Work

IMMU-40. Robust activation and clonal expansion of early, non-exhausted, stem-like endogenous T cells induced by chemo-immunotherapy treatment in patients with pediatric brain tumors is predictive of clinical outcome

Year: 2025

Type: article

Abstract: Pediatric brain tumors are widely considered non-immunogenic and do not respond to checkpoint blockade. We have developed a novel strategy to break immune tolerance to tumor by combining: (i) IDO pathway-inhibitor indoximod to promote dendritic cell maturation and antigen cross-presentation, and (ii) moderately intense oral chemotherapy to release a wave of tumor antigens. We hypothesize this cyclic chemo-immunotherapy combination stimulates normally quiescent T cells to become activated, clonally expand, and travel to tumor via the bloodstream to mount anti-tumor responses. We analyzed longitudinal blood samples from 52 patients with pediatric CNS tumors treated with indoximod plus either chemotherapy or chemotherapy plus BTK-inhibitor ibrutinib from trials NCT02502708, NCT04049669, NCT05106296. Patients in this cross-sectional “training cohort” were chosen to represent a wide range of tumor types, molecular risk factors, and overall survival. Blood samples (2-11 samples/patient depending on treatment duration) were analyzed by paired single-cell TCR and single-cell RNA sequencing. For each sample, a “Clonal Expansion Index” (CEI) was calculated as the sum of the number of T cells derived from treatment-expanded TCR clonotypes, normalized to the total number of T cells. High peak CEI values were predictive of longer overall survival and indicative of robust treatment-induced (pharmacodynamic) clonal expansion of predominantly CD8+ effector T cells. Many of these responding T cells were clonally linked to an early stem-like precursor population distinctly different from conventional “precursor-exhausted” T cells (Tpex). Treatment-expanded clones making up the CEI were an average of 100-fold more likely to be found in pre-treatment tumor biopsies by TCR-beta sequencing than random naïve T cells from the same patient; and up to 80% of CD8+ CEI T cells in circulation matched clonotypes found in tumor biopsies while on treatment. To our knowledge, this is the first report of immunotherapy-induced activation and clonal expansion of endogenous T cells in children.

Source: Neuro-Oncology

DOI: 10.1093/neuonc/noaf201.0838