AVA-001

Several CD19-targeting CAR-T cells are used to treat leukemias and lymphomas; however, relapsed and/or refractory (R/R) disease is still observed in a significant number of patients. Additionally, the success of CD19-CAR-T cell therapies is not uniform across hematological malignancies, particularly in chronic lymphocytic leukemia (CLL). In this study, we present the development of a novel CAR-T cell therapy targeting B-cell activating factor receptor (BAFF-R), a key regulator of B-cell proliferation and maturation. A new monoclonal antibody against BAFF-R was generated from a hybridoma clone and used to create a novel MC10029 CAR construct. Through a series of in vitro and in vivo models using the Nalm-6 cell line for leukemia and the Z138 cell line for lymphoma, we demonstrated the antigen-specific cytotoxicity of MC10029 CAR-T cells against tumor cells. Additionally, MC10029 CAR-T cells exhibited potent antitumor effects against CD19 knockout tumor cells, mimicking CD19-negative R/R disease. MC10029 CAR-T cells were specifically targeted to CLL, in which BAFF-R is nearly always expressed. The cytotoxicity of MC10029 CAR-T cells was first shown in the MEC-1 CLL cell line, before we turned our efforts to subject-derived samples. Using healthy donor-engineered MC10029 CAR-T cells against enriched primary tumor cells, followed by subject-derived MC10029 CAR-T cells against autologous tumor cells, we showed the efficacy of MC10029 CAR-T cells against CLL subject samples. With these robust data, we have advanced to the production of MC10029 CAR-T cells, using GMP lentivirus, and obtained an IND approval in preparation for a Phase 1 clinical trial.

In the 2000s, development of chimeric antigen receptor(CAR)gene transferred(modified)T-cell therapy(CAR-T)and cancer antigen-specific T-cell receptor gene transferred(modified)T-cell therapy(TCR-T)has been actively pursued. Since 2017, several CD19-CAR-T cell therapies have been approved for some CD19-positive B-cell lymphomas/leukemias, as well as CAR-T therapies targeting B-cell maturation antigen(BCMA)for multiple myeloma. However, CAR-T cell therapies are also being developed for solid tumors, but none are approved at this time. In addition, CAR-T cell therapies that recognize complexes of MHC and cancer antigen-derived peptides have recently been developed. This article reviews the development status and future challenges of gene-modified T-cell therapy for solid tumors.