Realising the promise of cancer vaccines

For years, the promise of therapeutic cancer vaccines has intrigued researchers working in the oncology space. And for good reason.

The concept of pre-emptively training the immune system to increase the frequencies of tumour-reactive T cells could be game-changing for cancer patients worldwide.

Preventative vaccines have already proven to be highly effective against certain cancer types. The Hepatitis B (HBV) vaccine and human papillomavirus (HPV) vaccines are key examples. Comparatively, realising the potential of therapeutic vaccines has been a challenging journey, with disappointing trial results dampening initial enthusiasm.

But, despite initial setbacks, the therapeutic potential of these cancer vaccines is far from over. Buoyed by recent technological advancements and a broadened understanding of tumour-associated antigens, therapeutic vaccines have undergone a resurgence of interest.

For Christopher Oelkrug, director of business development for Advanced Clinical, it’s an exciting time to investigate the clinical efficacy of therapeutic cancer vaccines. Particularly as recent results indicate that these treatments can help researchers address one of the biggest challenges in oncology – cancers’ so-called ‘stealth-mode’.

“The tumour environment is really problematic,” he explains. “Basically, tumours can go into ‘stealth mode’, which is not recognisable for the immune system. So, the ideal cancer vaccine has to overcome that immune suppression.”

Exposing the appearance of ‘stealth mode’ cancer cells

Overcoming cancer-induced immunosuppression and immunoresistance, or “stealth mode”, is a significant hurdle for those working to develop successful therapeutic cancer vaccines.

Unlike viruses and bacteria, which the immune system is highly adept at identifying as a foreign entity, some cancer cells undergo immune escape by MHC downregulation, immune checkpoint expression and/or tolerance inducing immune cells (Ma/Treg etc.) that makes them imperceptible to the immune system.

“The main challenge is to reactivate the immune system to see the tumour cell and recognise it as a threat,” says Oelkrug. “Cancer cells express tumour associated antigens and/or neoantigens. Even if you use these as a vaccine, you don’t really have an immunogenicity to them. You somehow have to increase that, so that the immune system gets primed.”

Mobilising the immune system is a primary function of therapeutic cancer vaccines. Whereas preventative vaccines work to prevent healthy cells transforming into tumour cells through viral infections, therapeutic vaccines are specifically designed to target tumour-induced immunosuppression, exposing the camouflaged cancer cells and jump-starting the immune response.

“Cancer vaccines have to induce humoral and cellular immunity,” explains Oelkrug. “With traditional vaccines, you normally have a humoural immunity, but in the cancer setting, you want CD8 cytotoxic T cell-mediated cellular immunity so that you have cytotoxic T cells that can actually attack the tumour.”

A decade of therapeutic innovation

Technological and scientific advancements have been instrumental in driving therapeutic cancer vaccine research.

Over the past decade, scientists have uncovered new information about the mechanisms that underpin immunotherapy treatments, including the advent of checkpoint inhibitors and mRNA vaccines. These breakthroughs have greatly expanded our understanding of the immune response to cancer and expanded the variety of patients eligible for immunotherapy treatments.

For Oelkrug, the disruption of COVID-19 has also contributed to growing interest and innovation in cancer vaccines. At the height of the pandemic, novel platforms received a surge of interest and investment, which ultimately led to the development and approval of a COVID-19 vaccine in just a few short months. Beyond the scope of this one disease, the mRNA vaccine technology has also been noted for its potential in developing cancer vaccines.

“Companies that were working on the COVID-19 mRNA vaccines, have already been working on cancer vaccines in the past and already had clinical trials ongoing,” he explains. “The next step is establishing the mRNA platform in the oncological field or as a therapeutic vaccine.”

How vaccines work with established treatments

As it stands, there is no one-size-fits-all solution for oncology, and vaccines form just one piece of a wider puzzle when it comes to treating and eradicating cancer.

