Translational development of a novel BAFF-R CAR-T therapy targeting B-cell lymphoid malignancies

• Published in: Cancer Immunology, Immunotherapy Vol. 72; no. 12; pp. 4031 - 4047
• Main Authors: Luo, Yan, Qie, Yaqing, Gadd, Martha E., Manna, Alak, Rivera-Valentin, Rocio, To, Tommy, Li, Shuhua, Yassine, Farah, Murthy, Hemant S., Dronca, Roxana, Kharfan-Dabaja, Mohamed A., Qin, Hong
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2023; Springer Nature B.V
• Subjects: Antigens, CD19; Antitumor activity; BLyS protein; Cancer Research; CD19 antigen; Cell culture; Cell proliferation; Cell therapy; Chronic lymphocytic leukemia; Cytotoxicity; Humans; Immunology; Immunotherapy, Adoptive; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - therapy; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma - therapy; Malignancy; Medicine; Medicine & Public Health; Monoclonal antibodies; Oncology; Receptors, Chimeric Antigen; Tumor cells; Tumors; BAFF-R; CAR-T; Lymphoma; Immunotherapy; Leukemia; B-cell malignancies
• ISSN: 0340-7004; 1432-0851; 1432-0851
• DOI: 10.1007/s00262-023-03537-w

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. Graphical abstract