Checkpoint inhibitor drug, an Immuno-oncology combination, resists liver tumor in mice
Merck’s anti-PD-1 blockbuster Keytruda, checkpoint inhibitor drugs, works fine in different types of cancers but becomes ineffective when the malignancy reaches the liver. But why?
In order to address this question, researchers at the University of California, San Francisco, came up with a discovery of a combination treatment. The treatment has been tested in metastases liver models of mouse and the treatment looks promising in the model trial.
The UCSF team discovered that the liver’s blood-filtering abilities can be used by the malignant liver cells in order to suppress the immune response of the liver to cancer. CTLA-4 is a drug that inhibits immune checkpoints. The team learned that PD-1 inhibitor with CTLA-4 can restore PD-1 effectiveness in mouse models.
Jeffrey Bluestone, UCSF, was the senior author of the study. He was among the original researchers in the 1990s who led studies on CTLA-4. His specialty is the study of regulatory T cells or Tregs (targeted regulation of the immune system).
The main target of the UCSF researchers team was to determine the role of Tregs in tumors primarily located in the liver. First, cancer cells were implanted under mice’s skin and in the liver or lung. This will enable the researchers’ team to study the differences in response in each organ to anti-PD-1 treatments. The survival rates of mice with liver tumors were lower than the survival rate in animals with lung tumors after PD-1 inhibition. Furthermore, the skin tumors showed no noticeable response to PD-1 inhibition in the mice with liver tumors.
James Lee, M.D., UCSF, lead author of the paper stated that they discovered that between the skin tumors of mice with liver cancers and the mice without liver cancers there was not a difference in the ‘quantity’ of Tregs but a difference in ‘quality’.
The UCSF team discovered that the liver tumors in Tregs were able to change gene expression. This resulted in the alteration of several other immune cells leading to suppressing the activity of cancer-killing T cells.
Two drugs to block CTLA-4 along with a PD-1 blocker were tested. The ability to unleash an immune response against liver tumors was restored by both the CTLA-4 inhibitors, but one of them was more effective. The ability of CTLA-4 blocker to act directly on Tregs and deplete them might have made the difference, suggested the team.
Bristol Myers Squibb’s PD-1 blocker Opdivo with its anti-CTLA-4 drug Yervoy is known to treat patients with different types of cancer, including melanoma, colorectal cancer, and lung cancer. This is an example of how CTLA-4 inhibitors are already being combined with anti-PD-1 drugs in oncology practices.
In patients with liver metastases who are unlikely to respond to traditional treatments, the UCSF team hopes to try the I-O combination approach.
James Lee said that the liver can choose what it wants to protect or not protect, i.e. liver can choose its enemy. He further intrigues what if, patients with liver metastasis, from the initial stage, could use a drug that depletes Tregs as a complement to immunotherapy?
The study was published in Science Immunology.
Checkpoint inhibitor drug, an Immuno-oncology combination resists liver tumor in mice