Clinical trials of self-replicating RNA-based cancer vaccines

Therapeutic cancer vaccines, designed to activate immune effectors against tumor antigens, utilize a number of different platforms for antigen delivery. Among these are messenger RNAs (mRNA), successfully deployed in some prophylactic SARS-CoV2 vaccines. To enhance the immunogenicity of mRNA-deliver...

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Bibliographic Details
Published in:Cancer gene therapy 2023-06, Vol.30 (6), p.803-811
Main Authors: Morse, Michael A, Crosby, Erika J, Force, Jeremy, Osada, Takuya, Hobeika, Amy C, Hartman, Zachary C, Berglund, Peter, Smith, Jonathan, Lyerly, H Kim
Format: Article
Language:English
Subjects:
Antigen (tumor-associated)
Antigens
Cancer vaccines
Cancer Vaccines - genetics
Carcinoembryonic antigen
Clinical trials
COVID-19 - genetics
Encephalitis Virus, Venezuelan Equine - genetics
Epitopes
ErbB-2 protein
Expression vectors
Genetic Vectors
Human papillomavirus
Humans
Immunogenicity
Immunotherapy
Monoclonal antibodies
mRNA
mRNA vaccines
Nanoparticles
Neoplasms - genetics
Neoplasms - therapy
PD-1 protein
Pembrolizumab
Replicon
Ribonucleic acid
RNA
RNA viruses
RNA, Messenger
RNA, Viral - genetics
SARS-CoV-2 - genetics
Severe acute respiratory syndrome coronavirus 2
Structural proteins
Tumors
Vaccines
Venezuelan equine encephalitis
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Summary:Therapeutic cancer vaccines, designed to activate immune effectors against tumor antigens, utilize a number of different platforms for antigen delivery. Among these are messenger RNAs (mRNA), successfully deployed in some prophylactic SARS-CoV2 vaccines. To enhance the immunogenicity of mRNA-delivered epitopes, self-replicating RNAs (srRNA) that markedly increase epitope expression have been developed. These vectors are derived from positive-strand RNA viruses in which the structural protein genes have been replaced with heterologous genes of interest, and the structural proteins are provided in trans to create single cycle viral replicon particles (VRPs). Clinical stage srRNA vectors have been derived from alphaviruses, including Venezuelan Equine Encephalitis (VEE), Sindbis, and Semliki Forest virus (SFV) and have encoded the tumor antigens carcinoembryonic antigen (CEA), human epidermal growth factor receptor 2 (HER2), prostate specific membrane antigen (PSMA), and human papilloma virus (HPV) antigens E6 and E7. Adverse events have mainly been grade 1 toxicities and minimal injection site reactions. We review here the clinical experience with these vaccines and our recent safety data from a study combining a VRP encoding HER2 plus an anti-PD1 monoclonal antibody (pembrolizumab). This experience with VRP-based srRNA supports recent development of fully synthetic srRNA technologies, where the viral structural proteins are replaced with protective lipid nanoparticles (LNP), cationic nanoemulsions or polymers.
ISSN:0929-1903
1476-5500
1476-5500
DOI:10.1038/s41417-023-00587-1