TCR clonality predicts pembrolizumab response in NSCLC

Pre-treatment T-cell receptor (TCR) clonality and reduced diversity predicted response rate in non-small cell lung cancer (NSCLC) patients with high PD-L1 treated with pembrolizumab.

Due to recombination and cellular selection, the immune system is able to produce up to 10¹¹ different TCRs. Increased clonality, reduced diversity, and increased convergence of TCRs have been suggested to reflect clonal expansion of antigen-specific T cells in the tumour microenvironment and to correlate with improved overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Moreover, increased clonality has been linked to increased risk of developing immune related toxicity.

To further explore the association between TCR repertoire and treatment outcomes, Australian investigators analysed the pre-treatment TCR repertoire in 29 patients with NSCLC (PD-L1 ≥50%) treated with single-agent pembrolizumab and follow-up for at least 18 months. Dr Afef Abed (Edith Cowan University, Australia) presented the results [1].

Reduced number of unique clones and reduced Shannon diversity was found to be associated with improved ORR to pembrolizumab (P=0.038 and P=0.021, respectively). Moreover, there was a significantly longer PFS in patients with reduced number of unique clones (HR 0.40; P=0.040), reduced Shannon diversity (HR 0.44; P=0.044), reduced Evenness (HR 0.31; P=0.033), and elevated clonality (HR 2.45; P=0.044). None of these parameters were statically significant in relation to OS. Three TCR families (TRBV6-4, TRBV10-2, and TRBV10-3) were observed to occur significantly more frequently among non-responders.

“So, increased pre-treatment TCR clonality and reduced diversity are associated with improved response rate and PFS, but not OS, in NSCLC patients with high PD-L1 treated with pembrolizumab monotherapy,” concluded Dr Abed. “Further maturation of this cohort will demonstrate whether the circulating pre-treatment TCR repertoire is a prognostic factor for immune checkpoint inhibition.”

1. Abed A. et al. Clinical value of pre-treatment T-cell receptors (TCR) repertoire in non-small cell lung cancer (NSCLC) patients treated with single agent immunotherapy. Abstract LBA68, ESMO Congress 2021, 16–21 September.

 

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Posted on 19 November 202115 February 2024