CAR (chimeric antigen receptor)-expressing T-cell therapy was developed as a novel cancer immune-gene therapy. Particularly, CD19-directed-CAR-T cell therapy brought substantial benefit to patients with relapsed/refractory B-cell malignancies (leukemia and lymphoma). However, long-term follow-up revealed that survival rates gradually decreased and that clinical outcomes were not satisfactory, and therefore, further improvement is needed to establish more efficacious treatment. The main reasons for relapse after CAR-T cell therapy are inadequate in vivo persistence of CAR-T cells and antigen escape of tumor cells. To overcome the former problem, improving the manufacturing process of CAR-T cells is being investigated (e.g. the development of culture methods to expand naïve-like T and/or memory T cell fractions). Further, next-generation CAR-T constructs are also being designed, including optimizing the molecular structures of CAR and additional modification of CAR-T cells (so-called “armored” CAR-T cells). In this study, as a novel approach, we will develop an inducer-responsive selective regulatory gene (SRG) system that can selectively and artificially control in vivo proliferation and survival of administered CAR-T cells. As a first step, we will construct the SRG that gives T-cells the ability to respond to an inducer (a drug that can be safely administered to humans), and will confirm that T-cells carrying SRG proliferate in vitro in response to an inducer. If we can develop SRG that stimulates the growth of immature T-cells, we will be able to manufacture SRG/CAR-T cells that will show better persistence in vivo after infusion. Effector T-cells are not appropriate to get therapeutic efficacy, because they disappear soon after infusion. On the other hand, naïve-like T and/or memory T cells persist longer in vivo, and they will cause better clinical outcomes. Therefore, therapeutic efficacy of CAR-T cell therapy will be improved if in vivo long-term survival of CAR-T cells can be obtained by the SRG system. As a second step, we will confirm the efficacy of SRG/CAR-T cell therapy by using tumor-bearing immune-deficient mice. By using the SRG system, we can stimulate the growth and/or survival of SRG/CAR-T cells by the administration of an inducer depending on the conditions of the patients, leading to the establishment of innovative next-generation CAR-T cell therapy. SRG technology will be a breakthrough in treating not only hematological malignancies but also solid tumors that are refractory to current CAR-T cell therapy. Moreover, SRG technology can also be applied to TCR (T-cell receptor)-T therapy, another type of gene-modified T-cell therapy.
Figure 1: Selective in vivo expansion and persistence of SRG/CAR-T cellsIn the current CAR-T cell therapy, disappearance of CAR-T cells is a main reason of the early relapse (upper diagram). As a novel approach, we will develop an inducer-responsive selective regulatory gene (SRG) system that can control the proliferation and survival of administered CAR-T cells. Using this method, in vivo longer persistence of SRG/CAR-T cells will be obtained, and the prolonged survival and cure can be expected (lower diagram).
Figure 2: Research OrganizationPrincipal Investigator (Keiya Ozawa) and 2 Co-Investigators (Ryosuke Uchibori, Ken Ohmine) promote the research.
