734MO - Deep sequencing of the T-cell receptor reveals common and reproducible CD8 T-cell receptor signatures of response to checkpoint immunotherapy

Background

Immune checkpoint blockade (ICB) has revolutionized the treatment of metastatic melanoma (MM). However, robust biomarkers of response and the identity of key antigenic targets remains lacking. We have previously demonstrated the importance of large peripheral CD8+ T cell clones in the ICB response; these clones being more cytotoxic and especially sensitive to ICB. However, identifying key groups of T cells based on their T cell receptor (TCR) usage has remained elusive.

Methods

We performed deep sequencing of the TCR of CD8+ T cells isolated from peripheral blood of patients receiving ICB (n=96) for MM at multiple timepoints, along with control samples (n=43) and resected tumour specimens (n=10). Using the GLIPH2 algorithm, we grouped TCR into specificity groups, based on putative shared antigenic recognition, and explored associations with clinical outcome. We attempted to replicate findings in two independent cohorts.

Results

We identify TCR specificity groups that significantly increase in size from pre- to post-treatment in patients who have a clinical response to ICB. We call these ‘Emergent Responder Specificity Groups’ – ERSGs. We show that ERSGs are enriched for published known tumour-associated TCR and are more likely to be expanded intra-tumourally than non-ERSGs. Further, ERSGs are more likely to contain large T cell clones and have a greater cytotoxicity. Finally, the quantity of ERSGs present post-ICB correlated with clinical outcome in both replication cohorts.

Conclusions

This work identifies peripheral CD8+ TCR signatures that expand with immunotherapy and are associated with long-term clinical responses. These results demonstrate the prognostic utility of the peripheral immune repertoire and have potential widespread application in aiding in the identification of key antigens, with implications for T cell therapeutics.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

The Wellcome Trust.

Disclosure

M.R. Middleton: Financial Interests, Personal, Advisory Board, Advice on drug development and clinical trial design: Alkermes, Kineta, Silicon Therapeutics, Immunocore, Replimune; Financial Interests, Personal, Advisory Board, Advice on patient experience measures and research design: BMS; Financial Interests, Institutional, Invited Speaker, Fees for clinical trial conduct: Replimune; Financial Interests, Institutional, Invited Speaker, Fees for trial conduct: BMS, Alkermes, GSK, Merck KGa, MSD, Pfizer, Regeneron, Bioline, Novartis, Roche, Medivir; Financial Interests, Institutional, Funding, Educational grant towards IIS; fees for clinical trial conduct: Immunocore; Financial Interests, Institutional, Invited Speaker, Grant towards IIS: GRAIL; Non-Financial Interests, Multiple roles as reviewer and committee member: Cancer Research UK; Non-Financial Interests, Member: AACR, ASCO, ACP. B.P. Fairfax: Financial Interests, Personal, Conference Support: Bristol Myers Squibb. All other authors have declared no conflicts of interest.