mRNA-Based Anti-TCR CDR3 Tumour Vaccine for T-Cell Lymphoma

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.

Recent advances in mRNA‐based vaccine for cancer therapy; bench to bedside

“…TLR‐7 and ‐8, which belong to the PRR family, play a major role in the detection of IVT mRNA within the endosome. This detection is then carried out by the MyD88 process, which in turn triggers Type‐1 interferon (IFN) processes and the release of proinflammatory cytokines 54–56 . Other PRR families, such as retinoic acid‐inducible gene‐I‐like (RIG‐I‐like) receptors, oligoadenylate synthetase (OAS) receptors, and RNA‐dependent protein kinase (PKR), detect these exogenous mRNAs in the cytosol.…”

“…This detection is then carried out by the MyD88 process, which in turn triggers Type-1 interferon (IFN) processes and the release of proinflammatory cytokines. [54][55][56] Other PRR families, such as retinoic acid-inducible gene-I-like (RIG-I-like) receptors, oligoadenylate synthetase (OAS) receptors, and RNAdependent protein kinase (PKR), detect these exogenous mRNAs in the cytosol. As previously discussed, [57][58][59] these PRRs have the ability to sensor various RNAs, such as double-stranded RNA (dsRNA) and single-stranded RNA, which prevents mRNAs translation.…”

The use of RNA-based treatments in the field of cancer immunotherapy

“…Multiple IVT mRNA-based cancer vaccines are currently tested in clinical trials, either encoding personalized neoantigens, or a cocktail of TAAs [622]. Deliver systems for these mRNA-based cancer vaccines include lipid polyplexes, CNEs, LNPs or protamine [2].…”

mRNA vaccines: A novel weapon to control infectious diseases

“…Unlike viral or DNA vaccines, mRNA vaccines are not integrated into the host genome ( Zhang et al, 2020b ). Instead, mRNA vaccines are designed to rapidly express the encoded antigen in the body and thereby quickly elicit an immune response ( Tusup et al, 2021 ). Although the instability of single-stranded mRNA and the inefficiency of in vivo delivery were initially challenging ( Asrani et al, 2018 ), these problems were eventually solved.…”