14P - Integrated modelling of T cell repertoires to identify clonotype signatures of ICI response

Background

Immune checkpoint inhibitors (ICI) have shown efficacy in activating immune responses to tumours and in improving survival among cancer patients. However, highly heterogeneous patient responses highlight the need for predictive pipelines that leverage the immune cell dynamics associated with ICI as a biomarker.

Methods

The OS-T platform (Omniscope Inc.) was applied to deeply profile single T cell clonotypes from peripheral blood of colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) patients before and after receiving ICI (e.g., anti-PD1 therapy). For an integrated immune repertoire analysis, we developed a novel computational framework for tracking and modelling TCR clonotype dynamics, combining three complementary approaches: (i) statistical noise model detecting differentially expanded clonotypes after treatment, (ii) sequence similarity and density-based clustering of sequences with inferred similar specificity, (iii) recombination model that computes generation probabilities of immune receptor sequences [Murugan, A., at al., 2012, 109(40), 16161-16166].

Results

We identified T cell clonotype clusters with treatment-related immune receptor sequences specific to or conserved across patients and cohorts. Such clonotype sequences allowed us to quantify treatment efficacy and to track patient response over time. Conserved clonotypes across patients enabled the identification of sequence signatures associated with patient response to ICI, potentially applicable for systematic efficacy tracking or patient stratification.

Conclusions

Our results suggest the combination of deep single-cell T-cell receptor profiling and receptor sequence modelling to efficiently identify candidate clonotypes for ICI response monitoring in CRC, NSCLC, and beyond. Moreover, combining such orthogonal approaches optimises the nomination of cancer-related T cell receptor sequences for targeted cell therapies and similar immune receptor-based strategies.

Legal entity responsible for the study

Omniscope Inc.

Funding

Omniscope Inc.

Disclosure

J. L. Melero, A. Mendizabal-Sasieta, U. Perron, D. Pravdyvets, N. Borcherding, B. Colom-Sanmartí, M. Grzelak, M. Soto, E. Planas Rigol: Financial Interests, Personal, Full or part-time Employment: Omniscope. J.C. Nieto: Financial Interests, Personal, Advisor of Omniscope. H. Heyn: Financial Interests, Personal, Co-founder of Omniscope, SAB member of Nanostring and MiRXES and consultant to Moderna and Singularity.