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Abstract

Chronic lymphocytic leukemia (CLL) is the most frequent type of B cell leukemia in adults. Treatment options against this incurable disease have continually been expanding with strategies using specific antibodies, inhibitors and individualized adaptive immunotherapy. However, none of these approaches is curative and devoid of adverse effects. In this preclinical ex vivo study, a novel therapeutic approach has been developed that uses B cell-specific antibodies coupled with antigens (antigen-armed antibodies, AgAbs) derived from the Epstein-Barr virus (EBV). The breadth of the immunogenic epitope repertoire within the coupled antigen is a critical factor for the immune response amplitude as it determines the potential number and diversity of memory T cell clones that can be reactivated. Along this line, a strongly immunogenic latent EBV antigen named EBNA3C was fragmented into large segments and conjugated to the antibody vehicles. Application of these antibody conjugates to leukocytes isolated from treatment-naïve CLL patients led to an efficient expansion of CD4+ T cells that recognized EBNA3C in all tested cases. Moreover, CLL cells pulsed with EBNA3C-AgAbs induced specific responses of these T cells with widely varying intensities across the patient population. Interestingly, a large proportion of the EBV-specific T cells consisted of highly efficient cytotoxic T lymphocytes (CTLs) that eliminated CLL cells loaded with EBNA3C through the granzyme B (GrB)/perforin-mediated pathway. The encouraging results from this study demonstrate the potential of AgAbs to redirect endogenous CD4+ CTLs against CLL cells loaded with EBV antigens in a high percentage of patients, and warrants the inception of clinical trials.