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Melanoma is the deadliest form of skin cancer. As such, new treatments for the disease are in strong demand. Norwegian immuno-oncology experts Ultimovacs are developing a type of cancer vaccine able to boost a patient’s immune system during cancer, and their top candidate UV1 is being tested in a phase I clinical trial and a phase II proof-of-concept study with different combination therapies in malignant melanoma patients. BioStock was able to get in touch with the company’s CMO Jens Bjørheim, and Senior Medical Advisor Steinar Aamdal to learn more about the disease and the phase I study, which recently produced results.

Cancer of the skin is quite common, especially among fair-skinned individuals whose skin cells are more vulnerable to harmful light rays coming from the sun. Roughly three million people are diagnosed with the disease globally every year, and according to the World Health Organization (WHO), one third of every cancer diagnosis is a skin cancer.

Skin cancer is typically dichotomized into two main types: non-melanoma and melanoma. Non-melanoma forms of skin cancer are the most common, and while melanoma skin cancers account for about 1 per cent of all skin malignant tumours, they are the most aggressive and most deadly, killing about 60,000 people each year world-wide.

Why Melanoma is so dangerous

Melanomas form when DNA is damaged in melanocytes, skin cells that produce melanin, the substance that gives skin its colour. The damaged DNA produces uncontrolled cell growth that leads to a tumour. The most common cause of this damage is prolonged exposure to ultraviolet radiation, most of which comes from the sun. In fact, the UK’s NHS references a study showing that having five or more sunburns during childhood can increase the risk of melanoma by 80 per cent.

»The checkpoint inhibitors, as monotherapy or in combinations, are the most efficient current therapy for malignant melanoma and prolong patients´ survival for many years. However, since the therapy only benefits about 50 per cent of the patients, there is still a strong medical need for improving the therapeutic landscape« — Steinar Aamdal, Senior Medical Advisor at Ultimovacs

If caught early, melanomas are fairly easy to treat. The most common treatment is surgical excision, however, depending on their location, stage and genetic profile, melanomas are also treated with chemotherapy, radiotherapy, and, more recently, immunotherapies like checkpoint inhibitors.

Despite the more recently developed combination treatments with immunotherapies being able to extend survival, up to several years in some patients, if melanomas become metastatic, prognosis is poor. About one third to one half of patients do not respond to treatment, resulting in early death even after introduction of immunotherapies. Thus the need for improved therapies is still significant.

Ultimovacs in clinical trials with universal vaccine

One biotech company that has recognized this and is developing a new kind of immunotherapy is Norwegian Ultimovacs. The immuno-oncology company is working to create a universal cancer vaccine able to work in combination with other forms of immunotherapy to generate an inflammatory response that would ultimately lead to the destruction of a tumour. Read more about the company’s technology here.

The company’s lead candidate is UV1, a peptide-based vaccine that induces a specific T-cell response against telomerase, an antigen expressed in all cancer types. Ultimovacs has conducted three phase I clinical trials where the candidate has been used either as monotherapy or in combination with different immunotherapies and in different cancer indications, including melanoma. All three studies, which are now completed, have consistently indicated that UV1 is safe and well-tolerated by patients.

Furthermore, Ultimovacs also has an ongoing clinical phase II proof-of-concept study (INITIUM) with 154 melanoma patients evaluating the safety and efficacy of UV1 in a triple combination with two checkpoint inhibitors, ipilimumab (Yervoy) and nivolumab (Opdivo).

Phase I trial in melanoma patients produces positive results

In 2018, Ultimovacs began yet another phase I trial, this time testing UV1 in combination with common checkpoint inhibitor pembrolizumab (Keytruda) in 30 Metastatic Malignant Melanoma patients. This US-based study was designed to assess the safety and tolerability of UV1 combined with pembrolizumab and to explore initial signs of clinical response.

Patient enrolment was completed in August this year, and recently the company announced positive topline results from an initial cohort of 20 patients in the study. After following these patients for one year after initial treatment, the overall survival (OS) rate was 85 per cent, and median Progression-Free Survival (mPFS) had not been reached, indicating that more than half of the participating patients had yet to show signs of disease progression. Furthermore, no safety issues related to UV1 were found, and the vaccine was well-tolerated, thus mirroring the positive results from the previous phase I trials with UV1.

