Gustav Ullenhag – Translational immunotherapy
Our research is translational with main focus to conduct immunotherapy studies in cancer patients.
Much of the work is performed in close collaboration with Angelica Loskog’s research group. Amongst others, we also collaborate with Sara Mangsbo´s 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 immerged as a promising treatment strategy where the immune system is modulated to target and kill cancer cells.
CD40 is an important co-stimulatory molecule. We have recently finished a study with intratumoural injections of 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.
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.
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 expresses 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 PD1 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 (HRQoL) will be 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 500 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 will start during spring 2020. Nineteen centers participate.
The project also includes data supporting that patients who are diagnosed with melanoma in situ have a better prognosis compared to the general population and we 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. Our main focus is malignant melanoma.
First in man studies with immune stimulating antibodies
Two first in man studies with immune stimulating antibodies, in patients with advanced solid cancer having received all established treatments, are ongoing. In one of the studies (ATOR-1015) a bispecific antibody against CTLA-4 and OX40 are given and in the other (ATOR-1017) an agonistic antibody against 4-1BB is administered.
Assessment of predictive markers for renal cell cancer
In another project, potential predictive markers for renal cell cancer (RCC) are assessed. Immunohistochemistry is applied on tumour tissue from a cohort of patients with advanced RCC (n=139) who have been treated with tyrosine kinase inhibitors. The most promising markers identified are cubilin and ANXA1 in collaboration with Fredrik Pontén´s research group, and in collaboration with Anna Dimberg´s research group, ELTD1.