Researchers Uncover Advanced Cancer Resistance Pathway
Researchers have discovered a mechanism of resistance to checkpoint inhibitors and how to reverse it. The biomarker results from the IMvigor210 study were reported at the ESMO Immuno Oncology Congress 2017.
The discovery is based on findings from the 300-patient IMvigor210 biomarker study, the results from which led to FDA approval of the anti-PD-L1 antibody atezolizumab for the treatment of advanced bladder cancer.
“Understanding why the remaining 70% to 80% are resistant would enable us to target the mechanism with an additional drug and extend the benefits of checkpoint inhibitors to more patients,” suggests Sanjeev Mariathasan, Ph.D., senior scientist, oncology biomarker department, at Genentech.
The IMvigor210 biomarker study investigated the drivers of efficacy and primary resistance to the anti-PD-L1 checkpoint inhibitor atezolizumab in 300 patients with bladder cancer. They used a combination of methods including immunohistochemistry, genome sequencing, and RNA expression.
The researchers found two drivers of efficacy and one driver of resistance. In terms of efficacy, tumours with the highest number of mutations – called a high mutation burden – were the most amenable to immunotherapy.
Tumours that had T cells present in the tumour microenvironment were also more responsive to immunotherapy. Regarding
resistance, tumours with high expression of the cytokine TGF-β tended to be unresponsive to immunotherapy.Mariathasan said that in “T cell excluded tumours”, the tumour may secrete a factor that builds a collagen-rich fortified wall around the tumours. The stromal microenvironment is like a Velcro that T cells stick to and do not enter the tumour. High expression of TGF-β and TGF-β-induced stromal genes in these excluded tumours were associated with non-responders, suggesting that these may help to fortify the tumour against T cell penetration.
The researchers then examined whether inhibiting TGF-β activity could improve the efficacy of atezolizumab with the help of a mouse model with the “T cell excluded tumour” phenotype which was used to compare four treatments: isotype antibody (control group), anti-PD-L1 alone, anti-TGF-β alone, and the combination of anti-TGF-β plus anti-PD-L1.
In the combination group, TGF-β activity in stromal cells was reduced, T cells penetrated into the centre of the tumour, and the tumour reduced in size.
Mariathasan said: “This suggests that giving anti-TGF-β and anti-PD-L1 together can remodel the stromal microenvironment and allow T cells into the tumour. The ‘T cell excluded’ phenotype is common in other cancers such as lung, pancreatic and colorectal, so this combination therapy could be tested in a wider group.”
When it comes to the need for further research, Professor Ignacio Melero, Senior Researcher, Centre for Applied Medical Research (CIMA), Pamplona, Spain, said: “In bladder cancer it makes sense to design and implement a clinical trial that would select patients based on a TGF-β signature and treat them with an anti-TGF-β agent plus PD-1 or PD-L1 blockade. Better anti-TGF-β agents need to be developed for use combination with immunotherapy agents.”
George Coukos, Congress Co-Chair, Professor and Director, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland, said the research had two main implications: “First of all it explains why T cells are perhaps retained in the stroma and are not able to move into the tumour. Most importantly, it opens the door for improving therapeutic responses to PD-1/PD-L1 blockade by simultaneously targeting the TGF-β pathway.”
