Immunotherapies that block the interaction between the ‘immune checkpoint’ receptor PD-1 and its ligand PD-L1 have significantly improved the treatment of solid tumours. However, most tumours that have spread to other parts of the body are resistant to such treatments, or they can become resistant to them.
The protein GDF-15 is a powerful immunosuppressor that is overexpressed in many solid tumours and hinders the effects of cancer immunotherapy.
After an initial Phase I study to determine the highest safe dose, patients with heavily pre-treated non-small-cell lung cancer, urothelial cancer or liver carcinoma were enrolled in a Phase II trial to receive combination therapy with an antibody against GDF-15 and an antibody against PD-1. All patients’ tumours had at that point recurred or become resistant to standard anti-PD-(L)1 therapy.
Using the antibody against GDF-15 and the antibody against PD-1 caused deep and lasting remissions, with 15–19% of individuals showing tumour shrinkages of at least 30% in diameter. In addition to this, over half of the observed responses were substantially stronger than those achieved under the first anti-PD-1 treatment, showing that GDF-15-targeted antibodies can reinvigorate and further improve responses to anti-PD-1 treatment. Importantly, the treatment combination was tolerated well, with high-grade adverse events occurring in less than 10% of treated individuals.
The study was led by Prof Ignacio Melero, Kidani Professor of Immunotherapy at NDM’s Centre for Immuno-oncology and the University of Navarra. Pro Melero said: ‘We are very excited with the results and two Phase III protocols are already written and about to be submitted to regulatory authorities. Although single-arm Phase II results are to be considered with caution our expectations are high.’
Moving forward, the group’s research will focus on other combinations that identify the GDF-15 receptor on leukocytes cells, collaborating with Ludwig Cancer Research Oxford who are starting to investigate a critical aspect of the pathway.