4-1BB Agonism Averts TIL Exhaustion and Licenses PD-1 Blockade in Glioblastoma and Other Intracranial Cancers

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.

 2019 Dec 23. pii: clincanres.1068.2019. doi: 10.1158/1078-0432.CCR-19-1068. [Epub ahead of print]