As part of our goal to commercialize gene medicine, we are also pursing the following clinical developments of gene therapies.

What is Gene Therapy?

This project is being developed in alliance with MolMed S.p.A., an Italian company in Milan, and we acquired the license from MolMed S.p.A. on the development and commercialization of this project in Asia. In this gene therapy, we use suicide gene-transduced donor lymphocytes for hematological malignancies. We aim to apply the cells in the donor lymphocyte infusion (DLI) therapy to treat relapsed leukemia patients after allogeneic hematopoietic stem cell transplantation, and also in the add-back therapy to treat patients with hematological malignancies receiving haplo-identical (HLA-mismatched) T-cell depleted stem cell transplantation.
Two kinds of genes, a herpes simplex virus thymidine kinase (HSV-TK) gene and a truncated low-affinity nerve growth factor receptor (ΔLNGFR) gene, are transduced ex vivo into donor-lymphocytes using the retroviral vectors which are altered unable to replicate. The gene-transduced lymphocytes are purified by using the monoclonal antibodies against ΔLNGFR molecules expressing on the cell surface, cultured further, tested for its quality, and then infused into the patient (See the figure below).
It is well known that the HSV-TK gene is a suicide gene and the HSV-TK transduced cell can be selectively eliminated by ganciclovir (GCV), a drug approved to treat against cytomegalovirus (CMV) infection. In this therapy, we expect that the gene-modified donor lymphocytes attack the leukemic cell inside the patient’s body (it is called Graft-versus-Leukemia effect: GVL effect) and also work to protect from infections as the reconstituted immune system. On the other hand, the donor lymphocytes may attack the patient’s normal organs or tissues as non-self (it is called Graft-versus-Host Disease: GVHD). GVHD can be serious and may cause the patient’s death. So it is most important to avoid serious GVHD in the DLI therapy. In this gene therapy, we can suppress GVHD almost completely by administrating GCV, even if the GVHD is serious or lethal one. Thus this gene therapy makes possible to effectively infuse enough number of donor lymphocytes for the therapy without safety concerns about serious GVHD.
In Japan, approximately 20,000 people suffer from hematological malignancies per year and about 10 % of those people need transplantations. Although the decrease of the number of children in Japan may lead into the shortage of donors for allogeneic stem cell transplantation, this gene therapy will enable to extend to use haplo-identical (HLA mismatched) relatives as donors for the transplantation. Again this gene therapy is also used for the DLI therapy to improve his/her poor prognosis, even if the patient’s leukemia relapses after the transplantation. We, Takara Bio intend to provide the innovative gene therapy through this project.

T-cell receptor (TCR) gene therapy project, is one of the new adoptive immunotherapies, which get attention as “tailor-made therapy” against cancers. Establishing this therapy will lead to build up the universal use of our RetroNectin^® in the field of cancer immunotherapies. In this gene therapy, the T-cell receptor genes which recognize cancer antigens are transduced into tumor-infiltrating lymphocytes or peripheral blood 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 returned into the patient’s body. The lymphocytes express the T-cell receptors on the surface, and that 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.
The T-cell receptor 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 of tumor cells specific for the cancer antigens. Also it is possible to determine the effective doses of infused transduced 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 trial of the TCR gene therapy for metastatic malignant melanoma. His group transduces the T-cell receptor genes which recognize melanoma cancer antigens, MART-1 or gp100, into the patient-derived lymphocytes for the trial.
On the other hand, we are promoting the clinical development of the first Japanese TCR gene therapy targeted for esophageal cancer, in collaboration with Mie University School of Medicine. We are developing new technologies to prepare the TCR gene-transduced cells with high quality, in which the TCR genes for the treatment are transduced into the peripheral blood lymphocytes from the patient with high efficiency using RetoroNectin^® (See the figure below).

MazF gene therapy project