Gustav Ullenhag – Translational immunotherapy
Our research is translational with main focus to conduct immunotherapy studies in cancer patients.
The work is performed in close collaboration with Angelica Loskog’s research group. We also collaborate with Sara Mangsbo and a project is planned with Anna Dimberg.
Aglaia Schiza, Sandra Irenaeus
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.
We plan to develop the CD40L concept further and will in the autumn 2017 launch a phase I/II study assessing intratumoural injections with an oncolytic virus 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.
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. Currently, nineteen centers participate and Holland will join in the spring 2018.
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 plan to investigate possible reasons for this finding.
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 so far are cubilin and ANXA1.