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

Journal Article (Journal Article)

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 intracranially and subcutaneously, characterized 4-1BB expression, and tested checkpoint blockade strategies in vivo. RESULTS: Our data reveal that 4-1BB is frequently present on nonexhausted CD8+ TILs 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 CT2A gliomas. Efficacy in all instances correlates with the levels of 4-1BB expression on CD8+ TILs, rather than with histology or with intracranial versus subcutaneous 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. CONCLUSIONS: Although 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.

Full Text

Duke Authors

Cited Authors

  • Woroniecka, KI; Rhodin, KE; Dechant, C; Cui, X; Chongsathidkiet, P; Wilkinson, D; Waibl-Polania, J; Sanchez-Perez, L; Fecci, PE

Published Date

  • March 15, 2020

Published In

Volume / Issue

  • 26 / 6

Start / End Page

  • 1349 - 1358

PubMed ID

  • 31871298

Pubmed Central ID

  • PMC7073290

Electronic International Standard Serial Number (EISSN)

  • 1557-3265

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-19-1068

Language

  • eng

Conference Location

  • United States