In the past, research into the efficacy and safety of therapeutic cancer vaccines analysed drug candidates as a standalone treatment. Ultimately, this yielded disappointing results. However, when studied as a combination therapy, alongside conventional treatments such as chemotherapy, results have proven far more promising.

Metronomic chemotherapy – the process of administering specific chemotherapy in a low dose – has been shown to eliminate immunosuppressive cells in the tumour microenvironment. When used alongside therapeutic vaccines, the two treatment approaches work in tandem to reveal the presence of a tumour to the immune system and stimulate a timely response.

“Combination is key here,” says Oelkrug. “If you look at clinical trials to enhance the survival of patients, studies have shown that patients have an enhanced survival rate when they were treated besides the cancer vaccines, for example, with cyclophosphamide, which is a type of chemotherapy that depletes regulatory T cells in the tumour microenvironment and leads to an enhanced T cell infiltration.

“With low dose metronomic chemotherapy, or other checkpoint inhibitors in a tandem therapy or combination of therapies, you are able to enhance the total immune response to the tumour,” he says.

Addressing challenges through delivery systems

Developing a successful therapeutic vaccine for a complex and evolving target is an ambitious goal for researchers.

While cancer vaccines are promising immune-therapeutics for establishing immune surveillance, Oelkrug notes that further research and the translation into the clinic has to be conducted by identifying neoantigens, developing combination therapies, and optimising the current vaccine platforms before cancer vaccines become a potent strategy in immunotherapy.

“The main problem of older generations of cancer vaccines was the low level of antigen production,” says Oelkrug. “Previous studies have shown an inefficient cellular delivery of plasmids when you look at, for example, DNA cancer vaccines, which led to an insufficient stimulation of the immune system.

“Therefore, you want to change different points within the whole development of cancer vaccines, and you can do that by the antigen design itself. You can look at different antigens, and the vector system you’re using, such as viral vectors, the dose, and how the vaccine is actually delivered.”

Moreover, it is important to acknowledge that cancer vaccines are more suitable for patients with a functioning immune system. Each patient will have individual needs, and while different routes of delivery make it possible to elicit specific immune responses, clinical trials of cancer vaccines should fully consider the patient’s immune system function, risk of recurrence, and tumour burden.

What’s next for therapeutic vaccines?

Success rarely happens overnight. Recent progress in the therapeutic cancer vaccine pipeline provides a strong example of how unforeseen industry innovation can push the boundaries of treatment beyond what is currently possible.

If the current trajectory of progress is maintained, therapeutic vaccines could become a reality for cancer patients around the world. Moreover, a greater understanding of the immune system will allow researchers to explore additional areas where vaccines could be impactful.

“More vaccines getting approved will lead to a huge impact on how we can treat cancer,” says Oelkrug. “Getting away from really harsh treatments and looking at cancers that are not operable, or where the survival rate is really low.”

For Oelkrug, this tenacity is an encouraging sign that further progress is attainable as each seemingly small step brings the industry and patients closer to the ultimate goal of eradicating cancer.

“There is no golden bullet to target tumour cells, like cancer,” he concludes. “It’s always the next challenge to try and get rid of them.”

Christopher Oelkrug

Christopher Oelkrug is a director of business development at Advanced Clinical. His main focus is on identifying new opportunities with clients to provide a better clinical experience. Based on his broad experience in Cancer Immunotherapy and Immunology and his entrepreneurial mindset, Christopher brings a unique perspective to novel developments within these therapeutic fields. He has a M.Sc. in Cancer Immunotherapy and was head of immunotherapy and oncology at a German research institute. Furthermore, Christopher is the holder of two patents in gut microbiome modulation and antibiotic resistance via IgY mediated therapy.

Advanced Clinical is a clinical development and strategic resourcing organisation committed to providing a better clinical experience across the drug development journey. Our goal is to improve the lives of all those touched by clinical research – approaching each opportunity with foresight, character, resilience, and innovation. Based on decades of experience, we help our clients achieve better outcomes by conducting candid conversations and anticipating potential issues through our customised solutions. Visit our website to learn more: www.advancedclinical.com.

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