Woroniecka et al. showed that in human glioblastoma (GBM), 4-1BB is highly expressed on non-exhausted, activated PD-1+CD8+ TILs. 4-1BB agonist antibody increased TIL IFNγ production in vitro in human and murine GBM TILs, and synergized with anti-PD-1 in mice with intracranial GBM to reduce the proportion of exhausted TILs, increase TIL function, and lead to 50% long-term survival in a CD8+, but not CD4+, T cell-dependent manner. Efficacy of the combination treatment correlated with levels of 4-1BB expression on TILs, but not with tumor location, across intracranial and subcutaneous glioma, lung, melanoma, and breast tumors.
PURPOSE: The success of checkpoint blockade against glioblastoma (GBM) has been disappointing. Anti-PD-1 strategies may be hampered by severe T-cell exhaustion. We sought to develop a strategy that might license new efficacy for checkpoint blockade in GBM. EXPERIMENTAL DESIGN: we characterized 4-1BB expression in tumor infiltrating lymphocytes (TIL) from human GBM. We implanted murine tumor models including glioma (CT2A), melanoma (B16), breast (E0771), and lung carcinomas (LLC) intracranially (IC) and subcutaneously (SC), characterized 4-1BB expression, and tested checkpoint blockade strategies in vivo. RESULTS: Our data reveal that 4-1BB is frequently present on non-exhausted CD8+ tumor-infiltrating lymphocytes (TIL) in human and murine GBM. In murine gliomas, 4-1BB agonism and PD-1 blockade demonstrate a synergistic survival benefit in a CD8+ T-cell dependent manner. The combination decreases TIL exhaustion and improves TIL functionality. This strategy proves most successful against intracranial (IC) CT2A gliomas. Efficacy in all instances correlates with the levels of 4-1BB expression on CD8+ 51 TIL, rather than with histology or with IC versus SC tumor location. Proffering 4-1BB expression to T-cells licenses combination 4-1BB agonism and PD-1 blockade in models where TIL 4-1BB levels had previously been low and the treatment ineffective. CONCLUSION: While poor T-cell activation and severe T-cell exhaustion appear to be limiting factors for checkpoint blockade in GBM, 4-1BB agonism obviates these limitations and produces long-term survival when combined with anti-PD-1 therapy. Furthermore, this combination therapy is limited by TIL 4-1BB expression, but not by the intracranial compartment, and therefore may be particularly well-suited to GBM.