Research Manipulating proteins to make 'cold' tumors responsive to immunotherapies
Some cancers create a hostile environment that allows them to evade immune attacks. That's why many cancer patients don't respond to immuno-oncology treatments like checkpoint inhibitors. Scientists are looking for ways to turn these so-called “cold” tumors into “hot” ones that are susceptible to immunotherapy.
Two separate research teams led by Yale University and the University of Cincinnati have discovered proteins that can be targeted to overcome resistance to cancer immunotherapy in animal models.
Researchers at Yale focused on cytokine therapies, which harness the body’s inflammatory molecules to guide immune cells to go after cancer cells. The team, led by Aaron Ring, M.D., Ph.D., hypothesized that tumors were employing immunological countermeasures to hamper a powerful cytokine called interleukin-18. That may explain why a recombinant IL-18 drug called SB-485232 from GlaxoSmithKline failed to induce a meaningful response in metastatic melanoma patients in a phase 2 study.
In a new study published in Nature, Ring and colleagues discovered that a “decoy receptor” called interleukin-18 binding protein (IL-18BP) was highly expressed in the microenvironment of many cancers. The protein lured IL-18 away and prevented it from binding to its true receptor on immune cells to trigger an immune response.
To solve the problem, the researchers used a process called directed evolution to search nearly 300 million different forms of IL-18 for candidates that can bind to the true receptor rather than the decoy. A modified version dubbed DR-18 with a high binding tendency toward the IL-18 receptor emerged from the process.
In mice with a variety of cancers, DR-18 significantly reduced tumor growth compared with wild-type IL-18. It also completely cleared tumors in many of the animals. Further analysis showed that the treatment changed the tumor microenvironment, leading to increased tumor-infiltrating lymphocytes and a type of stem-like precursor T cell that sustained a durable immune responses.
“We just changed IL-18's frequency in order to eliminate the jamming signal,” Ring explained in a statement.
Ring has turned the findings into a startup called Simcha Therapeutics, which just raised $25 million in series A funding. The company expects to advance its lead asset, a humanized IL-18 variant coded ST-067, into the clinic in 2021.
In a separate study published in the journal Cancer Research, scientists at University of Cincinnati showed a protein called FIP200 was responsible for limiting T-cell recruitment and activation in breast cancer, thereby making tumors unresponsive to immune checkpoint inhibitors.
Disrupting FIP200’s function led to increased inflammatory cytokine expression, the team showed. When coupled with a PD-1 inhibitor and a CTLA-4 inhibitor, the strategy led to reduced tumor growth in mice when compared to monotherapy with checkpoint inhibitors.
"These findings indicate that targeting FIP200 could create a 'hot spot' for immunotherapy within these tumors," said Syn Kok Yeo, Ph.D., a research instructor in the department of cancer biology at the University of Cincinnati, in a statement. The next step, he said, would be to develop drugs that target the protein and test them in combination with immune-boosting drugs in breast cancer.