Learning more about Melanoma and the clinical trial

BioStock reached out to two experts at Ultimovacs to learn more about Melanoma and about the importance of the clinical trial results released last week: Senior Medical Advisor, Steinar Aamdal, and Chief Medical Officer Jens Bjørheim.

»We are very happy that the safety profile seen in the first cohort were in line with earlier studies. This tells us that it is safe to combine the UV1 vaccine with pembrolizumab. We have done an earlier study with the combination of UV1 vaccine and ipilimumab in the same indication, so now we have good safety data on combination treatment both with CTLA-4 antibody and PD-L1 antibody. This is of high importance for a good design of future combinations studies« — Jens Bjørheim, CMO of Ultimovacs

Steinar, let me begin with you, could you tell us more about Melanoma and why it’s so deadly?

– Depending on the thickness of the melanoma, that is how far down into the skin the melanoma is growing, even small tumours can easily set off malignant cells into to the blood stream allowing metastases at distant sites to develop. The prognosis is serious when metastases have been established and can no longer be surgically removed.

– For many years, metastatic melanoma was an extremely difficult tumour to treat. Chemotherapy had little effect and was unable to prolong survival. It was not until immunotherapy was developed that melanoma treatment results radically changed. Immune checkpoint inhibitors became “game changers” with long-term survival benefits measured in years in many patients and in some even cures.

Why are current treatments for metastatic malignant melanoma unsatisfactory?

– The checkpoint inhibitors, as monotherapy or in combinations, are the most efficient current therapy for malignant melanoma and prolong patients´ survival for many years. However, since the therapy only benefits about 50 per cent of the patients, there is still a strong medical need for improving the therapeutic landscape.

What makes UV1 a promising candidate in your opinion, and why is it ideal for metastatic melanoma?

– UV1 is a therapeutic cancer vaccine consisting of peptides inducing CD4+ T helper type 1 (Th1) cells. These cells target the enzyme human telomerase reverse transcriptase (hTERT), which is expressed on the surface of tumour cells. That expression signals the presence of telomerase in the cell. Telomerase is an enzyme expressed almost universally in cancers and is functionally required for unlimited proliferation, which is one of the hallmarks of cancer. The selection of peptides in the UV1 vaccine is based on observation of long-time survivors (more than 10 years) in previous trials with an earlier version of the vaccine.

– UV1 may be particularly useful in melanoma since the tumour is already known to be responsive to immunotherapy. In fact, it was results from the early immune checkpoint trials in melanoma that paved the road for the general development of cancer immunotherapy. In addition, results from a previous trial with an earlier version of the vaccine in melanoma, indicated high immune responses to the vaccine.

Steinar Aamdal, Senior Medical Advisor at Ultimovacs

How does UV1 differ from other classes of immunotherapy?

The activity of checkpoint inhibitors relies on unleashing the already existing anti-tumour immune response in the patients. The UV1 vaccination, however, provides new antigens and creates new T-cells directed against the tumour, thereby broadening the anti-tumour response. In combination with checkpoint inhibitors the vaccine may enhance the anti-tumour activity of the therapy.

– Also, the UV1 vaccine can be used without pre-screening of the patients for HLA-status; it is an off-the-shelf product, easy to administer and proven to have a good safety profile in earlier trials.

– The target of the vaccine, telomerase, is present in 80-90 per cent of cancers and is therefore a potential universal cancer vaccine. A cancer expressing telomerase will do so in all cancer cells, meaning in all parts of the tumour, and will continue to do so over time, throughout the course of the cancer. This means that telomerase is likely to remain a relevant target for the immune system through different stages of a cancer and also reduces the chance of tumour escape due to heterogeneity.

Jens, turning to the clinical trial, in more details, what is the purpose of this phase I study for metastatic malignant melanoma patients where UV1 is given in combination with checkpoint inhibitor pembrolizumab?

– The primary endpoints in the trial are safety and tolerability. It is important to analyse if the combination of pembrolizumab and UV1 has an acceptable safety profile, as a guidance for further combination development.

– We have also two different cohorts in the trial: one cohort with a lower dose of the adjuvant GM-CFS (Leukine) and one with the standard, higher dose. The safety and efficacy results from the cohorts will give us valuable data in the preparation for a future filing of UV1.

