154P - Phase II study of nivolumab and relatlimab utilizing single cell analysis of circulating T cells reveals immune features associated with response to dual PD-1 and LAG-3 inhibition

Background

Uveal melanoma (UM), the most prevalent adult primary intraocular malignancy, frequently progresses to incurable metastatic disease with fatal outcomes. Unlike cutaneous melanoma, metastatic UM demonstrates limited response to PD-1 checkpoint inhibition, leading to a persistently poor prognosis. We previously reported significant expression of the inhibitory immune checkpoint molecule, LAG3, on CD8+ cytotoxic Tcells in metastatic UM. Consequently, we initiated a clinical trial to assess the therapeutic efficacy of dual PD-1/LAG3 blockade in metastatic UM with nivolumab/relatlimab (Nivo/Rela).

Methods

Single-cell RNA and TCR sequencing of circulating CD3+ Tcells from 27 UM patients receiving Nivo/Rela was performed at pre-treatment baseline, mid-treatment (n=5), and end-of-treatment (EOT), including a final cohort of 2 partial response (PR), 12 stable disease (SD), and 13 progressive disease (PD) patients.

Results

Several immune and transcriptomic features were identified associated with treatment response and resistance. PR individuals exhibited elevated levels of circulating CD8+ effector/memory Tcells at end-of-treatment. Transcriptomic profiling revealed differentially expressed genes (DEGs) in CD8+ Tcells linked with treatment response, with PR/SD patients showing upregulation of LAG3, JUN, and CCL4 at baseline compared to the PD cohort. Comparing EOT to baseline samples, the PD cohort upregulated FOS and JUN, whereas these DEGs were mainly downregulated in SD patients. TCR repertoire analysis revealed increased clonality of circulating Tcells in PR patients, while the SD cohort with mid-treatment timepoints (n=4) displayed TCR repertoire expansion during treatment with repertoire contraction by EOT. TCR epitope specificity analysis revealing anti-melanoma Tcell clones expressing LAG3 across the patient cohort, with enhanced anti-melanoma TCR clonality observed in the PR cohort.

Conclusions

Our study delineates transcriptional and clonality alterations in circulating CD8+ Tcells associated with response and identifies potential mechanisms and biomarkers related to the immunotherapeutic efficacy of Nivo/Rela in UM.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Bristol Myers Squibb.

Disclosure

Z. Correa, J.W. Harbour: Financial Interests, Personal and Institutional, Other: Castle Biosciences. J. Lutzky: Financial Interests, Personal, Other, reviewed grant applications for department of defense: general dynamics; Financial Interests, Personal, Advisory Board: Regeneron, Immunocore; Financial Interests, Personal, Other, safety monitoring committee: Agenus, Celldex; Financial Interests, Institutional, Research Grant, Funding for institutional trial: BMS; Financial Interests, Institutional, Local PI: Trisalus, Takeda, Vyriad, Tango, Immunocore, Replimune, Oncohost, Dragonfly, Iovance, Ideaya. All other authors have declared no conflicts of interest.