Breakthroughs with immunotherapy and the mRNA platform are heralding a new dawn for cancer treatment. Drs Daina Vanags, Cori Gorman and Christian K Schneider of Biopharma Excellence explore the potential for therapeutic cancer vaccines.
When the human papillomavirus (HPV) vaccine was approved, it established the principle that cancer can be prevented, perhaps even treated, by a vaccination. This success followed research which found that 95% of cervical cancers are due to HPV.
Now Merck, one of the leaders in HPV vaccination, is funding the development and worldwide license of a vaccine candidate to limit Epstein Barr virus (EBV) entry and infection of B cells after it was found that EBV increases the risk of some cancer types. The EBV candidate that Merck is developing in collaboration with ModeX is a nanoparticle vaccine.
Infection with human viruses found in tumours, such as EBV and HPV, are thought to represent the first step in the process leading to the generation of a malignant cell.
These developments are important next steps in the journey to better manage, treat and potentially cure cancer. They come as the field continues to witness breakthroughs with advanced immunotherapy treatments, offering clinicians and patients new options that go well beyond the traditional tools of surgery, chemotherapy and radiotherapy. Most notable are breakthroughs in genetically engineered T cells or chimeric antibody receptor (CAR)-specific T cell therapies, which utilize known tumour-associated antigens to attract tumour-specific T cells into the tumours.
Promising vaccine research
While the HPV vaccine and the EBV vaccine candidate are aimed at preventing infection, there is currently extensive research that establishes the potential for therapeutic vaccines to treat many different types of cancer, and potentially eradicate cancer cells. A search of ClinicalTrials.gov shows hundreds of studies into different types of cancer vaccines across all areas.
There is currently promising research into 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 phenotypes. A second area with potential is peptide-based specific, sometimes individualized, tumour vaccines. Advances in high-throughput genomic analysis as well as in epitope prediction “have enabled the design of personalized epitope peptides on the basis of mutations in cancer.”
Dendritic cells are seen as another good vehicle for tumour vaccination. While the one dendritic cell-based vaccine to receive approval, Sipuleucel-T for castration-resistant prostate cancer, has had limited uptake and was withdrawn from the EU in 2015 for commercial reasons, new approaches and agents show greater progress and promise for treating a variety of malignancies.
Hot versus cold tumours
Despite the promise, there are hurdles to overcome. One of these is the issue of hot versus cold tumours. Hot tumours are immunogenic, with an abundance of immune cells present, and T cells can be activated to attack tumour antigens. Cold tumours, are less immunogenic (as an example, pancreatic tumours are typically cold tumours); however, there are strategies to turn cold tumours into hot tumours to make them more sensitive to immunotherapy. Cold, or non-inflamed tumours, are generally characterized as having a lack of T-cell infiltration, which creates an immunosuppressive microenvironment around the tumour, allowing it to evade immune surveillance. Inflamed or hot tumours are characterized by high CD8+ T cell density and increased tumour PD-L1 expression.
For the vaccine to work, it must 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 be achieved 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.
Some of the autoimmunity issues facing cancer vaccines can perhaps be solved by using neoantigens, which, due to their underlying mutations, can signal the immune system to target cancer cells without seriously harming non-cancerous cells. As an example, a novel vaccine is being tested to target pancreatic cancer by supercharging the immune system, prompting immune cells to target the cancer 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 aim of shrinking the tumour. If the tumour returns and grows beyond a certain size, it is referred to as progression.
Vaccines, however, typically have a delayed response during which time the tumour might continue to grow. It would therefore be necessary to make a conscious decision to give the vaccine time to work.
Pseudoprogression is another consideration. This is where the tumour size appears to increase as the immune cells infiltrate the tumour before it shrinks, if treatment works as intended. Studies need to allow for this to ensure the cancer vaccine has time to demonstrate efficacy while at the same time not putting the patient at risk.
Often, for cancer vaccines to work effectively, and to be shown to work effectively, they need to be tested on patients with undamaged immune systems. Patients who previously have had chemotherapy treatment may not be suitable candidates.
There is a careful balance of considering that if the vaccine does not work for certain patients, those individuals could be exposed to risk, while the vaccine may fail to show efficacy when treated in patients who have been treated in other ways and have compromised immune systems. It is important, therefore, to consider all of this in trial design.
Exciting developments in mRNA
A further exciting development in cancer vaccine research is the mRNA platform. Some advantages are that mRNA vaccines can be modified more rapidly than protein-based vaccines. Additionally, they may generate more activated T-cells.
Next in cancer vaccine innovation is the use of novel technologies, such as next-generation sequencing (NGS) optimization using artificial intelligence, paired with scientific advances in areas such as mRNA or altered peptide ligands with powerful immunoactivators. Indeed, with peptide vaccines against RNA viruses, AI has been an important tool in helping to predict components that will produce an immune response, to understand and track the structure of viruses and to assess the value and potential of a vaccine. AI’s potential in supporting research into cancer vaccines is undeniable.
The fight against cancer has faced barriers both in terms of research and regulation. However, the latest breakthroughs suggest that effective therapies may soon be within reach. By combining scientific innovation with digital technologies such as AI-based algorithms to predict disease and working closely with regulatory bodies, the future of cancer vaccine therapies looks increasingly promising.
About the authors
Daina Vanags, Ph.D., is Principal Consultant, Senior Director Biopharma Excellence (BPE) and Head of Development Consulting and Scientific Affairs PharmaLex, and a member of the Strategic and Scientific Consulting Advisory Board. She has more than 18 years of commercial experience spanning scientific research, product development and executive management in the biotechnology industry.
Cori Gorman, Ph.D., is Senior Director, Biopharmaceutical CMC and Regulatory Affairs at Biopharma Excellence. She has more than 25 years of expertise in integrated drug development including modulating gene expression in vivo/in vitro and in innovative drugs in the field of monoclonal antibodies. Her career includes the development of innovative drug modalities such as non-viral gene therapies (Valentis), cancer vaccines and cell therapies, both autologous and allogeneic (Agenus).
Christian K Schneider, M.D., is Head of Biopharma Excellence and Chief Medical Officer (Biopharma) at PharmaLex. He was previously interim Chief Scientific Officer at the UK’s MHRA, where he was also Director of the National Institute for Biological Standards and Control (NIBSC) for five years. He has also held leading positions at the Danish Medicines Agency and at the Paul-Ehrlich-Institut, Germany’s Federal Agency for Vaccines and Biomedicines.
At EMA, he has chaired the Committee for Advanced Therapies (CAT) as well as the Biosimilar Medicinal Products Working Party (BMWP), and served as a member of the Committee for Medicinal Products for Human Use (CHMP). He is one of the key architects of EMA’s advanced therapies and biosimilars framework. As a regulatory scientist, Christian has published 50+ articles in international, peer-reviewed journals.
References
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