FDA批準(zhǔn)MSI檢測(cè)論文解讀MismatchrepairdeficiencypredictsresponseofsolidtumorstoPD1blockade課件

1、Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade 王羅 2017-6-19 1 FDA批準(zhǔn)MSI檢測(cè)論文解讀 Mismatchrepairdeficiencypredictsresponseofsolidtu morstoPD1blockade Highlights of this late-breaking clinical trials 1、Colorectal cancers with MMR deficiency were sensitive to immune checkpoin

2、t blockade with anti-PD-1 antibodies. 2、Large proportion of mutant neoantigens in MMR deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers tissue of origin. 3、Checkpoint blockade induces peripheral expansion of tumor specific T cells and that mismatch repair

3、 deficient tumors harbor functional MANA-specific T cells. 2 FDA批準(zhǔn)MSI檢測(cè)論文解讀 Mismatchrepairdeficiencypredictsresponseofsolidtu morstoPD1blockade Background Microsatellite instability (MSI) refers to the hypermutability of short repetitive sequences in the genome caused by impaired DNA mismatch repair

4、. 3 FDA批準(zhǔn)MSI檢測(cè)論文解讀 Mismatchrepairdeficiencypredictsresponseofsolidtu morstoPD1blockade Background 4 FDA批準(zhǔn)MSI檢測(cè)論文解讀 Mismatchrepairdeficiencypredictsresponseofsolidtu morstoPD1blockade Patients 5 FDA批準(zhǔn)MSI檢測(cè)論文解讀 Mismatchrepairdeficiencypredictsresponseofsolidtu morstoPD1blockade Summary of therapeutic

5、response to pembrolizumab (anti-PD-1) treatment Radiographic responses, progression-free survival (PFS) and overall survival (OS) estimates were measured using the Response Evaluation Criteria In Solid Tumors (RECIST v1.1) guidelines. Patients were considered not evaluable if they did not undergo a

6、12-week scan due to clinical progression. The rate of disease control was defined as the percentage of patients who had a complete response, partial response, or stable disease for 12 weeks or more.NR, not reached. 6 FDA批準(zhǔn)MSI檢測(cè)論文解讀 Mismatchrepairdeficiencypredictsresponseofsolidtu morstoPD1blockade

7、Patient survival and clinical response to Pembrolizumab across 12 different tumor types with mismatch repair deficiency 7 FDA批準(zhǔn)MSI檢測(cè)論文解讀 Mismatchrepairdeficiencypredictsresponseofsolidtu morstoPD1blockade patients with measurable radiographic disease have varying degrees of inflammation, fibrosis an

8、d mucin 8 FDA批準(zhǔn)MSI檢測(cè)論文解讀 Mismatchrepairdeficiencypredictsresponseofsolidtu morstoPD1blockade 15 TCR clones with the highest fold change in frequency after treatment that was also found in the original tumor 9 FDA批準(zhǔn)MSI檢測(cè)論文解讀 Mismatchrepairdeficiencypredictsresponseofsolidtu morstoPD1blockade TCR clon

9、al dynamics and mutation associated neoantigen recognition in patients responding to PD-1 blockade 10 FDA批準(zhǔn)MSI檢測(cè)論文解讀 Mismatchrepairdeficiencypredictsresponseofsolidtu morstoPD1blockade MANA specific clones were identified by significant expansion in response to the relevant peptide 11 FDA批準(zhǔn)MSI檢測(cè)論文解讀

10、 Mismatchrepairdeficiencypredictsresponseofsolidtu morstoPD1blockade Frequency of MANA-specific clones, carcinoembryonic antigen (CEA) and radiographic response in the tumor 12 FDA批準(zhǔn)MSI檢測(cè)論文解讀 Mismatchrepairdeficiencypredictsresponseofsolidtu morstoPD1blockade Affinity kinetics of each relevant MANA

11、and the corresponding WT peptide for their restricting HLA I allele 13 FDA批準(zhǔn)MSI檢測(cè)論文解讀 Mismatchrepairdeficiencypredictsresponseofsolidtu morstoPD1blockade 12,019 cancers representing 32 distinct tumor types were evaluated for MMR- deficiency using an NGS based approach 14 FDA批準(zhǔn)MSI檢測(cè)論文解讀 Mismatchrepairdeficiencypredictsresponseofsolidtu morstoPD1blockade Conclusion A large proportion of mutant neoantigens in MMR- deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers tissu