Dynamics and survival associations of T cell receptor clusters in patients with pleural mesothelioma treated with immunotherapy

Our plain-English summary of Dynamics and survival associations of T cell receptor clusters in patients with pleural mesothelioma treated with immunotherapy, by A.P. Desai, F. Kosari, M. Disselhorst, et al (Journal for Immunotherapy of Cancer, 2023).

The study

• Authors: A.P. Desai, F. Kosari, M. Disselhorst, J. Yin, A. Agahi, T. Peikert, J. Udell, S.H. Johnson, J. Smadbeck, S. Murphy, G. Karagouga, A. McCune, J. Schaefer-Klein, M.J. Borad, J. Cheville, G. Vasmatzis, P. Baas, A. Mansfield
• Journal: Journal for Immunotherapy of Cancer
• Published: 2023;11(6)
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Immune checkpoint inhibitors (ICIs) are now a first-line treatment option for patients with pleural mesothelioma with the recent approval of ipilimumab and nivolumab. Mesothelioma has a low tumor mutation burden and no robust predictors of survival with ICI. Since ICIs enable adaptive antitumor immune responses, we investigated T-cell receptor (TCR) associations with survival in participants from two clinical trials treated with ICI.

Methods: We included patients with pleural mesothelioma who were treated with nivolumab (NivoMes, NCT02497508) or nivolumab and ipilimumab (INITIATE, NCT03048474) after first-line therapy. TCR sequencing was performed with the ImmunoSEQ assay in 49 and 39 pretreatment and post-treatment patient peripheral blood mononuclear cell (PBMC) samples. These data were integrated with TCR sequences found in bulk RNAseq data by TRUST4 program in 45 and 35 pretreatment and post-treatment tumor biopsy samples and TCR sequences from over 600 healthy controls. The TCR sequences were clustered into groups of shared antigen specificity using GIANA. Associations of TCR clusters with overall survival were determined by cox proportional hazard analysis.

Results: We identified 4.2 million and 12 thousand complementarity-determining region 3 (CDR3) sequences from PBMCs and tumors, respectively, in patients treated with ICI. These CDR3 sequences were integrated with 2.1 million publically available CDR3 sequences from healthy controls and clustered. ICI-enhanced T-cell infiltration and expanded T cell diversity in tumors. Cases with TCR clones in the top tertile in the pretreatment tissue or in circulation had significantly better survival than the bottom two tertiles (p<0.04). Furthermore, a high number of shared TCR clones between pretreatment tissue and in circulation was associated with improved survival (p=0.01). To potentially select antitumor clusters, we filtered for clusters that were (1) not found in healthy controls, (2) recurrent in multiple patients with mesothelioma, and (3) more prevalent in post-treatment than pretreatment samples. The detection of two-specific TCR clusters provided significant survival benefit compared with detection of 1 cluster (HR<0.001, p=0.026) or the detection of no TCR clusters (HR=0.10, p=0.002). These two clusters were not found in bulk tissue RNA-seq data and have not been reported in public CDR3 databases.

Conclusions: We identified two unique TCR clusters that were associated with survival on treatment with ICI in patients with pleural mesothelioma. These clusters may enable approaches for antigen discovery and inform future targets for design of adoptive T cell therapies.

