Gustav Ullenhag – Translational immunotherapy

Our research is translational with main focus 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

While the treatment options for malignant melanoma patients have improved greatly in recent years most patients do not benefit and the side effects can be severe. Immunotherapy has emerged as an important treatment strategy where the immune system is modulated to target and kill cancer cells.

CD40 is an important co-stimulatory molecule. We have completed a study with intratumoural injections of an adenovirus carrying the gene for CD40 (AdCD40L) in metastatic melanoma patients (n=24). AdCD40L was given alone or in combination with a low dose cyclophosphamide, and with or without radiation therapy. Low dose cyclophosphamide can suppress regulatory T cells and enhance NK cell functions. The goal with this immune-stimulatory gene therapy is to obtain not only local but systemic anti-tumoural effects by converting the patients cancer into a vaccine.

Patient study with AdCD40L

The first six patients received AdCD40L only, the second group (n=9) addition of low dose cyclophosphamide 1-2 days before the first and fourth AdCD40L treatment. The third group (n=9) also received an 8 Gy fraction towards the lesion to be injected one week before start of AdCD40L therapy. Most patients received the treatment in a liver metastasis through ultrasound guidance.

The addition of low dose cyclophosphamide seems to enhance the treatment effect, without adding side effects while our results indicate that the irradiation does not add any benefit. In addition, some patients with other solid cancers have received this treatment.

Assessment of the reinforced virus LOAd 703

In spring 2018 we launched a phase I/II study assessing intratumoural injections with an oncolytic virus (LOAd 703) in pancreatic, colorectal, biliary and ovarian cancer patients with advanced disease. In addition to CD40L, this virus carries the gene for 4-1BBL which also stimulates the immune system. Furthermore, in February 2020 we initiated a study with LOAd 703 in metastatic malignant melanoma patients who have experienced disease progression on checkpoint inhibitors.

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 national randomized phase 3 study (TRIM) with Uppsala as the primary site opened in June 2017. The study compares overall survival (OS), disease-free survival (DFS), 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.

Patients in the experimental arm are followed with radiological assessments (FDG-PET or CT) and blood tests during three years, in addition to the standard follow up scheme with physical examinations only. Almost 1000 patients have so far been included and in collaboration with professor Yvonne Brandberg, an ad hoc study investigating whether supplements increase the risk of relapse started during spring 2020. Nineteen centers participate.

Register based research

We have established a research database, MMBaSe through linkage of 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 and so far, we have shown that patients who are diagnosed with melanoma in situ have a better prognosis compared to the general population and investigate possible reasons for this finding.

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 patients. Our main focus is malignant melanoma.

In different subprojects we investigate whether flu vaccination should be given adjacent to treatment with immune checkpoint inhibitors, different ways to predict side effects from immunotherapy and differences in side effects from treatment with different immune checkpoint inhibitors.

First in man studies with immune stimulating antibody and virus given intravenously

One first in man study with an agonistic antibody against 4-1BB is ongoing. In an upcoming study, a vesicular stomatitis virus encoding CD80 will be given. In both studies, the drug is given intravenously and the first patients receive the drug at very low dose levels followed by gradually increasing doses in subsequent patients (3 + 3 design) providing that no severe side effects appear. The studies encompass patients with advanced solid cancer having received all established treatments.