Disappearance of MMR-deficient subclones after controlled IL-12 and PD-1 inhibition in a glioma patient

McCord, Matthew; Lukas, Rimas V.; Amidei, Christina; Demars, Nathan; Gelb, Arnold B.; Buck, Jill; Sachdev, Sean; Feldman, Alexander; Tate, Matthew C.; Dixit, Karan; Brat, Daniel J.; Jennings, Lawrence J.; Horbinski, Craig

doi:10.1093/noajnl/vdab045

Cited by 5 publications

(8 citation statements)

References 15 publications

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“…In contrast, in de novo TMB-H gliomas ICB has shown encouraging results reported in series studies [17,20] and in several case reports [17,19 ▪ ,21,22,26,27,28]. These findings were confirmed in a recent nonpeer reviewed preprint [20].…”

Section: Treatment Of Hypermutated Gliomas With Immune Checkpoint Blo...mentioning

confidence: 54%

“…Approaches aimed at increasing both tumor infiltration by cytotoxic lymphocytes are therefore likely both necessary in order to improve the response to immunotherapy in gliomas. Among several current strategies under investigation, IL-12 gene therapy combined with ICB showed safety and biological efficacy (production of IFN-g) in HGG patients including one patient with post-treatment hypermutation [22,90].…”

Section: Discussionmentioning

confidence: 99%

“…However, the correlation between TMB and ICB clinical benefit was mainly driven by data from a limited number of cancers such as melanoma, lung carcinomas and known mismatch repair deficient (MMR-d) cancers, and it remains unclear whether TMB-H and MMR-d are universally predictive in rare cancers not represented in these studies [13,14 ▪▪ ]. Gliomas are one of such cancers, as these tumors typically harbor a strong immunosuppressive TME [15] and conflicting data have been reported regarding their benefit from ICB, even in the presence of TMB [16,17,18,19 ▪ ,20–22,23 ▪ ,24–28].…”

Section: Introductionmentioning

confidence: 99%

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Mutational burden and immune recognition of gliomas

Prost

Bielle

Ligon

et al. 2021

Current Opinion in Oncology

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Purpose of reviewRecent evidence suggests high tumor mutational burden (TMB-H) as a predictor of response to immune checkpoint blockade (ICB) in cancer. However, results in TMB-H gliomas have been inconsistent. In this article, we discuss the main pathways leading to TMB-H in glioma and how these might affect immunotherapy response. Recent findingsRecent characterization of TMB-H gliomas showed that 'post-treatment' related to mismatch repair (MMR) deficiency is the most common mechanism leading to TMB-H in gliomas. Unexpectedly, preliminary evidence suggested that benefit with ICB is rare in this population. Contrary to expectations, ICB response was reported in a subset of TMB-H gliomas associated with constitutional MMR or polymerase epsilon (POLE) defects (e.g., constitutional biallelic MMRd deficiency). In other cancers, several trials suggest increased ICB efficacy is critically associated with increased lymphocyte infiltration at baseline which is missing in most gliomas. Further characterization of the immune microenvironment of gliomas is needed to identify biomarkers to select the patients who will benefit from ICB.

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Section: Treatment Of Hypermutated Gliomas With Immune Checkpoint Blo...mentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutational burden and immune recognition of gliomas

Prost

Bielle

Ligon

et al. 2021

Current Opinion in Oncology

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“…MMR mutations can be detected through routine NGS panels or immunohistochemistry (IHC) with loss of staining for one or more MMR proteins (Fig. 3 ) [ 7 , 28 , 140 , 141 , 179 , 200 ]. IHC may be particularly useful as non-neoplastic brain cells (native glial cells, neurons, and endothelial cells) retain nuclear reactivity in cases of acquired MMR mutation, while these cells should also be negative in cases with germline mutations [ 141 , 179 , 200 ], although notably in many cases mutations resulting in MMR-deficiency are only present at a subclonal level, which may be evident with IHC staining [ 140 , 209 ].…”

Section: Mismatch Repair (Mmr) Protein Defects and Microsatellite Ins...mentioning

confidence: 99%

Genetic and epigenetic instability as an underlying driver of progression and aggressive behavior in IDH-mutant astrocytoma