Could you tell us more about the significance of the results that came out last week regarding the phase I trial?

– We are very happy that the safety profile seen in the first cohort were in line with earlier studies. This tells us that it is safe to combine the UV1 vaccine with pembrolizumab. We have done an earlier study with the combination of UV1 vaccine and ipilimumab in the same indication, so now we have good safety data on combination treatment both with CTLA-4 antibody and PD-L1 antibody. This is of high importance for a good design of future combinations studies. We have already started a phase II randomized trial in metastatic malignant melanoma where we combine the UV1 vaccine, ipilimumab and nivolumab.

– It is always difficult to interpret efficacy results from phase I studies; first, the study has a single arm design, and second, there is a limited number of patients. We observed overall survival (OS) and median Progression-Free Survival (mPFS) at one year that were on the positive side if you compare with historical controls. I think it will be very interesting to follow the data over the next years to see if the treatment matures into a superior long-term OS.

How do these results compare to previous studies conducted in metastatic melanoma patients?

– While, as mentioned earlier, it is difficult to compare with other studies, from our perspective, an appropriate historical comparison for our trial is the cohort in the KEYNOTE006 trial in which patients with advanced melanoma without prior treatment history were treated with pembrolizumab only. Results from that study demonstrated a 68 per cent OS and a mPFS of 11.6 months.

– In our trial the one-year landmark result was 85 per cent OS rate. mPFS was not reached at 12 months. We are encouraged by the results and look forward to additional data readouts over the next years that will demonstrate if the initial signs of efficacy in this cohort persist and mature into long-term added clinical benefit for the patients.

Jens Bjørheim, CMO of Ultimovacs

This is the second phase I trial conducted in metastatic malignant melanoma. The first trial, which was completed in 2016, was studying UV1 in combination with another checkpoint inhibitor, ipilimumab (Yervoy). What is the purpose of testing your candidate with different immunotherapies within the same indication?

– The mode of action for UV1 is to induce T-cell-recognizing telomerase (hTERT). For these cells to be effective, it is important that the treatment is combined with other interventions that allow the immune cells to attack the cancer.

– Over the last few years, we have seen that different classes of immunotherapy (CTLA-4, PD-1, PD-L1) have clinically-relevant effects in different cancer indications, e.g. malignant melanoma. The UV1 vaccine, which has a target present in 80-90 per cent of all cancers, will likely be combined with different drug combinations that improve the immune system’s ability to target the cancer in different indications. Therefore, it is also important for us to have safety and tolerability data in different UV1 combinations.

Ultimovacs also has a proof-of-concept study ongoing with 154 metastatic melanoma patients. That project is called INITIUM, and it involves a triple combination: UV1 with two checkpoint inhibitors, ipilimumab (Yervoy) and nivolumab (Opdivo). What can you tell us about this project and how does it relate with the phase I trials?

– INITIUM is a randomized phase II trial in patients with metastatic malignant melanoma. Patients that are included in the study are first-line patients, which means that they have not received cancer treatment for their metastatic disease earlier. Standard of care for a proportion of these patients is ipilimumab plus nivolumab. In our study, we randomize patients from this group to receive either nivolumab in combination with ipilimumab or nivolumab combined with both ipilimumab and UV1. Since we already have obtained safety data for UV1 combined with both PD-1 and CTLA-4 antibodies we could go directly into phase II with the triple combination.

– The INITIUM trial has already started patient inclusion, and we expect to report the primary endpoint (mPFS ) during the second half of 2022. The study will be conducted at close to 40 hospitals throughout the US and Europe.

Now that these results from the first cohort of patients (20 of 30 patients) have been published, what are the next steps for this phase I trial? When can we expect results from the rest of the patients?

– The presented results were the top-line results from the first cohort. A more detailed presentation with even more mature data from cohort 1 is planned during the first half of 2021 at an international cancer conference.

– The patients in the second cohort will have a one-year follow up in the third quarter of 2021, so next autumn both one-year data from cohort 2 and two-year data from cohort 1 will be available.

The content of BioStock’s news and analyses is independent but the work of BioStock is to a certain degree financed by life science companies. The above article concerns a company from which BioStock has received financing.

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