bMMRD GBM has a higher neoantigen load than tumors that respond to immune checkpoint inhibitors.

  • Major finding: bMMRD GBM has a higher neoantigen load than tumors that respond to immune checkpoint inhibitors.

  • Clinical relevance: The PD-1 inhibitor nivolumab achieved durable responses in two patients with bMMRD GBM.

  • Impact: Immune checkpoint inhibition may have promise in treating bMMRD-driven GBM.

Glioblastoma multiforme (GBM) is an aggressive brain tumor, and no effective therapies exist for recurrent tumors. Pediatric GBMs are often associated with cancer predisposition syndromes, including biallelic mismatch repair deficiency syndrome (bMMRD), which is caused by homozygous germline mutations in MMR genes. As a result of germline MMR mutations and somatic DNA polymerase mutations, bMMRD GBMs have the highest mutation loads of all human cancers. Given that non-bMMRD tumors with high mutational burdens have been shown to be particularly responsive to immune checkpoint therapy due to an increased neoantigen load, Bouffet, Larouche, Campbell, and colleagues hypothesized that immune checkpoint inhibitors might have utility in bMMRD GBM. Exome sequencing of 32 malignant bMMRD tumors revealed that all were hypermutated, with bMMRD brain tumors having the highest mutational load and bMMRD GBMs having a higher mutational load than sporadic pediatric and adult gliomas and other brain tumors. Moreover, somatic neoepitope analysis identified a higher number of predicted neoantigens in bMMRD GBMs than in melanomas, lung cancers, and microsatellite-unstable colorectal cancers that have responded to immune checkpoint inhibitors. Based on this information, two patients with recurrent, disseminated bMMRD GBM were treated with the PD-1 inhibitor nivolumab. Both patients experienced significant tumor shrinkage and clinical improvement and remained clinically stable after 9 and 5 months of therapy, respectively. Altogether, these findings show that immune checkpoint blockade has the potential to lead to durable responses in recurrent hypermutant GBM and provide support for further clinical evaluation of immune checkpoint inhibitors in bMMRD GBM.

Bouffet E, Larouche V, Campbell BB, Merico D, de Borja R, Aronson M, et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol 2016 Mar 21 [Epub ahead of print].

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.