Abstract
Efficient vaccination can be achieved by injections of in vitro transcribed mRNA (ivt mRNA) coding for antigens. This vaccine format is particularly versatile and allows the production of individualised vaccines conferring, T-cell immunity against specific cancer mutations. The CDR3 hypervariable regions of immune receptors (T-cell receptor, TCR or B-cell receptor, BCR) in the context of T- or B-cell leukaemia or lymphoma are targetable and specific sequences, similar to cancer mutations. We evaluated the functionality of an mRNA-based vaccine designed to trigger immunity against TCR CDR3 regions in an EL4 T-lymphoma cell line-derived murine in vivo model. Vaccination against the hypervariable TCR regions proved to be a feasible approach and allowed for protection against T-lymphoma, even though immune escape in terms of TCR downregulation paralleled the therapeutic effect. However, analysis of human cutaneous T-cell lymphoma samples indicated that, as is the case in B-lymphomas, the clonotypic receptor may be a driver mutation and is not downregulated upon treatment. Thus, vaccination against TCR CDR3 regions using customised ivt mRNA is a promising immunotherapy method to be explored for the treatment of patients with T-cell lymphomas.
Highlights
Design of an Ivt mRNA Coding for the T Cell Receptor (TCR) CDR3 Regions
Our work demonstrates that a recombinant mRNA coding for the TCR CDR3 alpha and beta regions formulated in a vaccine liposome can provide some protection against a tumour cell line expressing the corresponding TCR
In the light of our present data, it could be postulated that to the EL4 cell, the L12R4 cells can lose expression of V beta 12 and escape an immune response directed against this antigen
Summary
Vaccines based on in vitro-transcribed messenger RNA (ivt mRNA) have been shown to trigger specific immunity against the encoded antigen (cancer-associated antigens or proteins from pathogens) [1,2,3,4,5,6]. Several formulations are currently being evaluated in clinical studies for the treatment of cancers (e.g., melanoma, lung carcinoma) and infectious diseases (e.g., SARS-CoV-2, rabies, Zika virus, influenza) [7,8,9,10]. SARS-CoV-2 infection and the first to be approved [11]. Their implementation on a global scale is helping to curtail the current pandemic.
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