PDCT-09. HYPERMUTATION AND NEOANTIGEN FORMATION IS DIAGNOSTIC AND PREDICT RESPONSE TO IMMUNE CHECKPOINT INHIBITION IN CHILDHOOD BIALLELIC MISMATCH REPAIR DEFICIENT BRAIN TUMORS

Purpose Recurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition. Patients and Methods We performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab. Results All malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 ± standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 ± standard deviation, 1,043), similar to other cancers that responded favorably to immune checkpoint inhibitors. bMMRD GBM had a significantly higher mutational load than sporadic pediatric and adult gliomas and all other brain tumors (P < .001). bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in immunoresponsive melanomas, lung cancers, or microsatellite-unstable GI cancers (P < .001). On the basis of these preclinical data, we treated two bMMRD siblings with recurrent multifocal GBM with the anti–programmed death-1 inhibitor nivolumab, which resulted in clinically significant responses and a profound radiologic response. Conclusion This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD.

Download Full-text

Abstract 3167: Immune checkpoint inhibition re-challenge after a planned treatment interruption in patients with pancreatic adenocarcinoma with mismatch repair deficient tumors

10.1158/1538-7445.am2020-3167 ◽

2020 ◽

Author(s):

Vaia Florou ◽

Chris Nevala-Plagemann ◽

Kristin Barber ◽

Jenna Mastroianni ◽

Courtney Christine Cavaliery ◽

...

Keyword(s):

Mismatch Repair ◽

Pancreatic Adenocarcinoma ◽

Immune Checkpoint ◽

Treatment Interruption ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition

Download Full-text

Immune Checkpoint Inhibition as Primary Adjuvant Therapy for an IDH1-Mutant Anaplastic Astrocytoma in a Patient with CMMRD: A Case Report—Usage of Immune Checkpoint Inhibition in CMMRD

Current Oncology ◽

10.3390/curroncol28010074 ◽

2021 ◽

Vol 28 (1) ◽

pp. 757-766

Author(s):

Rebekah Rittberg ◽

Craig Harlos ◽

Heidi Rothenmund ◽

Anirban Das ◽

Uri Tabori ◽

...

Keyword(s):

Mismatch Repair ◽

Immune Checkpoint ◽

Anaplastic Astrocytoma ◽

Early Stage ◽

Young Female ◽

Hereditary Cancer Syndrome ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Cancer Syndrome ◽

Dna Mismatch

Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessive hereditary cancer syndrome due to biallelic germline mutation involving one of the four DNA mismatch repair genes. Here we present a case of a young female with CMMRD, homozygous for the c.2002A>G mutation in the PMS2 gene. She developed an early stage adenocarcinoma of the colon at the age of 14. Surveillance MRI of the brain at age 18 resulted in the detection of an asymptomatic brain cancer. On resection, this was diagnosed as an anaplastic astrocytoma. Due to emerging literature suggesting benefit of immunotherapy in this patient population, she was treated with adjuvant dual immune checkpoint inhibition, avoiding radiation. The patient remains stable with no evidence of progression 20 months after resection. The patient’s clinical course, as well as the rational for considering adjuvant immunotherapy in patients with CMMRD are discussed in this report.

Download Full-text

β-catenin and PD-L1 expression in mismatch repair deficient endometrial carcinomas

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2020-001239 ◽

2020 ◽

Vol 30 (7) ◽

pp. 993-999

Author(s):

Margaret Rowe ◽

Rahul Krishnan ◽

Anne Mills ◽

Kari Ring

Keyword(s):

Endometrial Cancer ◽

Lynch Syndrome ◽

Mismatch Repair ◽

Immune Checkpoint ◽

Immune Cell ◽

Predictive Biomarker ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Programmed Death Ligand 1 ◽

