Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer
Naiyer A Rizvi1, Matthew D Hellmann2, Alexandra Snyder3
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY, 10065, USA. chant@mskcc.org.
Abstract:
Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non-small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti-PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti-PD-1 therapy.
Insights
Genomic factors like mutation burden and smoking signatures predict response to immune checkpoint inhibitors (programmed cell death-1 or PD-1) in lung cancer. Higher mutation burden and neoantigen load correlate with better treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immune checkpoint inhibitors, such as anti-PD-1 antibodies, are transforming cancer therapy by activating T cells against tumors.
- Understanding the genetic factors influencing patient response to these therapies is crucial for optimizing treatment strategies.
Purpose of the Study:
- To identify genomic determinants associated with response to pembrolizumab (anti-PD-1 therapy) in non-small cell lung cancer (NSCLC).
- To explore the relationship between tumor mutational burden, molecular signatures, and clinical efficacy.
Main Methods:
- Whole-exome sequencing was performed on NSCLC tumors from patients treated with pembrolizumab.
- Analysis of two independent cohorts to assess correlations between genomic features and treatment response.
- Evaluation of objective response, durable clinical benefit, and progression-free survival.
Main Results:
- Higher nonsynonymous mutation burden in tumors was significantly associated with improved objective response, durable clinical benefit, and progression-free survival.
- Treatment efficacy correlated with molecular smoking signature, neoantigen burden, and DNA repair pathway mutations, all linked to mutation burden.
- In one patient, tumor regression was accompanied by enhanced neoantigen-specific CD8+ T cell responses, suggesting a mechanism of action.
Conclusions:
- The genomic landscape of lung tumors plays a significant role in shaping response to anti-PD-1 therapy.
- Tumor mutational burden and related genomic features are key predictors of efficacy for immune checkpoint inhibitors in NSCLC.
