy targeting acute myeloblastic leukemia (AML) and myelodysplastic syndromes (MDS).

Phase I clinical trials(investigator-initiated trials) for the MAGE-A4 antigen-specfic TCR gene therapy began in March 2014.

Further, the Company is also preparing to start up a new project involving NY-ESO-1 antigen-specific TCR gene therapy with the aim of commencing a Phase I clinical trial.

MazF gene therapy project

Oncolytic virus HF10 MazF gene therapy uses MazF, an endoribonuclease derived from Escherichia coli, as a retroviral technology for HIV gene therapy. In HIV disease, HIV infects a type of immune cell called helper T-cells or macrophages and subsequently replicates, causing deficiencies in the helper T-cells and the entire immune system. MazF gene therapy uses expression vector to transduce autologous helper T-cells ex vivo with genes that express MazF conditionally upon HIV infection. The MazF-modified T-cells that are infused back into the patients are expected to block the replication of HIV when it infects the transduced T-cells, thereby maintaining sufficient immune functions. Thus, autologous transplantation of MazF-modified T-cells is an attractive strategy for HIV gene therapy.

Takara Bio, in a joint effort with the University of Pennsylvania and Drexel University, commenced in December 2012 MazF gene therapy Phase I clinical trial in the United States for patients that have been infected by the HIV. This Phase 1 clinical trial is open labeled study and the patients will be monitored for safety, tolerability and immunogenicity of the autologous helper T-cells modified with the MazF endoribonuclease for six months. The MazF retroviral vector for this study is manufactured at the GMP compliant facility of Takara Bio (Kusatsu, Shiga, Japan). The patients' helper T-cells were modified with MazF retroviral vector at the University of Pennsylvania.

Information of the HF10 clinical trial:
Redirected MazF-CD4 Autologous T Cells for HIV Gene Therapy

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