To evade detection, cancer cells commonly take advantage of immune checkpoints that are naturally in place to prevent the body from attacking itself. They do this by producing proteins that bind to checkpoint receptors on T cells that effectively stops them from recognizing and attacking the tumor.
To fight back and allow T cells to recognize the tumor cells again, immune checkpoint inhibitor (ICI) drugs block this interaction. First approved by the FDA in 2011 with ipilimumab (Yervoy) from Bristol-Myers Squibb for the treatment of unresectable or metastatic melanoma, ICIs have led to dramatic increases in long-term survival for some patients. Their use has now expanded to a range of cancers, including non-small cell lung cancer, renal cell carcinoma, head and neck cancer, and bladder cancer.
Yet, across all cancer types, only about 20 to 40 percent of patients respond to ICIs, highlighting the need for new strategies to make them a more effective therapy for all. Recently, two new publications have revealed novel insights into patients’ lack of responses to ICIs — and how to overcome them.
In new work published in Science Advances, Yi Zheng’s lab at Cincinnati Children’s Hospital uncovered a mutation that leads to resistance to ICIs targeting the PD-1 (programmed death 1) checkpoint receptor. Specifically, Zheng’s team showed that a mutation in the RAC1 (Ras-related C3 botulinum toxin substrate 1) gene called A159V causes the development of an immunosuppressive tumor microenvironment that prohibits the efficacy of ICI drugs in mice. They showed that this happens through the activation of mTORC1 signaling, which increases glucose consumption of the tumor, suppresses chemokine production, and decreases IFNGR1 (interferon gamma receptor 1) expression, preventing the immune system from attacking the tumor effectively.
The team also showed that giving the mice rapamycin — an FDA-approved drug that inhibits mTORC1 signaling — successfully sensitized tumor cells to the ICI drug, overcoming the resistance from the genetic mutation.
“If further research confirms this effect in humans, these findings may facilitate stratifying patients carrying this gene mutation who may benefit from a combination form of treatment,” said Zheng in the press release.
A second paper published in the Journal for ImmunoTherapy of Cancer revealed a new way to create second-generation therapies to target the PD-L1 (programmed death-ligand 1) checkpoint protein. Tumor cells express PD-L1 on their surface that binds to PD-1 on T cells, sending an “off” signal that suppresses the immune response. Normally, PD-L1 is taken back inside the cell and then recycled up to the tumor cell surface again, allowing the tumor to maintain this immune-suppressive effect.
Through the use of in vivo humanized PD-1/PD-L1 mouse tumor models, Haidong Dong’s lab at the Mayo Clinic developed a novel anti-PD-L1 antibody, H1A, that resulted in greater tumor control than typical ICI drugs because it boosted the activity of myeloid cells. Enhanced myeloid cell activity promoted PD-L1 degradation on tumor cells rather than its recycling, enhancing immune system recognition and attack of the tumor.
"We now have a tool that can completely remove PD-L1 and in doing so we have more myeloid cell activation," said Michelle Hsu, a biomedical scientist at Mayo Clinic and first author on the study in the press release. The release also states that the team is now planning a Phase 1 clinical trial with H1A.
These discoveries could pave the way for more effective ICI drugs — and emphasize the continued importance of basic research that identifies new and creative solutions that could allow many more patients to respond and reap the benefits.
