Abstract
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.
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Abbreviations
- ALL:
-
Acute lymphocytic leukemia
- BAFF-R:
-
B-cell activating factor receptor
- BCR:
-
B-cell receptor
- CAR:
-
Chimeric antigen receptor
- CLL:
-
Chronic lymphocytic leukemia
- CR:
-
Complete remission
- DLBCL:
-
Diffuse large B-cell lymphoma
- EGFR:
-
Epidermal growth factor receptor
- E:T:
-
Effector to target cell
- FL:
-
Follicular lymphoma
- GFP:
-
Green fluorescent protein
- GMP:
-
Good manufacturing practices
- IV:
-
Intravenous
- KO:
-
Knock out
- MCL:
-
Mantle cell lymphoma
- MOI:
-
Multiplicity of infection
- NHL:
-
Non-Hodgkin lymphoma
- NSG:
-
NOD scid gamma
- PBMCs:
-
Peripheral blood mononuclear cells
- PBS:
-
Phosphate-buffered saline
- scFv:
-
Single-chain variable fragment
- R/R:
-
Relapsed and/or refractory
- VSVG:
-
Vesicular stomatitis virus G
- WPRE:
-
Woodchuck hepatitis virus post-transcriptional regulatory element
- WT:
-
Wild type
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Acknowledgements
The authors thank the Animal Resource Center at Mayo Clinic Florida for daily care of mice used in this study and the flow cytometry facilities at Mayo Clinic Florida. The authors thank the MD Anderson Antibody Core Facility for their efforts to generate BAFF-R monoclonal antibodies.
Funding
We would like to acknowledge the generous funding support to HQ, which includes the Florida Health Grant (#MOG07, SB2500) and the Mayo Clinic Florida CAR-T Manufacturing Program Fund. HQ and MA K-D were also supported by the Fred C. and Katherine B. Andersen Foundation, Mayo Clinic Cancer Center, and the Mayo Clinic President's Discovery Translation Program Award.
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HQ and YL designed the project and studies. YL, YQ, AM, RR-V, SL and TT performed experiments and analyzed data. FY, HSM, and MAK-D organized subject selection and sample collection. MEG, HQ and YL contributed to manuscript writing. MEG generated final figures and participated in the final review with RD, HSM, MAK-D, and HQ. MAK-D and HQ supervised the entire project.
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HQ has equity with Pepromene Bio, Inc. and Innolifes Inc. The other authors have no competing interests.
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Luo, Y., Qie, Y., Gadd, M.E. et al. Translational development of a novel BAFF-R CAR-T therapy targeting B-cell lymphoid malignancies. Cancer Immunol Immunother 72, 4031–4047 (2023). https://doi.org/10.1007/s00262-023-03537-w
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DOI: https://doi.org/10.1007/s00262-023-03537-w