The Covid-19 pandemic boosted advancing technology to create vaccines incorporating messenger RNA. Professor Alain Astier discusses how these vaccines have further potential to be rapidly tailored to target oncogenic profiles and provide significant benefits in personalising cancer treatment.
Edward Jenner’s pioneering work in his 1801 treatise On the Origin of the Vaccine Inoculation and the first successful vaccination against smallpox heralded the development of vaccine therapy from the second part of the 19th century onwards.
One area in which exciting progress has been made is in immunotherapy and the development of cancer vaccines including messenger RNA (mRNA) variants. Unlike traditional immunisation, the situation in cancer is more complex. It requires sophisticated approaches to develop appropriate vaccines as the cancer cells more closely resemble normal, healthy cells than bacterial or fungal allergens do.
Preventive or therapeutic?
The first preventive cancer vaccine, against hepatitis B virus-induced hepatocarcinoma, was launched in 1982. Other preventive vaccines, such as those against human papillomavirus, are currently in use.
There are four main types of therapeutic cancer vaccines:
1. Cell-based vaccines
Cell-based cancer vaccines use all the antigens expressed by tumour cells: tumour-associated antigens (TAAs) and tumour-specific antigens (TSAs).
TAAs, such as HER2/neu, are self-proteins (antigens originating within the body) abnormally overexpressed by cancer cells. TSAs are antigens specific to some tumour cells, such as mutated Kras or β-catenin.
In cellular cancer vaccines, cultured cells from tumour cell banks are injected globally to provoke the immune response, similar to classic vaccination, or incubated with cultured dendritic cells. The dendritic cells present the antigens to T lymphocyte CD4+ helper and CD8+ cytotoxic cells, which induces activation, multiplication and migration into the tumour through the lymphatic system.
Cancer cell cultures can also liberate soluble TAAs or TSAs into the culture media, which can be injected as an alternative to the cells.
‘Antigenic essence’ technologies comprise a target fraction of cellular antigens, the composition of which is precisely controlled by mass spectrometry. Antigenic essence technology makes it possible to update many existing cellular vaccines and to develop new ones, thereby introducing a further direction for anticancer vaccine research.
2. Viral-based vaccines
Viral-based cancer vaccines use engineered viruses as vectors to deliver tumour antigens to the immune system. This requires virus proliferation and requires complex and potentially hazardous handling.
3. Peptide-based vaccines
Peptide-based cancer vaccines stimulate the immune system using antigenic peptides corresponding to cancer epitopes of interest. These antigenic peptides can be produced via fractionating larger antigen proteins or by bioengineering after the DNA sequences coding for them are identified.
4. Nucleic acid-based vaccines
Nucleic acid-based cancer vaccines utilise DNA or RNA to encode tumour antigens that are presented to the immune system using various delivery platforms such as liposomes or nanoparticles. A typical nucleic acid vaccine is the mRNA Covid-19 vaccine. Although designed to fight a non-oncogenic virus, it provoked much interest in the potential of mRNA vaccine technologies in cancer.
Production, penetration and personalisation
At the industrial level, the production of cancer vaccines is a complex process. Indeed, mass culture, which requires trypsinisation to detach the adherent cells, all under strict aseptic conditions, is complicated and expensive.
In the case of personalised vaccines, the cancer cells are derived from individual patients, and the industrial-scale production of cellular-based vaccines can, again, be complex and challenging. However, production at the local level, such as within hospitals, could be encouraged.
The production of peptide-based vaccines is more affordable. Mass production of peptides via automation does not require cell culture; it only involves sequencing of the DNA coding for the protein or peptides of interest.
The principle is to obtain a tumour sample from an individual patient or a cancer cell bank to establish a DNA mutation map compared to healthy cells from the same patient or from normal cells and the organ of origin. The map is used to identify the corresponding DNA sequence of numerous tumour antigens and to synthesise the corresponding peptides. However, this approach requires producing and purifying large quantities of peptides.
Problems with protein or peptide handling, such as aggregation or instabilities, frequently occur and require substantial expertise. Moreover, these foreign peptides can also induce severe allergic responses.
