Just ten years ago it was hard to predict the progress that has been made within the field of cancer therapy. A cancer vaccine, including a universal cancer vaccine, as the ultimate goal is for many the holy grail, and several Norwegian companies are paving the way.

Cancer accounted for nearly ten million deaths in 2020, according to data from the World Health Organization (WHO), and the disease will cost the world 25 trillion USD over next 30 years (Kreier, Nature, 2023). However, the development of immunotherapy has been a game-changer within the field and these new cancer therapies are transforming the lives of patients as well as opening up exciting avenues for further research.

The concept dates back to the 1970s and in short  is a cancer treatment designed to boost the body’s natural defenses to the fight the cancer in the body. Important milestones include the identification of the structure of an antibody, Sir Frank Macfarlane Burnet’s theory of immune surveillance against cancer, and Nobel Laureates James Allison and Tasuko Honjo’s discoveries, which led to immune checkpoint therapy. For example, the checkpoint protein PD-1 in T cells acts as a type of “off switch” to prevent the T cells from attacking other cells. More recently, drug developers have come up with medicines (such as Keytruda and Opdico) to target those brakes. With the approved check point inhibitors (CPIs) many patients have a better prognosis now as compared to only ten years ago.

Read more: Interview James Allison

Read more: Interview Tasuko Honjo

Cancer immunotherapy could mean unleashing the body’s natural immune response to cancer but also helping the immune system find and destroy cancer cells. This therapy, also called immuno-oncology, can be divided into different types, one of which is cancer vaccines. According to Allied Market Research, the global cancer vaccines market is projected to reach 7 billion USD by 2027, from 4 billion USD in 2019.

The first cancer vaccines

Cancer vaccines started to be developed as soon as the link between human papillomavirus (HPV) and cancer was discovered in the 1980s. Nobel Laureate Harald zur Hausen and his colleagues discovered that two papilloma types, HPV 16 and HPV 18, were present in more than 70% of cervical cancers. They also found that part of the HPV genome was integrated into the human DNA in cervical cells that gave rise to cancer, leading to new ways of treating the disease.

In 2005–2006, more than 20 years after his discovery, the life science industry succeeded in developing an HPV vaccine to prevent cervical cancer. In addition to the HPV vaccine preventing cervical cancer, therapies to prevent hepatitis B, which can cause liver cancer, were created as well. These vaccines were the first-ever anti-cancer preventative treatments (prophylactic cancer vaccines).

Read more: Interview Harald zur Hausen

Therapeutic cancer vaccines

Besides preventative vaccines, there are great hopes for new therapeutic cancer vaccines, meant to treat cancer by stimulating the immune system so that it recognizes the cancer cells as foreign and attacks the cells. These are sometimes made with cells from the patient’s own tumor, which are modified in the lab and then returned to stop, destroy or delay the growth of the cancer. In 1990, Bacillus Calmette-Guérin – a vaccine for tuberculosis – became the first immunotherapy to be approved by the FDA for the treatment of early-stage bladder cancer.

Today, several decades later, therapeutic cancer vaccines have started to show efficacy and potential to help patients resistant to other immunotherapies. For example, recently Moderna and Merck announced that, when used together with Merck’s cancer immunotherapy Keytruda, their mRNA cancer vaccine reduced the risk of certain skin cancers from returning and patient deaths by 44% (compared with Keytruda alone). Although the study was small, these are promising results. In January the British government also announced that it was partnering with BioNTech to enroll as many as 10,000 patients in trials of a new mRNA cancer vaccine.

The pandemic has created a new sense of openness and trust to share early data and novel ideas. We’ve opened doors for one another, and I believe the way we are working now will carry forward into our future.”

The pandemic is one big reason behind the accelerated progress within vaccine research in general, many scientists state, but also within cancer. The world’s pharma companies and scientists came together and developed a vaccine against COVID-19 in record time. In an interview with NLS, Mikael Dolsten, CSO at Pfizer said, “The pandemic has created a new sense of openness and trust to share early data and novel ideas. We’ve opened doors for one another, and I believe the way we are working now will carry forward into our future.”

