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

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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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Author notes

  1. Yan Luo and Yaqing Qie have equally contributed to the project.

Authors and Affiliations

  1. Regenerative Immunotherapy and CAR-T Translational Research Program, Mayo Clinic, 4500 San Pablo Rd S, Jacksonville, FL, 32224, USA

    Yan Luo, Yaqing Qie, Martha E. Gadd, Alak Manna, Tommy To, Shuhua Li & Hong Qin

  2. Division of Hematology and Medical Oncology, Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, USA

    Hemant S. Murthy, Roxana Dronca, Mohamed A. Kharfan-Dabaja & Hong Qin

  3. Blood and Marrow Transplantation and Cellular Therapy Program, Inpatient Hematology Unit, Mayo Clinic, Jacksonville, FL, USA

    Farah Yassine, Hemant S. Murthy & Mohamed A. Kharfan-Dabaja

  4. Department of Pediatric Hematology-Oncology, University of Florida-Jacksonville, Jacksonville, FL, USA

    Rocio Rivera-Valentin

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  1. Yan Luo
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Contributions

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.

Corresponding authors

Correspondence to Mohamed A. Kharfan-Dabaja or Hong Qin.

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Conflict of interest

HQ has equity with Pepromene Bio, Inc. and Innolifes Inc. The other authors have no competing interests.

Consent to participate

Informed consent was implemented for sample collection.

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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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