Our body has mechanisms to regulate the immune system. Effective immunity requires the body to know when to ramp up the immune system when a threat, such as abnormal cells that could develop into cancer. On the other hand, the body also needs to know when to minimize the immune response, preventing it from destroying healthy cells.
Proteins called “immune checkpoints,” present on the surface of immune cells, play a significant role in immune regulation. When immune checkpoints bind to corresponding proteins, known as “ligands,” present on other cells, they communicate an “off” signal to the immune cells. While this mechanism is beneficial to limit immune activation when it’s unnecessary, we do not want our bodies turning off the immune system while facing a cancer threat. Downregulation of immunity, in this case, could prevent the immune system from destroying that cancer.
Immune checkpoint inhibitors (ICIs) have transformed the cancer treatment scene by targeting the interaction between immune checkpoints and their ligands. In 2011, the FDA approved the first ICI to treat advanced cases of melanoma. Since then, eight more ICIs have received FDA approval. Oncologists use ICIs to treat over a dozen types of cancer, including many late-stage, advanced, and metastatic malignancies.
ICIs have brought effective therapeutic options to patients who previously had minimal to no treatment options. Despite the promising therapeutic efficacy associated with ICIs, they can also get side effects, which, in some cases, can rise to a severity requiring patients to discontinue treatment. Because ICIs target the immune response, many toxicities associated with their use emerge because of too much immune stimulation. Overstimulation of the immune response can lead to the attack of healthy cells resulting in symptoms that mimic those experienced by patients with autoimmune diseases. Thus, these toxicities became known as immune-related adverse events (irAEs).
Common irAEs include rash, colitis, and pancreatitis. Because irAEs occur due to overactive immunity, patients who develop these symptoms may be the same patients whose cancer responds best to ICIs. A recent study published in JAMA Oncology suggests this is true in advanced non–small cell lung cancer (NSCLC) patients receiving the ICI atezolizumab.
The researchers pooled data from three randomized, multicenter clinical trials where patients with stage IV NSCLC received chemotherapy with or without atezolizumab (NCT02367781, NCT02657434, and NCT02366143). The analysis included data from over 2,5000 patients, 1,577 receiving chemotherapy with atezolizumab (atezolizumab group) and 926 receiving chemotherapy without atezolizumab (control group).
Patients in the atezolizumab group had longer overall survival than those in the control group. Notably, patients with mild to moderate irAEs (known as grade 1 or 2) had longer survival than patients without irAEs or those experiencing more severe grade 3 – 5 irAEs. The authors indicate that their study supports using atezolizumab with chemotherapy for first-line treatment of stage IV NSCLC.
Sources: Immune Netw, JAMA Oncol