scholarly journals NFB-18. IMMUNE FUNCTION IN CHILDREN TREATED WITH TRAMETINIB

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii421-iii421
Author(s):  
Perla Moukhaiber ◽  
Anna Samolej ◽  
Palita Somsri ◽  
Geoffrey McCowage
Keyword(s):  
T Cells ◽  
Immune Function ◽  
Treated Patient ◽  
Cytotoxic T Cells ◽  
White Cell Count ◽  
Plexiform Neurofibroma ◽  
Low Grade ◽  
Vaccine Antigens ◽  
Antibody Titres ◽  
Tumor Types

Abstract BACKGROUND Trametinib (Tr) has been applied in the treatment of children with various tumor types, often for prolonged periods. Little is known regarding immune function (IF) following prolonged Tr in this age group. OBJECTIVE Describe laboratory measures of IF in children on Tr. METHOD Patients receiving Tr had low grade glioma with BRAF anomalies (6), or neurofibromatosis-1 (16) with glioma or plexiform neurofibroma. IF was evaluated using leukocyte/lymphocyte counts, immunoglobulin levels, and antibody titres. RESULTS 22 patients received Tr. 2 also received Dabrafenib. Median age at Tr initiation of Tr was 7.75 years. As of June 2020, 7 patients have had IFT; results are pending on 15. Median duration of Tr therapy at time of IF was 3.5 years (0.8 – 4). In these 7 patients, median white cell count was 6.9 x 10^9/L (4.1 – 12.6), neutrophils 4.2 x 10^9/L (1.8 – 6.8) and lymphocytes 3.2 x 10^9/L (1.4 – 7). IgG levels, B cells and CD8 cytotoxic T cells were normal across 7/7 patients:medians 9.47 g/L (8.62 – 17), 0.51 x 10^9/L (0.2 – 1.26) and 0.58 x 10^9/L (0.25 – 2.03) respectively. CD3 and CD4 T cells: median 2.08 x 10^9/L (0.67 – 4.62) and 1.34 x 10^9/L (0.35 – 2.31), borderline low in 1 heavily pre-treated patient. An adequate immune response was present in all 4 vaccine antigens tested in 5/5 patients. CONCLUSION IF appears relatively intact, relevant for immunisation and infection precautions in children on Tr. Data on the complete cohort will be presented.

scholarly journals Weak Cytotoxic T Cells Activation Predicts Low-Grade Dysplasia Persistence in Ulcerative Colitis

2019 ◽  
Vol 10 (7) ◽  
pp. e00061
Author(s):  
Andromachi Kotsafti ◽  
Renata DʼIncà ◽  
Melania Scarpa ◽  
Matteo Fassan ◽  
Imerio Angriman ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
T Cells ◽  
Cytotoxic T Cells ◽  
Low Grade ◽  
Low Grade Dysplasia

scholarly journals Natural evolution mechanisms of the IDH mutant glioma revealed by multi-omics sequencing of a long-term survivor

2021 ◽  
Author(s):  
Long Wang ◽  
Feilong Zhao ◽  
Xuegang Li ◽  
Tunan Chen ◽  
Hua Feng ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cytotoxic T Cells ◽  
Adoptive Cell Therapy ◽  
Adaptive Immune Response ◽  
Tumor Evolution ◽  
Low Grade ◽  
Natural Evolution ◽  
Adaptive Immune ◽  
Highly Correlated

Abstract Purpose Low-grade gliomas(LGG) almost invariably progress into secondary glioblastoma with limited therapeutic options. The currently proposed progression mechanisms were mainly based on treatment intervened patients, seldom is known about the mechanisms under natural evolution.Methods A high-grade glioblastoma (G4) occurred at the posterior of the primary LGG (G2) of a 67-year-old woman carried the glioma for eight years without any serious treatment. Tumor samples and peripheral blood of the patients were collected and subjected to integrated genomic analyses, including whole-exome sequencing, gene expression and DNA methylation profiling.Results The center and edge of the tumor were diagnosed as LGG and GBM, respectively. They shared the same trunk mutations including IDH, TP53, and ATRX. They both have mixing cell origins and they have a highly correlated methylation level at the probe level. CIC, BRCA2, and RPA4 mutation which occurred only in G4 with mutant allele frequency(MAF) higher than 15% may contribute to evolution. NAF1 of which the MAF increased by 70% and the mutant RNA reads nearly doubled in G4 may also involve in the evolution. In the pathway level, the MSP-RON pathway was strongly up-regulated in G4. Concomitant with the tumor evolution, we discovered enhanced inflammatory signals represented by the up-regulation of the NF-κB pathway and the recruitment of mast cell, of which the absolute cell proportion increased from 3.9% to 6.9%. Contradictorily, the adaptive immune response was suppressed as we found pathways associated with IL17, dendritic cells, and cytotoxic T cells were down-regulated and the infiltration level of CD4+ and CD8+ T cells were both decreased. As for the TCR profile, only about 2% of blood clonotypes were detected in the tumor microenvironment. Nevertheless, two clonotypes were found significantly expanded. Clone frequencies of them were 38% and 19% in G2, respectively. And these were 24% and 11% in G4, respectively.Conclusion. Mutation of CIC, BRCA2, RPA4, and NAF1 and activation of the MSP-RON pathway could promote glioma evolution under natural conditions. Increased inflammatory response and decreased adaptive immune response may also contribute to the process. Besides, two highly expanded TCR clonotypes discovered in this case may serve as a potential adoptive cell therapy source in glioma.

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