In an effort to stimulate T cell and antibody responses against tumor-expressed antigens, numerous platforms like proteins, peptides, viral vectors, DNA plasmids, and RNA have been modified for use as therapeutic cancer vaccines. Despite the long-standing enthusiasm for using mRNA as a platform for vaccines, difficulties have included its short half-life and transient protein expression. This is despite its safety (inability to integrate into the genome or produce infectious virus), innate immunity induction, and convenience. As described in many journals, encoding replicases, single-stranded, self-replicating, positive sense RNA (srRNA), and target tumor antigens in place of viral structural proteins can convey more antigen over a longer period of time and produce enormous amounts of mRNA coding for the target tumor antigen compared to non-replicating mRNA. Rapid production, simplicity of administration, safety, and powerful and long-lasting immune responses have all been shown in preclinical and clinical evidence.
Breast Cancer
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Anti-CEA antibody titer elevated
The development of these vaccines for the treatment of cancer, where the ability to provoke an immune response and the safety and possibility of combination with other therapies can be challenging, has been supported by the positive clinical experience with srRNA for infectious disease applications, which is substantially further along in development.
The majority of research using viral replicon particles (VRP) generated from the alphaviruses Venezuelan Equine Encephalitis virus (VEE), Semliki Forest Virus (SFV), and Sindbis make up the clinical experience using srRNA vectors in patients with cancer. However, preliminary research using entirely synthetic srRNAs, where the protective lipid nanoparticle (LNP) shell is used in place of the viral structural proteins, has also shown significant safety and immunogenicity.
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A group of patients with advanced HER2+ breast cancer has recently undergone clinical trial testing. A combination of self-replicating RNA and the anti-PD-1 antibody pembrolizumab was employed. Since many adenocarcinomas have high levels of carcinoembryonic antigen (CEA), immunotherapy techniques, including this trial, usually target this molecule. The VRP-CEA(6D) (AVX-701) vaccine is based on VEE and expresses CEA(6D). T cell receptor recognition is improved by this.
A total of 28 patients received 4 doses of intramuscular injections of VRP-CEA(6D) every three weeks for a total of four vaccinations. The vaccine was well tolerated, there was minimal reaction at the site of injection and no fever. After immunization, beginning with the second or third dose, CEA-specific immune responses, measured by anti-CEA antibody titer and T-cell tests, grew and then appeared to plateau after the first four doses. One patient experienced total response while two were stable. On follow-up, 3 patients were cancer free.
Clinical significance
Clinical trials using viral replicon-based srRNA vaccines have shown safety with little injection-related harm. The development of srRNA platforms for malignancy will benefit from the knowledge obtained with srRNA and its delivery vehicles during their development for infectious illness indications.
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Final thoughts
Enhanced T-cell penetration into tumor tissue when srRNA vaccinations are combined with immune checkpoint inhibition has been observed. The goal of the HER2 and pembrolizumab randomized phase II study was to determine whether the two drugs work better together to improve intratumoral T-cell responses and clinical activity in patients with advanced illness.
References
Morse, M. A., Crosby, E. J., Force, J., Osada, T., Hobeika, A. C., Hartman, Z. C., Berglund, P., Smith, J., & Lyerly, H. K. (2023). Clinical trials of self-replicating RNA-based cancer vaccines. Cancer Gene Therapy, 30, 803-811. https://doi.org/10.1038/s41417-023-00587-1
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