Programmed Death

IntroductionPredictors of non-response in mismatch repair deficiency cancers are poorly understood. Upregulation of the canonical Wnt pathway has been associated with decreased immune cell infiltration in many cancer types. The relationship between Wnt/β-catenin pathway activation and the programmed death-ligand 1 axis in endometrial cancer remains poorly characterized. This study evaluates β-catenin expression in a well characterized cohort of endometrial cancers by mismatch repair status and programmed death-ligand 1 expression.MethodsWhole sections of formalin-fixed, paraffin embedded tissue from 23 Lynch syndrome-associated carcinomas, 20 mutL homolog-1 (MLH1) promoter hypermethylated carcinomas, and 19 mismatch repair intact carcinomas were evaluated. Immunohistochemistry staining for β-catenin and programmed death-ligand 1 was performed on all cases. Programmed death-ligand 1 expression was scored in both the tumor and the peri-tumoral immune compartment. Tumor staining was classified as positive when membranous (programmed death-ligand 1) staining was present in ≥1% of tumor cells. Immune stromal staining was scored as positive when ≥5% of peritumoral and intratumoral immune cells (including lymphocytes and macrophages) showed reactivity.ResultsSix tumors (6/62, 9.7%) demonstrated nuclear expression of β-catenin (4 were Lynch syndrome-associated, 1 was MLH1 methylated, 1 was mismatch repair intact). The majority of tumors with nuclear β-catenin expression demonstrated concomitant tumoral programmed death-ligand 1 expression (5/6, 83.3%) and were more likely to demonstrate tumoral programmed death-ligand 1 expression compared to tumors without nuclear β-catenin expression (83.3% vs 39.3%, p=0.04). Both tumoral and immune cell expression of programmed death-ligand 1 was statistically significantly associated with mismatch repair deficient tumors.DiscussionTumors demonstrating nuclear β-catenin expression were more likely to express tumoral programmed death-ligand 1 staining than tumors without nuclear β-catenin expression. Nuclear β-catenin expression could be a potential predictive biomarker for non-response to immune checkpoint inhibition in mismatch repair deficient tumors. Nuclear β-catenin expression status should be considered as a translational endpoint in future clinical trials of immune checkpoint inhibition in endometrial cancer.

Download Full-text

HG-53HYPERMUTATION AND NEOANTIGEN FORMATION PREDICT RESPONSE TO IMMUNE CHECKPOINT INHIBITION IN CHILDHOOD BIALLELIC MISMATCH REPAIR DEFICIENT GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/now073.49 ◽

2016 ◽

Vol 18 (suppl 3) ◽

pp. iii59.2-iii60

Author(s):

Brittany Campbell ◽

Eric Bouffet ◽

Valerie Larouche ◽

Gary Mason ◽

Alyssa Reddy ◽

...

Keyword(s):

Mismatch Repair ◽

Immune Checkpoint ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition

Download Full-text

The Role of Immune Checkpoint Inhibition in the Treatment of Brain Tumors

Neurotherapeutics ◽

10.1007/s13311-017-0513-3 ◽

2017 ◽

Vol 14 (4) ◽

pp. 1049-1065 ◽

Cited By ~ 10

Author(s):

Andrew S. Luksik ◽

Russell Maxwell ◽

Tomas Garzon-Muvdi ◽

Michael Lim

Keyword(s):

Brain Tumors ◽

Immune Checkpoint ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition

Download Full-text

IMMU-18. FAVORABLE OUTCOME IN REPLICATION REPAIR DEFICIENT HYPERMUTANT BRAIN TUMORS TO IMMUNE CHECKPOINT INHIBITION: AN INTERNATIONAL RRD CONSORTIUM REGISTRY STUDY

Neuro-Oncology ◽

10.1093/neuonc/noaa222.374 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii363-iii363

Author(s):

Eric Bouffet ◽

Sumedha Sudhaman ◽

Jiil Chung ◽

Jacalyn Kelly ◽

Ailish Coblentz ◽

...

Keyword(s):

Brain Tumors ◽

Immune Checkpoint ◽

Single Agent ◽

Pediatric Brain Tumors ◽

Favorable Outcome ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Registry Study ◽

Tumor Mutational Burden ◽

Nonspecific Immune Response

Abstract Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond to immune checkpoint inhibition (ICI). We performed a consortium registry study of ICI in recurrent RRD cancers. Clinical and companion biomarkers were collected longitudinally on all patients. Biomarkers included tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference was obtained by RNAseq and T cell rearrangement was collected in the tumor and in blood throughout treatment. Of the 46 tumors on the study, 32 were brain tumors with glioblastoma in 96%. Rapid, objective responses (>50%) were observed in 50% of glioblastomas. Three year overall survival for the whole cohort was 48+/-8% which compares favorably with historical controls. Brain tumors fared worse with OS of 39+/-10% and late recurrences observed even after 2 years of therapy (p=0.02). Tumor size and acute “flare” constitute poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens correlated with response to ICI (p=0.02). Specific signatures extracted from SNVs and total mutations predicted response to ICI and favorable outcome (p=0.005). RNA inference and TCR reveal that the FLARE phenotype is mostly acute nonspecific immune response and not true progression. Finally, glioblastomas (n=8) which failed single agent ICI had favorable responses to combinational immunotherapies with prolonged survival of 65%+/-8% at one year after failure vs 0 for other patients (p=0.01). RRD glioblastomas exhibit favorable outcome and responses to ICI. Combinational therapies based on tumor and immune signatures of these cancers are necessary.

Download Full-text