A CD19-Anti-ErbB2 scFv Engager Protein Enables CD19-Specific CAR T Cells to Eradicate ErbB2 + Solid Cancer

The efficacy of CD19-specific CAR T cells in the treatment of leukemia/lymphoma relies, at least in part, on the unique properties of the particular CAR and the presence of healthy B cells that enhance the target cell lysis and cytokine secretion through repetitive stimulation. Here, we report to ap...

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Bibliographic Details
Published in:Cells (Basel, Switzerland) Switzerland), 2023-01, Vol.12 (2), p.248
Main Authors: Hombach, Andreas A, Ambrose, Christine, Lobb, Roy, Rennert, Paul, Abken, Hinrich
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Antibodies
Antigens
Antitumor agents
B-Lymphocytes
Cancer
CD19
CD19 antigen
Cell activation
Cell cycle
Cell fusion
chimeric antigen receptor
Cytotoxicity
ErbB-2 protein
ErbB2 (Her2/neu)
Fibroblasts
Fusion protein
herceptin
Humans
Hypotheses
Lymphocytes
Lymphocytes B
Lymphocytes T
Lymphoma
Lysis
Malignancy
Neoplasms - therapy
Proteins
Receptor, ErbB-2
scFv fusion protein
Solid tumors
T-Lymphocytes
Trastuzumab
Tumors
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Summary:The efficacy of CD19-specific CAR T cells in the treatment of leukemia/lymphoma relies, at least in part, on the unique properties of the particular CAR and the presence of healthy B cells that enhance the target cell lysis and cytokine secretion through repetitive stimulation. Here, we report to apply the same CAR to target solid tumors, such as ErbB2 carcinoma. CD19 CAR T cells are redirected towards the ErbB2 cells by a fusion protein that is composed of the herceptin-derived anti-ErbB2 scFv 4D5 linked to the CD19 exodomain. The CD19-4D5scFv engager enabled CD19 CAR T cells to recognize the ErbB2 cancer cells and to suppress the ErbB2 tumor growth. The primary killing capacity by the ErbB2-redirected CD19 CAR T cells was as efficient as by the ErbB2 CAR T cells, however, adding CD19 B cells furthermore reinforced the activation of the CD19 CAR T cells, thereby improving the anti-tumor activities. The ErbB2-redirected CD19 CAR T cells, moreover, showed a 100-fold superior selectivity in targeting cancer cells versus healthy fibroblasts, which was not the case for the ErbB2 CAR T cells. The data demonstrate that the CD19 CAR T cells can be high-jacked by a CD19-scFv engager protein to attack specifically solid cancer, thereby expanding their application beyond the B cell malignancies.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells12020248