Gustav Ullenhag – Immunotherapy for cancer focusing on malignant melanoma

Our main research focus is to conduct immunotherapy studies in cancer patients with a special focus on malignant melanoma.

Much of the work is performed in close collaboration with Angelica Loskog’s research group. Amongst others, we also collaborate with Antonis Valachis’ research group.

Immune stimulating gene therapy with AdCD40L and LOAd 703

Many patients with advanced cancer (mainly malignant melanoma and pancreatic cancer) have been treated in studies with repeated ultrasound-guided intra-tumoral injections with an adenovirus. The aim is to achieve a systemic immune response by converting the patient's own tumour to an individualized therapeutic vaccine.

CD40L is an important co-stimulatory molecule. The first study included metastatic malignant melanoma patients and the adenovirus (AdCD40L) which carried the gene for CD40L was given in last line. Low dose cyclophosphamide can suppress regulatory T cells and enhance NK cell functions, and will be given as conditioning chemotherapy. We investigated the effects of combining the virus treatment with low dose cyclophosphamide given intravenously, and with radiotherapy to the lesion to be injected.

Oncolytic adenovirus combined with chemotherapy or checkpoint inhibitor

In the studies that followed, the patients received an oncolytic adenovirus (LOAd 703) which in addition to CD40L carries the gene for 4-1BBL, which also can enhance the immune response. In addition to the virus, the patients received gemcitabine-based chemotherapy (standard treatment or as conditioning) or anti-PDL-1 antibody.

There is currently no clinical study recruiting patients, but the preclinical development continues. The aim is to launch another translational trial in cancer patients with advanced disease.

The arms of a person pipetting in a flow hood

Photo: Mikael Wallerstedt

Detection of relapse with scans

The introduction of PD-1 inhibitors in malignant melanoma patients makes it likely that earlier detection of relapse with scans is of benefit. A nationwide academic randomized phase 3 study (TRIM), with Uppsala as the primary site, opened in June 2017. In total, nineteen centres participate.

The study is the largest interventional study conducted in Sweden in malignant melanoma patients. It compares overall survival, disease-free survival, economic cost effectiveness, and quality of life in patients with two different schedules for follow-up after radical surgery for high-risk malignant melanoma. Health related quality of life is assessed by QLQ30 and HAD.

Radiological assessments and blood tests

Patients in the experimental arm are followed with radiological assessments (FDG-PET or CT) and blood tests for three years, in addition to the standard follow up scheme with physical examinations only. Around 1300 patients have so far been included.

In collaboration with Professor Yvonne Brandberg, an ad hoc study investigating whether supplements increase the risk of relapse started during spring 2020 and has included around 280 patients.

Shorter adjuvant immunotherapy in malignant melanoma patients

Billions of SEK are spent worldwide each year on adjuvant immunotherapy for cancer patients. The study Grand SLAM (Short, Long, Adjuvant, malignant Melanoma) aims to shorten treatment duration from 12 to 6 months, thereby reducing side effects and healthcare resources, including drug costs.

In this non-inferiority academic phase 3 study, patients who have undergone surgery for high-risk melanoma are randomized 1:1 to receive (neo)adjuvant treatment with PD-1 inhibitor for 12 months (standard arm) or for 6 months (experimental arm). The aim is to include 1,880 patients and the co-primary endpoints are distant metastasis free and relapse free survival at 2 years.

Largest malignant melanoma drug study

Grand SLAM is the largest drug study in malignant melanoma patients ever launched by a Swedish initiative and it received a record-breaking grant from the Swedish Cancer Society.

University medical centres in Sweden (in Sweden also county hospitals), Norway and Finland participate and several centres in the UK, Italy, Germany and Spain will join. A biomarker sub-study will start soon.

Register based research

We have established the research database MMBaSe by linking the following registers: the Swedish Melanoma Register (SweMR), the National Patient Register (NPR), the National Prescribed Drug Register, the Multi-Generation Register, the Cause of Death Register (CDR), the Swedish Cancer Register (SCR), the Total Population Register and the Longitudinal Integrated Database for Health Insurance and Labor Market Studies (LISA).

The database enables a lot of projects. So far, we have shown that patients who are diagnosed with melanoma in situ and early malignant melanoma have a better prognosis compared to the general population, despite a higher risk of dying in malignant melanoma.

Treatment with checkpoint inhibitors in routine clinical practice

In collaboration with Associate Professor Antonis Valachis, Örebro University Hospital, we assess the effects of treatment with checkpoint inhibitors in routine clinical practice. We have established a cohort of around 600 cancer patients.

In different subprojects, we have so far investigated whether flu vaccination should be given adjacent to treatment with immune checkpoint inhibitors and different ways to predict side effects from immunotherapy. We have also studied the association of multiple side effects with treatment benefit, and differences in side effects from treatment with PD-1 and PD-L1 checkpoint inhibitors.

First in man studies with immune stimulating gene therapy

We are investigating an adenovirus expressing the genes for the glycan α-GAL and neutrophil activation protein-1 (NAP). Galactose-alpha-1,3-Galactose is commonly known as α-Gal. Anti-α-Gal antibodies are some of the most common in humans. NAP is a virulence factor of Helicobacter pylori which activates neutrophils and monocytes to produce Th1-associated cytokines.

Low dose cyclophosphamide will be given as conditioning chemotherapy. The virus is given intratumorally and cyclophosphamide intravenously. The first patients receive the virus at very low dose levels, followed by gradually increasing doses in subsequent patients (3 + 3 design), provided that no severe side effects appear.

Assessing toxicity, immune responses and clinical effects

The study encompasses patients with advanced solid cancer having received all established treatments. The primary endpoint is toxicity but immune responses (in blood and intratumorally) and clinical effects will also be assessed. Based on the results of this study, the goal is to launch a phase 2 trial.