Disarming cancer's defenses to improve immunotherapy

Many cancers express stress proteins which act as "kill me" signals to the immune system, but they also produce enzymes to shed these proteins. (Image: PDPics)

While checkpoint inhibitors have proved effective in certain cancers, such as lung cancer and melanoma, they work only for a small percentage of patients. The hunt is on for ways to make these treatments more widely useful. 

One approach is to combine immunotherapies. Researchers from the University of Southampton tested out a PD-1 blockade and Celldex Therapeutics' CD27-targeting antibody, varlilumab, in mice. When given alone, each treatment produced 10% protection from cancer, but when administered together, they provided 60% protection, according to a statement. 

The treatments target different but "synergistic" pathways, the researchers said: While the PD-1 blocker overcomes cancer cells' resistance to the immune system, the CD27 antibody kickstarts immune cells to find and kill the cancer cells. 

"Using checkpoint blockade has revolutionized the field of cancer immunotherapy, but it is not enough to simply stop the cancer from evading the immune system, we need to boost the immune system to fight the cancer off. By combining checkpoint blockade with an anti-CD27 antibody, we have been able to show that the two approaches can be harnessed to potentially improve current treatment options," said Aymen Al-Shamkhani, a professor of immunology at the University of Southampton. 

The findings support ongoing clinical trials that are already testing the combo in patients. 

"Cancer Research UK is funding several studies, looking at combining different types of immunotherapy so we can provide more treatment options and help more people beat their cancer," said Catherine Pickworth, M.D., of Cancer Research UK, which funded the study alongside Celldex.

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Another approach attacks tumors' ability to "hide" from the immune system. Many cancers present the stress proteins MICA and MICB, which identify them to the immune system as cells that should be killed. To avoid this fate, cancer cells produce enzymes that cleave these proteins, effectively shedding them and escaping detection. 

In an effort to stop this shedding, a team led by Lucas Ferrari de Andrade of Dana-Farber targeted the spot where MICA and MICB are cleaved. They found that using the antibody mAb 7C6 in mouse models of melanoma and lung cancer stepped up the infiltration of natural killer cells within tumors, in addition to increasing the amount of MICA and MICB expressed on the cancer cells. 

"These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model," the authors wrote in their study.