A universal vaccine

Both Moderna’s and BioNTech’s vaccines are personalized, i.e., specific to each patient, but our Nordic frontrunner, Ultimovacs, has a universal vaccine candidate (UV1) in the pipeline. The antigen the company vaccinates against is the enzyme telomerase (hTERT), a highly relevant target because 80-90% of all cancer indications express this antigen. As a result, this vaccine might become relevant for a very large number of cancer patients.

“The medical and scientific communities have been working for decades to develop an effective cancer vaccine. In the early days of cancer vaccine development, the industry saw some good immune responses in T cells, however clinical efficacy for patients disappointed,” says Jens Bjørheim, CMO at Ultimovacs. “We believe part of the challenge was the inability for these T cells to access the tumor. This challenge was critically addressed with the development of CPIs, which “opened the door” to the tumor. At the same time, CPIs are dependent on a good T cell repertoire in the individual patient for good efficacy, so we see potential for a mutual or synergistic benefit between CPIs and cancer vaccines.”

 

Jens Bjørheim, CMO, Ultimovacs. Photo: Anton Soggiu

 

In combination with the CPI pembrolizumab, UV1 has demonstrated a 60% objective response rate in metastatic malignant melanoma. The company has also announced that tumors were reduced to undetectable levels, a 30% complete response rate, in three patients.

We are currently investigating UV1 in malignant melanoma, pleural mesothelioma, head and neck cancer, ovarian cancer and non-small cell lung cancer, combined with different checkpoint inhibitors.”

“We apply a portfolio approach for our randomized Phase II program. We are currently investigating UV1 in malignant melanoma, pleural mesothelioma, head and neck cancer, ovarian cancer and non-small cell lung cancer, combined with different checkpoint inhibitors. We expect to report the results from the first two out of five Phase II clinical trials this year, both of which have completed enrollment,” describes Bjørheim.

The NIPU trial for patients with pleural metastatic mesothelioma, where patients receive either ipilimumab and nivolumab, or ipilimumab, nivolumab and UV1, is expected to report first half of 2023. The company also expects to report results from the INITIUM trial for patients with advanced or metastatic malignant melanoma, where patients also receive ipilimumab and nivolumab or ipilimumab, nivolumab and UV1, in the second half of 2023.

“For Ultimovacs, a top priority has been to develop the right peptides for the vaccination to enable a long lasting and relevant immune response in all parts of the tumor. We are encouraged by strong efficacy signals that we have seen in our Phase I studies, including in patients that might not be expected to benefit from CPI treatment alone. These data give us confidence that UV1 has the potential to improve outcomes for cancer patients, and we look forward to the upcoming readout from our Phase II trials,” says Bjørheim.

Illustration: Ultimovacs

 

DNA plasmid – the backbone of Nykode

Another example of Nordic company developing cancer vaccines is Nykode Therapeutics. The company has over the years focused its efforts on building a vaccine technology that is safe and well tolerated and “that can generate strong and broad CD8 T cell immune responses against the antigens they incorporate,” describes Michael Engsig, CEO of Nykode.

The company has recently announced encouraging results from a trial investigating the use of their therapeutic cancer vaccine candidate VB10.16 in combination with Roche’s cancer immunotherapy Tecentriq in patients with advanced or recurrent, non-resectable HPV16-positive cervical cancer. Not only did they see patients on average live longer, but 7 of the 14 patients who received all treatments are still alive and without signs of progression.

“This trial strongly indicates a long lasting effect which translate into survival benefit for the patients,” says Engsig.

In addition, DNA plasmid, which constitute the backbone of the company’s technology, are inherently easier to produce and handle compared to many other vaccine technologies such as the mRNA technologies, he says, highlighting the advantages with their approach.

We plan to start a potential registrational trial in advanced cervical cancer at the end of the year and hope it could reach the US market somewhere in 2027.”

In the light of our results in advanced cervical cancer Nykode feels obliged to bring VB10.16 forward in development and towards the market and patients as fast as possible, states Engsig.