A more innovative approach is theoretically to inject the corresponding mRNAs directly, which ‘orders’ the synthesis of corresponding peptides by the patient’s cells with good efficiency and safety.
Thus, after identifying the DNA sequence coding for the antigenic peptides and combining it with today’s methods for nucleic acid synthesis, it is straightforward to produce sufficient mRNA.
However, a severe limitation previously was significant instability and poor intrinsic cellular penetration due to the very polar nature of the mRNA. Moreover, simple mRNAs are recognised as foreign substances and are rapidly eliminated from the body.
Thanks to the 2023 Nobel Laureates Katalin Karikó and Drew Weissman, whose pivotal discoveries concerning nucleoside base modification enabled the development of effective mRNA vaccines against Covid-19, it is now possible to overcome the underlying instability of engineered mRNAs.
State-of-the-art mRNA constructs confer many improvements regarding purification, the structure and length of untranslated regions, regulatory elements and modifications of coding sequences.2 For example, replacing uridine bases with pseudouridine in an mRNA sequence dramatically improves the yield of the corresponding protein.1
Using nano-delivery systems can overcome the difficulties in transporting and encapsulating these custom-made mRNAs into cells.3,4 These include lipid-based nano vectors, such as liposomes or lipoplex particles, and dendrimer polymer nano vectors, which are often commercially available or easily manufactured.5
Moreover, mRNAs can also be vectorised by viruses or polypeptides rich in arginine, which neutralise very polar polynucleotides and facilitate penetration through the cell membrane.
The benefits of the mRNA approach
The main benefits of the mRNA approach to producing vaccines are the ease of manufacture on an individual scale, the lack of need to handle viruses or perform cell culture, the lack of complex protein production, and very rapid processes that are less expensive than those for classical vaccines.
Thus, small-scale units such as academic facilities can easily produce personalised vaccines. Several mRNAs coding for several cancer antigens can be administered simultaneously. The rapidity of obtaining mRNAs could also permit adapting the vaccine to the evolution of the tumour in terms of neoantigen expression. Furthermore, an excellent tolerance has been demonstrated in several clinical trials as an mRNA vaccine is, per se, non-immunogenic.
mRNAs can also help promote the production of a corresponding antibody by the host B cells. In this case, the idea is to replace the repetitive administration of a large quantity of a monoclonal antibody with a single injection of its corresponding mRNA.
As demonstrated by Pardi and colleagues, a single injection of the mRNAs that encode the VRC01 monoclonal antibody against HIV surface protein led to robust production of this antibody protein in the livers of mice within 24 hours.6 A weekly injection was enough to maintain high levels of circulating VRC01 antibodies.
This approach could also benefit by dramatically simplifying the production of anticancer monoclonal antibodies, making it achievable at the hospital level.
Building on mRNA success
From the pioneering work with mRNA anti-Covid vaccines, mRNA therapeutic vaccines are now regarded as an attractive and promising alternative to conventional vaccines for transmissible diseases and cancers.7,8
Although most of these cancer vaccines are still experimental, some have shown promising results in clinical trials, with positive responses in shrinking tumours and improving patient survival.
Author
Alain Astier PharmD PhD
Honorary head of the Department of Pharmacy, Henri Mondor University Hospital, and French Academy of Pharmacy, Paris, France
References
1 Karikó K et al. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 2005;23,(2):165–75.
2 Duan L-J et al. Potentialities and Challenges of mRNA Vaccine in Cancer Immunotherapy. Front Immunol 2022;13:923647.
3 Liu T, Liang Y, Huang L. Development and delivery systems of mRNA vaccines. Front Bioeng Biotechnol 2021;9:718753.
4 Hou X et al. Lipid nanoparticles for mRNA delivery. Nat Rev Mater 2021;6(12):1078–94.
5 Campani V et al. Lipid Nanovectors to Deliver RNA Oligonucleotides in Cancer. Nanomaterials 2016;6(7):131.
6 Pardi N et al. Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge. Nat Commun 2017;2:8:14630.
7 Jackson NAC et al. The promise of mRNA vaccines: a biotech and industrial perspective. npj Vaccines 2020;5:11.
8 Li Y et al. mRNA vaccine in cancer therapy: Current advance and future outlook. Transl Med 2023;13:e1384.
