Monitoring botensilimab- and balstilimab-induced T-cell dynamics in refractory mismatch repair proficient metastatic colorectal cancer.

Abstract

3527 Background: Mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) responds poorly to immune checkpoint inhibition (ICI). A better understanding of local and systemic immune cell activities is critical for improving ICI treatment efficacy. T cells elicit anti-tumor specificity through their T cell receptors (TCR) and dynamic changes in the TCR repertoire are associated with clinical outcomes. Circulating T cells in the blood provide an accessible liquid biomarker to quantify and track T cell activity at systems level and longitudinally. Here, we present temporal T cell tracking as a correlate of ICI efficacy in refractory pMMR mCRC patients treated with botensilimab (BOT; Fc-enhanced anti-CTLA-4 antibody) with or without balstilimab (BAL; anti-PD-1 antibody). Methods: 10 patients from the open-label, phase 2 study (NCT05608044) with BOT in refractory pMMR CRC (without metastatic liver disease) were included. In this trial patients were randomized into BOT (75mg or 150mg Q6W, 4x) monotherapy or in combination with BAL (240mg Q2W, for 2 years), versus standard of care (regorafenib or trifluridine/tipiracil). TCR dynamics were longitudinally assessed (0,2,4,6,12 weeks) from circulating T cells, based on deep TCR sequencing (OS-TCR, Omniscope) and quantified using functional clustering. Results: 2 mCRC patients out of 10 (20%) showed partial response (PR) while 8 (80%) had progressive disease (PD), however at variable timepoints. However circulating T cells showed significant expansion of both pre-existing and novel clonotypes in all patients, detectable at conserved frequencies at sequential time points. The magnitude of induced T cell clonotypes varied across treatment cycles, with repeated boosting effects observed in responders. Scoring T cell activity based on quantitative and qualitative TCR repertoire metrics, allowed to rank patients by their response. Intriguingly, TCR repertoire dynamics strongly correlated with clinical outcomes, establishing its potential as a quantitative biomarker for monitoring treatment efficacy. Conclusions: Deep T cell repertoire profiling detected dynamics of circulating T cells with quantitative and qualitative difference related to ICI response. Immune cell tracking from liquid biopsies is a powerful tool to quantify ICI efficacy in real time.