Chronic lymphocytic leukemia

Antibodies conjugated with viral antigens elicit a cytotoxic T cell response against primary CLL ex vivo

Abstract

Chronic lymphocytic leukemia (CLL) is the most frequent B cell malignancy in Caucasian adults. The therapeutic armamentarium against this incurable disease has recently seen a tremendous expansion with the introduction of specific pathway inhibitors and innovative immunotherapy. However, none of these approaches is curative and devoid of side effects. We have used B-cell-specific antibodies conjugated with antigens (AgAbs) of the Epstein–Barr virus (EBV) to efficiently expand memory CD4+ cytotoxic T lymphocytes (CTLs) that recognized viral epitopes in 12 treatment-naive patients with CLL. The AgAbs carried fragments from the EBNA3C EBV protein that is recognized by the large majority of the population. All CLL cells pulsed with EBNA3C–AgAbs elicited EBV-specific T cell responses, although the intensity varied across the patient collective. Interestingly, a large proportion of the EBV-specific CD4+ T cells expressed granzyme B (GrB), perforin, and CD107a, and killed CLL cells loaded with EBV antigens with high efficiency in the large majority of patients. The encouraging results from this preclinical ex vivo study suggest that AgAbs have the potential to redirect immune responses toward CLL cells in a high percentage of patients in vivo and warrant the inception of clinical trials.

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Acknowledgements

This work was supported by the German Cancer Aid (Deutsche Krebshilfe) (VS, MI, and DGvZ). The authors thank all participants, patients, and healthy volunteers, as well as physicians, nurses, and clinical investigators. We thank Martin Müller, PhD (DKFZ, F035), Remy Poirey, PhD, and Zhe Li (DKFZ, F100) for helpful discussions.

Author contributions

VS performed the experiments, analyzed the data, and wrote the manuscript. MI and DGvZ undertook research and provided technical support. PD designed the clinical protocol and provided blood samples. SF designed the clinical investigation protocol and undertook research. JM provided T cell clones and oversaw research. HJD planned the study, oversaw the research, and wrote the manuscript. All authors approved the article.

Funding

This work was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe).

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Correspondence to Henri-Jacques Delecluse.

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The authors declare that they have no conflict of interest.

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