May 2023 • PharmaTimes Magazine • 28-29
// VACCINES //
Empire strikes back
Therapeutic cancer vaccines can destroy our most formidable enemy
Laboratory research, digital technologies and regulatory authorities are working hand in hand to bring therapeutic cancer vaccines to market.
Cancer research has come a long way in a short space of time. As immunotherapy and gene therapy pioneer Dr Stephen Rosenberg has pointed out, the traditional tools available to treat cancer – surgery, chemotherapy and radiotherapy – now have a fourth pillar. immunotherapy.
Advances in immunotherapy treatments, starting with early steps such as interleukin-2, and more recently the US FDA-approved immunotherapies that target critical immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death receptor 1 (PD-1) represent significant advances and are now standard of care treatments for advanced melanoma.
More recently, genetically engineered T cells or chimeric antibody receptor (CAR)-specific T cell therapies, which utilise known tumour-associated antigens to attract tumour-specific T cells into the tumours, have dramatically improved outcomes for many cancer patients.
Fine lines
An important next step in the journey is the development of cancer vaccines. There has been huge success with vaccination against human papillomavirus (HPV), following evidence that 95% of cervical cancers are due to HPV – specifically HPV types 16 and 18 and further findings that HPV is likely to be responsible for 70% of oropharyngeal cancers.
Although the HPV vaccines do not clear existing HPV infections, the success of the HPV vaccines has established the principle that cancer can be prevented, perhaps even treated, by a vaccination.
Current research sets out the potential for therapeutic vaccines to treat patients with cancer with the hope of eradicating cancer cells – and not just those caused by viruses. Areas in which promising research into therapeutic vaccines is taking place include vaccines to induce an immune response against E6 and E7 oncoproteins in advanced cancers of the head and neck. E6 and E7 are the main oncoproteins in high-risk HPV types.
Another area with potential is peptide-based specific, sometimes individualised, tumour vaccines. Advances in high-throughput genomic analysis as well as in epitope prediction ‘have enabled the design of personalised epitope peptides on the basis of mutations in cancer.’
A third area that has shown promise is cell-based vaccines with dendritic cells. In fact, one therapeutic cancer vaccine that has received regulatory approval is a dendritic cell-based vaccine (Sipuleucel-T) for castration-resistant prostate cancer, which the US FDA approved in 2010.
The vaccine stimulates immune cells with an antigen – in this case prostatic acid phosphatase (PAP) – and an immune stimulant (GM-CSF).
The product was withdrawn from the EU in 2015 for commercial reasons and, according to reports, there has been limited uptake of Sipuleucel-T in the clinic. Although dendritic cell vaccines have not shown good clinical response since then, improved methods are being researched.
In addition, a comprehensive search of ClinicalTrials.gov shows there is a wealth of research in the field with hundreds of products in various stages of clinical research across many different cancers.
‘Current research sets out the potential for therapeutic vaccines to treat patients with cancer with the hope of eradicating cancer cells’
Surmountable hurdles
Nevertheless, many companies have hit barriers in their attempts to develop targeted therapeutic cancer vaccines.
The first, as with immunotherapy, is the issue of hot versus cold tumours. Cold tumours are less immunogenic, while hot tumours are immunogenic with an abundance of immune cells present, and T cells can be activated to attack tumour antigens.
There are a number of strategies to turn cold tumours into hot tumours to make them more sensitive to immunotherapy. Cold, or non-inflamed tumours, are generally characterised as having a lack of CD8+ T lymphocytes, an abundance of the immunosuppressive cell populations such as tumour-associated macrophages, T-regulatory cells and myeloid-derived suppressor cells, a low mutational load, low major histocompatibility complex (MHC) class I and low PD-L1 expression.
These create an immunosuppressive microenvironment around the tumour, which is then able to evade immune surveillance. Inflamed or hot tumours are characterised by high CD8+ T cell density, which are functionally active and increased tumour PD-L1 expression.
The conundrum is that for a vaccine to work, it has to break down the body’s natural tolerance of the immune system against ‘self’ structures as they are found in tumours, and that can trigger autoimmunity.
This would occur either by forcing an immune response against tumour antigens that show similarity with the body’s own structures, or by activating other T cells as well in the drive to overcome immune system silencing, thus activating autoimmune T cells, which are usually dormant.
A solution to some of the autoimmunity issues facing cancer vaccines has perhaps been found in the use of neoantigens, which due to their underlying mutations can signal the immune system to target cancer cells without seriously harming non-cancerous cells.
There is also a need to consider tumour progression. Before a patient is enrolled for chemotherapy, the tumour is measured and treatment is then applied with the objective of shrinking the tumour. If the tumour returns and grows beyond a certain diameter, it is referred to as progression.
With vaccines, however, there is typically a delayed response during which time the tumour might continue to grow. There would therefore have to be a conscious decision to give the vaccine time to work.
The other issue is pseudoprogression, where the tumour size appears to increase as the immune cells infiltrate the tumour before it shrinks – assuming the treatment works as intended. Any study needs to consider this to allow the cancer vaccine treatment time to be effective, while balancing the potential need to start a different treatment regimen.
Ultimate aims
Apart from CAR-T cells, possibly the biggest recent game changer in cancer vaccine research is the mRNA platform, thanks to its potency, specificity, adaptability, safety, and the fact that it can be scaled up quickly for extensive and relatively low-cost manufacturing.
Indeed, the success of the COVID-19 vaccines can be attributed to many years of mRNA cancer vaccine research, which demonstrated the safety and low side-effect profile of mRNA vaccines. From a regulatory perspective, the success of the COVID-19 vaccines perhaps instils a level of trust in the technology and is seen as a proof of concept.
Technologies such as next-generation sequencing optimisation using artificial intelligence, along with scientific advances in areas such as mRNA or altered peptide ligands with powerful immunoactivators, may be the key to cancer vaccine innovation.
This combination of laboratory research and digital technologies working alongside regulatory authorities is vital to bring therapeutic cancer vaccines to market and deliver enhanced patient outcomes.
Daina Vanags, Cori Gorman, Christian K Schneider are from Biopharma Excellence.
Go to biopharma-excellence.com
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