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

  • Clin Cancer Res. 2020 Mar 15;26(6):1349-1358. doi: 10.1158/1078-0432.CCR-19-1068.
Karolina I Woroniecka  1  2  3 ,  Kristen E Rhodin  2  3 ,  Cosette Dechant  2  3 ,  Xiuyu Cui  3 ,  Pakawat Chongsathidkiet  1  3 ,  Daniel Wilkinson  3 ,  Jessica Waibl-Polania  1  3 ,  Luis Sanchez-Perez  3  4 ,  Peter E Fecci  5  2  3  4
Affiliations
  • 1. Department of Pathology, Duke University Medical Center, Durham, North Carolina.
  • 2. Duke University School of Medicine, Durham, North Carolina.
  • 3. Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.
  • 4. Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.
  • 5. Department of Pathology, Duke University Medical Center, Durham, North Carolina. [email protected].
PMID: 31871298 DOI: 10.1158/1078-0432.CCR-19-1068
Abstract

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.

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