IMMU-39. T cell receptor diversity is a predictor of therapy response in patients with gliomas treated with Delta-24-RGD

Abstract Malignant gliomas pose a significant therapeutic challenge. Remarkably, complete tumor regressions have been observed in a subset of patients with recurrent malignant gliomas treated with Delta-24-RGD oncolytic adenovirus in phase 1 and 2 clinical trials. Radiographical pseudo-progressions preceded tumor regressions, suggesting the involvement of an anti-tumor immune response. To evaluate the role of T cells, we confirmed CD3+ T cell infiltration in tumors obtained during a phase 1 clinical trial (NCT00805376) and further investigated the T cell landscape using T cell receptor (TCR) sequencing. Notably, tumors resected two weeks post-treatment (n=9) exhibited significantly reduced TCR diversity compared to pre-treatment tumors (n=6, p = 0.036). An independent dataset of peripheral blood from pediatric DIPG patients treated with Delta-24-RGD (NCT03178032) confirmed the decrease in TCR diversity post-treatment (n=10, p = 0.043). Notably, patients who retained higher TCR diversity post-treatment demonstrated prolonged survival (p = 0.022), strongly suggesting a link between immune repertoire retention and clinical outcomes. Further analysis of pre- and post-treatment samples revealed limited overlap in T cell clonotypes, with only 20% of the post-treatment clonotypes detected in pre-treatment tumors. The degree of overlap correlated with patient survival (p = 0.039). Using GLIPH2 clustering, we identified 617 specificity groups among 2,737 tumor-derived CDR3b sequences, with CDR3 motifs including RHAG, KSFS and S%SPKET shared with an independent glioma dataset, potentially indicating glioma-reactive T cells. In summary, our findings provide for the first time a clinically relevant assessment of T cell dynamics in oncolytic-adenovirus-treated glioma patients. Based on our clinical data revealing the significance of TCR diversity and repertoire overlap, we demonstrate that immune profiling is a potential biomarker for therapy response and survival, paving the way for more precise and effective immunotherapy strategies for glioma.