“We plan to start a potential registrational trial in advanced cervical cancer at the end of the year and hope it could reach the US market somewhere in 2027. In addition, we plan to expand the use of VB10.16 into head and neck cancer starting the first trial during the summer. We also look at bringing development to the earlier stages of cancer. The so-called adjuvant setting which constitute an even larger number of patients and where the safety and long-lasting effect will fit very well.”

The company is also developing a personalized cancer vaccine, VB10.NEO, together with Genentech/Roche. This vaccine has a potential to address unmet needs across a wide range of solid tumors and is currently being investigated in a trial enrolling patients with more than ten different cancer types. “We also have a multi-target agreement with Regeneron covering five programs focused on off-the-shelf vaccines for cancer and infectious diseases,” describes Engsig.

 

Michael Engsig

Michael Engsig, CEO, Nykode.

 

Personalized vs Universal

Compared to personalized cancer vaccines Jens Bjørheim believes that UV1 has several benefits.

“First, the vaccine target, telomerase, is expressed in more than 85% of cancer types, through all stages of the tumor growth, and in all parts of the tumor. Since the vaccine target is relevant throughout the course of the cancer, the tumor cells can not mutate away from expressing telomerase. This implies that the vaccine has a potential for broad applicability in different kinds of solid tumor cancers,” he says. “Second, UV1 does not require any sort of “patient matching” to a specific HLA type, thereby enabling potentially broad use. In contrast, personalized vaccines will often need to identify patients with specific HLA types. Third, UV1 is simple to administer and does not require long lead times for manufacture, upfront collection of patient cells or specialized equipment. It is provided as an “ready, off-the-shelf” product with a long shelf-life and easy storage conditions (via standard refrigeration). Not only does this facilitate use generally, including in centers without access to advanced medical equipment, but it is also an advantage when patients need urgent treatment.”

We believe that cancer vaccines have the potential to enhance the efficacy and durability of response in solid tumors.”

As many other scientists, Jens Bjørheim sees a future where cancer vaccines are used in combination with different immunotherapies. “CPIs have transformed cancer therapy but not all patients have a durable response. We believe that cancer vaccines have the potential to enhance the efficacy and durability of response in solid tumors,” he says and adds they he also expects to see relevant clinical efficacy data for both personalized and universal cancer vaccines.

“Recent presentation by Moderna and Merck certainly highlights the opportunity for personalized vaccines,” he adds.

Based on the results from the upcoming readouts in their randomized Phase II program, Ultimovacs’ plans to consult with their medical advisors and regulatory authorities with a goal of moving swiftly into pivotal studies. “With positive data, we estimate that the cancer vaccine can be available in clinics before the end of the decade,” he concludes.

Michael Engsig, Nykode, believes the future will hold place for both personalized and universal cancer vaccines, given their respective advantages. “Universal cancer vaccines, also referred to as off-the-shelf cancer vaccines has the benefit of immediate administration to the patient, but they require the patient to harbor specific antigen targets,” he says.

“Personalized cancer vaccines can be tailor-made to each patient, but will always need to undergo manufacturing before administration and therefore taking a bit longer before being administered to the patient. We could see a scenario where patients are put on an off-the-shelf vaccine immediately while a personalized vaccine is being produced, if the patient harbors the antigens in an available off-the-shelf cancer vaccine.”

The key focus for players in the field of cancer vaccines right now is to develop the underlying vaccine technology to achieve not only a fast, strong and long lasting immune response but as importantly the right type of immune response, adds Engsig. “The immune system is a highly complex system and the patient need different types of response depending on whether it’s a viral infection, bacteria or a tumor. Different vaccine technologies will result in varying types of immune responses even when targeted against the same antigen such as a tumor specific antigen,” he explains.

The winning technology we will the one who can generate a strong and broad CD8 T Cell response with a long lasting effect without any significant side effects.”

In the field of cancer vaccines he believes the winning technology we will the one who can generate a strong and broad CD8 T Cell response with a long lasting effect without any significant side effects. “Added to that, when it comes to personalized cancer vaccines it also becomes important to be able to produce the individual vaccine fast,” he concludes.