Richardson,

Walker,

Hambardzumyan

et al. 2024

Acta Neuropathol

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In recent years, the classification of adult-type diffuse gliomas has undergone a revolution, wherein specific molecular features now represent defining diagnostic criteria of IDH-wild-type glioblastomas, IDH-mutant astrocytomas, and IDH-mutant 1p/19q-codeleted oligodendrogliomas. With the introduction of the 2021 WHO CNS classification, additional molecular alterations are now integrated into the grading of these tumors, given equal weight to traditional histologic features. However, there remains a great deal of heterogeneity in patient outcome even within these established tumor subclassifications that is unexplained by currently codified molecular alterations, particularly in the IDH-mutant astrocytoma category. There is also significant intercellular genetic and epigenetic heterogeneity and plasticity with resulting phenotypic heterogeneity, making these tumors remarkably adaptable and robust, and presenting a significant barrier to the design of effective therapeutics. Herein, we review the mechanisms and consequences of genetic and epigenetic instability, including chromosomal instability (CIN), microsatellite instability (MSI)/mismatch repair (MMR) deficits, and epigenetic instability, in the underlying biology, tumorigenesis, and progression of IDH-mutant astrocytomas. We also discuss the contribution of recent high-resolution transcriptomics studies toward defining tumor heterogeneity with single-cell resolution. While intratumoral heterogeneity is a well-known feature of diffuse gliomas, the contribution of these various processes has only recently been considered as a potential driver of tumor aggressiveness. CIN has an independent, adverse effect on patient survival, similar to the effect of histologic grade and homozygous CDKN2A deletion, while MMR mutation is only associated with poor overall survival in univariate analysis but is highly correlated with higher histologic/molecular grade and other aggressive features. These forms of genomic instability, which may significantly affect the natural progression of these tumors, response to therapy, and ultimately clinical outcome for patients, are potentially measurable features which could aid in diagnosis, grading, prognosis, and development of personalized therapeutics.

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“…Clinically this suggests that subsequent treatment with TMZ, or other DNA-damaging alkylating agents, would be unsuccessful. However, hypermutated tumors might be more amenable to immunotherapy [ 20 , 21 , 22 , 23 , 24 , 25 ], although this is controversial in gliomas [ 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Modeling Therapy-Driven Evolution of Glioblastoma with Patient-Derived Xenografts

McCord

Bartom

Burdett

et al. 2022

Cancers

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Adult-type diffusely infiltrating gliomas, of which glioblastoma is the most common and aggressive, almost always recur after treatment and are fatal. Improved understanding of therapy-driven tumor evolution and acquired therapy resistance in gliomas is essential for improving patient outcomes, yet the majority of the models currently used in preclinical research are of therapy-naïve tumors. Here, we describe the development of therapy-resistant IDH-wildtype glioblastoma patient-derived xenografts (PDX) through orthotopic engraftment of therapy naïve PDX in athymic nude mice, and repeated in vivo exposure to the therapeutic modalities most often used in treating glioblastoma patients: radiotherapy and temozolomide chemotherapy. Post-temozolomide PDX became enriched for C>T transition mutations, acquired inactivating mutations in DNA mismatch repair genes (especially MSH6), and developed hypermutation. Such post-temozolomide PDX were resistant to additional temozolomide (median survival decrease from 80 days in parental PDX to 42 days in a temozolomide-resistant derivative). However, temozolomide-resistant PDX were sensitive to lomustine (also known as CCNU), a nitrosourea which induces tumor cell apoptosis by a different mechanism than temozolomide. These PDX models mimic changes observed in recurrent GBM in patients, including critical features of therapy-driven tumor evolution. These models can therefore serve as valuable tools for improving our understanding and treatment of recurrent glioma.

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Disappearance of MMR-deficient subclones after controlled IL-12 and PD-1 inhibition in a glioma patient

Cited by 5 publications

References 15 publications

Mutational burden and immune recognition of gliomas

Mutational burden and immune recognition of gliomas

Genetic and epigenetic instability as an underlying driver of progression and aggressive behavior in IDH-mutant astrocytoma

Modeling Therapy-Driven Evolution of Glioblastoma with Patient-Derived Xenografts

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