Durable Response to Nivolumab in a Pediatric Patient with Refractory Glioblastoma and Constitutional Biallelic Mismatch Repair Deficiency

Alharbi, Musa; Mobark, Nahla Ali; AlMubarak, Latifa; Aljelaify, Rasha; AlSaeed, Mariam; Almutairi, Amal; Alqubaishi, Fatmah; Hussain, Mushtaq; Balbaid, Ali Abdullah O; Marie, Amal Said; Alsubaie, Lamia; Alshieban, Saeed; Al-Tassan, Nada A.; Ramkissoon, Shakti; Abedalthagafi, Malak

doi:10.1634/theoncologist.2018-0163

Cited by 59 publications

(45 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…High tumor mutational burden (TMB; >20 mutations/mb) has previously been identified as an independent prognostic variable to response with ICI, and melanoma has some of the highest TMB of all malignancies, possibly contributing to the encouraging clinical results. Similar observations have also been reported in a subset of GBMs with high mutational burden due to mismatch repair deficiencies, and in these cases ICIs have also been shown to achieve complete and durable responses . Most brain tumors, however, including GBM and pediatric brain tumors, have low TMB and have been less responsive to ICIs .…”

Section: Introductionsupporting

confidence: 78%

“…Similar observations have also been reported in a subset of GBMs with high mutational burden due to mismatch repair deficiencies, and in these cases ICIs have also been shown to achieve complete and durable responses. 17,18 Most brain tumors, however, including GBM and pediatric brain tumors, have low TMB and have been less responsive to ICIs. 19 Encouragingly, neoadjuvant ICI prior to surgical resection has been shown to mediate a survival benefit in recurrent GBM, possibly by augmenting endogenous T cell responses.…”

mentioning

confidence: 99%

See 1 more Smart Citation

CAR T cells for brain tumors: Lessons learned and road ahead

Akhavan

Alizadeh

Wang

et al. 2019

Immunological Reviews

173

161

View full text Add to dashboard Cite

Malignant brain tumors, including glioblastoma, represent some of the most difficult to treat of solid tumors. Nevertheless, recent progress in immunotherapy, across a broad range of tumor types, provides hope that immunological approaches will have the potential to improve outcomes for patients with brain tumors. Chimeric antigen receptors (CAR) T cells, a promising immunotherapeutic modality, utilizes the tumor targeting specificity of any antibody or receptor ligand to redirect the cytolytic potency of T cells. The remarkable clinical response rates of CD19‐targeted CAR T cells and early clinical experiences in glioblastoma demonstrating safety and evidence for disease modifying activity support the potential of further advancements ultimately providing clinical benefit for patients. The brain, however, is an immune specialized organ presenting unique and specific challenges to immune‐based therapies. Remaining barriers to be overcome for achieving effective CAR T cell therapy in the central nervous system (CNS) include tumor antigenic heterogeneity, an immune‐suppressive microenvironment, unique properties of the CNS that limit T cell entry, and risks of immune‐based toxicities in this highly sensitive organ. This review will summarize preclinical and clinical data for CAR T cell immunotherapy in glioblastoma and other malignant brain tumors, including present obstacles to advancement.

show abstract

Section: Introductionsupporting

confidence: 78%

mentioning

confidence: 99%

CAR T cells for brain tumors: Lessons learned and road ahead

Akhavan

Alizadeh

Wang

et al. 2019

Immunological Reviews

173

161

View full text Add to dashboard Cite

show abstract

“… 12 However, progression-free survival rates remain poor for these patients, highlighting the need for new therapeutic options, including small molecules and/or immunotherapy alone or in combination with chemotherapy regimens. 13 Although the etiology and genomic drivers of glioblastoma are diverse, 14 - 16 a common finding in pediatric HGG, especially infantile HGGs, is the presence of fusions involving NTRK , ALK , and ROS1 , among others. TRK fusion proteins are oncogenic drivers that have been reported in a wide range of adult and pediatric tumors that occur at high frequencies (≥ 90%) in rare cancer types.…”

Section: Discussionmentioning

confidence: 99%

Regression of ETV6-NTRK3 Infantile Glioblastoma After First-Line Treatment With Larotrectinib

Alharbi

Mobark

Balbaid

et al. 2020

JCO Precision Oncology

Self Cite

View full text Add to dashboard Cite

“…[ 8 ]. This information can also provide personalized targeted treatment programs, once the genetic basis of the CMMRD tumor is understood [ 52 , 53 ].…”

Section: Cmmrd Diagnosismentioning

confidence: 99%

“…It is likely that the combination of check-point inhibitors and neoantigen vaccination will hold the most promise for CMMRD. Indeed, our own recent studies highlight the benefits of incorporating genomic and/or molecular testing for CMMRD into routine paediatric oncology, whereby clinical care can identify a subset of patients likely to benefit from targeted treatment regimens, dependent on their MMR mutation status [ 53 ].…”

Section: Neoantigen Vaccinationmentioning

confidence: 99%

Constitutional mismatch repair-deficiency: current problems and emerging therapeutic strategies

Abedalthagafi

2018

Oncotarget

Self Cite

View full text Add to dashboard Cite

Mismatch repair (MMR) proteins remove errors from newly synthesized DNA, improving the fidelity of DNA replication. A loss of MMR causes a mutated phenotype leading to a predisposition to cancer.In the last 20 years, an increasing number of patients have been described with biallelic MMR gene mutations in which MMR defects are inherited from both parents. This leads to a syndrome with recessive inheritance, referred to as constitutional mismatch repair-deficiency (CMMRD). CMMRD is a rare childhood cancer predisposition syndrome. The spectrum of CMMRD tumours is broad and CMMRD-patients possess a high risk of multiple cancers including hematological, brain and intestinal tumors. The severity of CMMRD is highlighted by the fact that patients do not survive until later life, emphasising the requirement for new therapeutic interventions.Many tumors in CMMRD-patients are hypermutated leading to the production of truncated protein products termed neoantigens. Neoantigens are recognized as foreign by the immune system and induce antitumor immune responses. There is growing evidence to support the clinical efficacy of neoantigen based vaccines and immune checkpoint inhibitors (collectively referred to as immunotherapy) for the treatment of CMMRD cancers. In this review, we discuss the current knowledge of CMMRD, the advances in its diagnosis, and the emerging therapeutic strategies for CMMRD-cancers.

show abstract

Durable Response to Nivolumab in a Pediatric Patient with Refractory Glioblastoma and Constitutional Biallelic Mismatch Repair Deficiency

Cited by 59 publications

References 15 publications

CAR T cells for brain tumors: Lessons learned and road ahead

CAR T cells for brain tumors: Lessons learned and road ahead

Regression of ETV6-NTRK3 Infantile Glioblastoma After First-Line Treatment With Larotrectinib

Constitutional mismatch repair-deficiency: current problems and emerging therapeutic strategies

Contact Info

Product

Resources

About