Abstract
Researchers discovered that patients with a higher proportion of clonal neoantigens than subclonal neoantigens in their tumors are most likely to respond to immunotherapy. The findings may help guide the use of checkpoint inhibitors and lead to development of vaccines that stimulate the immune system to target specific neoantigens.
Researchers have discovered new details about how the genetic complexity of patients' tumors affects their responses to immunotherapy. The findings may help fine-tune how immune checkpoint inhibitors are used and guide development of new treatments.
Investigators analyzed genetic sequencing data stored in The Cancer Genome Atlas (TCGA) from more than 200 patients with adenocarcinoma and squamous cell carcinoma of the lungs. They determined the number of neoantigens in each tumor and what proportion of those were clonal neoantigens—those that develop early, sometimes through driver mutations, and are shared throughout the tumor—versus subclonal—those that appear in a subset of cells as tumors evolve. They then compared overall survival across all tumors and found that, generally, patients with a higher proportion of clonal neoantigens lived longer.
“Our findings begin to highlight that clonal neoantigens might be important for immune surveillance,” says the study's co-lead, Charles Swanton, PhD, group leader of the Translational Cancer Therapeutics Laboratory at the Francis Crick Institute in London, UK. “We have been developing drugs against driver mutations, but less is known regarding whether clonal neoantigens are relevant and in what context.”
Swanton, in collaboration with Sergio Quezada, PhD, at the University College London Cancer Institute, analyzed samples from two patients with non–small cell lung cancer (NSCLC) and identified T cells capable of recognizing clonal neoantigens and expressing high levels of the PD-1 protein on their surface. They then reanalyzed TCGA data and found that tumors with a high proportion of clonal neoantigens also expressed high levels of PD-L1 at the transcriptional level. The finding suggests that these tumors may be responsive to drugs targeting the PD-1 protein receptor or its ligand, PD-L1.
The investigators examined data from a recent study in which patients with NSCLC were treated with the PD-1 antibody pembrolizumab (Keytruda; Merck). They found that patients whose tumors had many clonal antigens were more likely to respond well to treatment compared with patients with more subclonal antigens in their tumors.
The researchers also examined data from a study of patients with melanoma treated with the anti–CTLA-4 antibodies ipilimumab (Yervoy; Bristol-Myers Squibb) or tremelimumab (AstraZeneca) and found that a high clonal neoantigen burden was associated with significantly improved overall survival. They also found that some patients who had been previously treated with the chemotherapy drug dacarbazine had a higher proportion of subclonal neoantigens and were less likely to respond to immunotherapy.
“This study suggests that the mutations that are more important to the cancer's survival—the ones that have been there the longest—are the ones we need to target,” says Elizabeth Jaffee, MD, deputy director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, MD. “This goes against what many oncologists have been thinking, which is that the mutations that form earliest in the disease process may be hardest to target because they have built up more immune tolerance.”
The findings lay the foundation for developing vaccines that stimulate the immune system to target clonal neoantigens, say Swanton and Quezada. They plan to expand their investigations to larger groups of patients with lung cancer as well as other cancers.
“We've learned that it might matter where the neoantigen is on the phylogenetic tree when it comes to optimizing response to treatment or considering new therapies,” says Swanton. “What we're trying to exploit is the mutational burden that's carried with the first invasive tumor cell prior to branched evolution.” –Janet Colwell