Immunotherapy with checkpoint inhibitor drugs is an emerging treatment for renal cell carcinoma. Now investigators from Brigham and Women’s Hospital have reported the results from lab research looking at a potential new way to boost the immune system’s ability to fight cancer.
The approach, which uses a small molecule to target the protease inhibitor SerpinB9, not only affects tumor cells themselves but also cells in the microenvironment, including immunosuppressive cells. Results from this work were published recently in Cell.
“Not much is known about this protein and its role in tumor immunity, so more work needs to be done,” said Reza Abdi, MD, of the Brigham’s Division of Renal Medicine and the paper’s senior author. “But based on our early work, we thought that targeting SerpinB9 would introduce a potentially more multifaceted approach than current checkpoint inhibitor drugs.”
Targeting a Molecule That Protects Cells From Attack
SerpinB9 is an inhibitor of granzyme B, a protease that induces apoptosis. Granzyme B is commonly found in two types of immune cells, natural killer cells and cytotoxic T cells, and they use it to attack tumor cells. The role of SerpinB9 is to prevent granzyme B from attacking the immune cells themselves.
“It appears, however, that tumor cells put out their own SerpinB9 to fight against immune cells,” Dr. Abdi said. “That makes this protease inhibitor a potential target for anticancer therapy.”
In the paper, the investigators report that when they used a small molecule to block SerpinB9, it slowed the growth of tumor cells, indicating this molecule is important for tumor growth. The research was done in cell cultures and in mouse models of several types of cancer, including renal cancer. Additionally, targeted SerpinB9 appeared to affect both the tumor stromal cells and immunosuppressive cells in the tumor.
Looking for Synergistic Effects and Future Applications
Dr. Abdi said that one focus of his current work is optimizing the molecules that could be used to target SerpinB9. Additional research is needed on the binding and kinetics as well as on potential toxicities. He explained that because SerpinB9 can be blocked with a small molecule rather than an antibody, this type of drug may prove less costly to develop.
“Checkpoint inhibitors can have frequent and sometimes lethal toxicities,” he noted. “This should prompt us to look for other approaches and compare them head to head for both efficacy and toxicity.”
Dr. Abdi also plans to study in more depth whether adding a SerpinB9-targeting drug to treatment with an immune checkpoint inhibitor could have a synergistic effect. “Immune checkpoint drugs don’t work very well on ‘cold’ tumors that lack immune infiltration,” he said. “Because SerpinB9 is also found in the tumor microenvironment, blocking it may make these drugs work better.”
In addition to its potential applications for renal cancer, this drug could prove effective in other solid tumors as well. The paper also studied it in models of melanoma, breast cancer and lung cancer. “This is an exciting field, and the ability to target a different mechanism of action in cancer opens up new opportunities for treatment,” Dr. Abdi concluded.