A Composite Decision Rule of CD8+ T-cell Density in Tumor Biopsies Predicts Efficacy in Early-stage, Immunotherapy Trials

Abstract Purpose: To examine whether CD8+ T-cell numbers in paired tumor biopsies in early-stage clinical trials can be used as an early indicator of clinical benefit for cancer immunotherapies. Experimental Design: Paraffin sections of tumor biopsies were stained immunohistochemically for CD8+ T cells, which were digitally enumerated. The tumor biopsies were from cancer patients in early-phase trials testing novel immunotherapeutic agents. Paired biopsies taken before the start of treatment and on-treatment were compared. A total of 155 patients were used as the training set and an additional 221 patients were used as the validation set. Results: Using the Cox proportional hazard model, a ≥0.9- increase in fold change (FC) on a ln scale in CD8+ T cells (corresponding to a 2.5-fold increase on the linear scale), from baseline, demonstrated a greater association with prolonged progression-free survival and allowed improved differentiation between groups above and below the threshold. Similarly, a ≥6.2 threshold in geometric mean of the on-treatment density (OTD) of T cells, which approximately corresponds to 500 cells/mm2, correlated with longer PFS. The combination of both criteria (FC and OTD) provided the best discrimination between clinically nonactive and active compounds. Conclusions: We propose that a composite score of CD8+ T-cell density in paired biopsies taken before and on-treatment may be a new biomarker to inform on clinical outcomes in early immunotherapy clinical trials.