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

In plain English

This study examined immune cells called T cells in people with pleural mesothelioma. Patients received nivolumab alone or with ipilimumab after earlier platinum chemotherapy, in two Netherlands Cancer Institute trials that treated 68 patients. The authors sequenced T-cell receptors in blood and identified them computationally in tumor RNA-sequencing data, from samples taken before treatment and about 6 weeks in. They grouped receptors into clusters predicted to share a target, excluding clusters found in healthy people. Tumors had significantly more clusters during treatment than before. Patients in the top third for clusters before treatment survived significantly longer than the bottom two thirds, in tumor (hazard ratio 0.44, 95% confidence interval 0.200 to 0.986) and in blood (hazard ratio 0.41, 95% confidence interval 0.187 to 0.898). Two specific clusters found in on-treatment blood were linked to longer survival. Ten patients had one or both, and what these clusters recognize is unknown. The authors concluded that the two clusters were associated with improved survival. They noted the small sample, second-line or later treatment, and a mostly epithelioid group. The study did not examine asbestos exposure.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory and computational (bioinformatic) analysis of blood and tumor samples from patients in two clinical trials of immune checkpoint inhibitor treatment, looking for links between T-cell receptor clusters and overall survival
• Who was studied: 68 patients with pleural mesothelioma treated on the NivoMes (n=34) and INITIATE (n=34) trials at the Netherlands Cancer Institute. Samples comprised 49 pretreatment and 39 on-treatment blood (PBMC) samples, 42 pretreatment and 31 on-treatment tumor biopsies, and 33 patients with both a pretreatment biopsy and blood. The 49 patients in Table 1 included 39 men and 10 women; 42 had epithelioid and 7 non-epithelioid histology; median age was 66. Publicly available T-cell receptor sequences from 589 healthy controls without cancer were used for comparison. Study dates are not given.
• Exposure: No asbestos exposure was studied. The exposure was immunotherapy: nivolumab alone (19 of 49 patients) or nivolumab with ipilimumab (30 of 49), given after previous platinum-based chemotherapy, with samples taken before treatment and after 6 weeks.
• Main results:
  • In tumor biopsies, the number of T-cell receptor clusters was significantly higher in on-treatment samples than in pretreatment samples (p=0.017).
  • Patients whose pretreatment tumor biopsies were in the top third for T-cell receptor clusters (n=14) survived significantly longer than those in the bottom two thirds (n=28): p 0.034, HR 0.44, 95% CI 0.200 to 0.986.
  • Patients whose pretreatment blood samples were in the top third for T-cell receptor clusters (n=16) survived significantly longer than those in the bottom two thirds (n=33): p 0.033, HR 0.41, 95% CI 0.187 to 0.898.
  • Among 33 patients with both a pretreatment biopsy and blood, those in the top third for T-cell receptor clones shared between tumor and blood (n=11) had significantly better overall survival than the others (n=22): p 0.012; HR 0.33, 95% CI 0.129 to 0.837.
  • A group of patients (n=18) whose pretreatment blood was enriched for commonly occurring clusters had a 61% overall response rate, compared with 19% in the other patients (n=31), p=0.003. This group also had better overall survival (HR 0.47, p 0.038; 95% CI 0.226 to 0.989).
  • None of the T-cell receptor clusters in pretreatment blood were associated with survival after correction for multiple testing.
  • Two specific T-cell receptor clusters in on-treatment blood were linked to survival. Both clusters were detected in five patients and one cluster in five patients. Detecting both was associated with better survival than detecting one (HR<0.001, p=0.026) or none (HR=0.10, p=0.002). The antigen these clusters recognize is unknown.
  • Similar survival trends were seen with clusters in on-treatment biopsies and blood, but these were not always statistically significant.
• The authors' conclusion: The authors concluded that they had identified two T-cell receptor clusters associated with improved survival in patients with pleural mesothelioma treated with immune checkpoint inhibitors. They stated that, if validated, these clusters may have predictive value and may inform future treatment approaches.
• Limitations the authors state:
  • The sample size was limited.
  • Patients received immunotherapy as second-line or later treatment, so the results may not apply to first-line treatment.
  • Most patients had the epithelioid type of pleural mesothelioma.
  • A single biopsy is unlikely to capture all the T cells in a tumor.
  • The methods used could not determine the paired alpha and beta chains of the T-cell receptor.
  • The antigen specificity of T cell clones is hard to determine, and it is unknown for the survival-associated clusters.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Immunotherapy, checkpoint inhibitors, Ipilimumab (Yervoy), Nivolumab (Opdivo), Mesothelioma, Clinical Trial, First-line Therapy.

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