Removing The Brakes On The Immune System

Tumor-associated myeloid cells suppress the immune system's ability to target cancer, but a new experimental drug helps to overrule their inhibitory influence - boosting the effect of immunotherapy

Immunotherapy works extremely well for many patients, but it doesn't work for everyone. One of the reasons for this is the precise makeup of each individual's cancer, and whether they contain significant numbers oftumor-associated myeloid cells (TAMCs). These cells are a barrier to successful immunotherapy because they essentially impose a brake on the immune system, directly inhibiting targeting of the tumour.

One common immunotherapy strategy is called checkpoint blockade, which involves using antibodies to block the inhibitory signals; unleashing the immune system once again. We now know that if an individual has particularly high numbers of TAMCs, it makes it much less likely they will respond to checkpoint blockade therapy. Developing ways to overcome TAMC influence is therefore an important goal in the evolution of immunotherapy. 

"Though checkpoint inhibitors have durable effects when they work, not all patients respond to the treatment. Part of the reason for this is that some tumors harbor tumor-associated myeloid cells, or TAMCs, that prevent T cells from attacking tumor cells"

Removing the brakes

Research at the Memorial Sloan Kettering Cancer Center has used an experimental drug called IPI-549, produced by Infinity Pharmaceuticals, to target these TAMCs. IPI-549 is designed to block the action of a protein called PI3 kinase-gamma, and in turn shift the behaviour of these cells into a more active stance favouring immune attack; essentially reprogramming their behaviour.

When the researchers tested IPI-549 alongside checkpoint blockade therapy, they found that it was able to significantly enhance response to the therapy. The rate of complete remission in the studied mice following checkpoint blockade therapy without IPI-549 was around 20%. This jumped to 80% when the drug was administered at the same time. 

Confirming the theory

While the drug is only effective on tumours harbouring these TAMCs, its ability to kickstart immune response once again highlights how detrimental these cells are. When the team specifically grew numbers of these TAMCs by providing targeted growth stimulants, they found that the response to immunotherapy tactics was reduced even more. This strongly supports the need to alter TAMC behaviour in conjunction with immunotherapy, in patients that require it. The research also displays how important personalised cancer tactics are, considering that each individual's cancer is likely to require a tailored approach. 

Read more at MedicalXpress