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      Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy

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          Abstract

          <div class="section"> <a class="named-anchor" id="d6741873e229"> <!-- named anchor --> </a> <h5 class="section-title" id="d6741873e230">Background.</h5> <p id="d6741873e232">Despite a multiplicity of clinical trials testing immune checkpoint inhibitors, the frequency of expression of potential predictive biomarkers is unknown in glioma. </p> </div><div class="section"> <a class="named-anchor" id="d6741873e234"> <!-- named anchor --> </a> <h5 class="section-title" id="d6741873e235">Methods.</h5> <p id="d6741873e237">In this study, we profiled the frequency of shared biomarker phenotypes. To clarify the relationships among tumor mutational load (TML), mismatch repair (MMR), and immune checkpoint expression, we profiled patients with glioma ( <i>n =</i> 327), including glioblastoma (GBM) ( <i>n =</i> 198), whose samples had been submitted for analysis from 2009 to 2016. The calculation algorithm for TML included nonsynonymous mutation counts per tumor, with germline mutations filtered out. Immunohistochemical analysis and next-generation sequencing were used to determine tumor-infiltrating lymphocyte expression positive for programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1) expression on tumor cells, MMR ( <i>MLH1</i>, <i>MSH2</i>, <i>MSH6</i>, and <i>PMS2</i>) protein expression and mutations, and DNA polymerase epsilon ( <i>POLE</i>) mutations. </p> </div><div class="section"> <a class="named-anchor" id="d6741873e261"> <!-- named anchor --> </a> <h5 class="section-title" id="d6741873e262">Results.</h5> <p id="d6741873e264">High TML was only found in 3.5% of GBM patients (7 of 198) and was associated with the absence of protein expression of mutL homolog 1 (MLH1) ( <i>P = .</i>0345), mutS homolog 2 (MSH2) ( <i>P = .</i>0099), MSH6 ( <i>P = .</i>0022), and postmeiotic segregation increased 2 (PMS2) ( <i>P = .</i>0345) and the presence of DNA MMR mutations. High and moderate TML GBMs did not have an enriched influx of CD8+ T cells, PD-1+ T cells, or tumor-expressed PD-L1. <i>IDH1</i> mutant gliomas were not enriched for high TML, PD-1+ T cells, or PD-L1 expression. </p> </div><div class="section"> <a class="named-anchor" id="d6741873e281"> <!-- named anchor --> </a> <h5 class="section-title" id="d6741873e282">Conclusions.</h5> <p id="d6741873e284">To clarify the relationships among TML, MMR, and immune checkpoint expression, we profiled the frequency of shared biomarker phenotypes. On the basis of a variety of potential biomarkers of response to immune checkpoints, only small subsets of glioma patients are likely to benefit from monotherapy immune checkpoint inhibition. </p> </div>

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          Most cited references15

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          Mutation of the PIK3CA gene in ovarian and breast cancer.

          Phosphatidylinositol 3'-kinases are lipid kinases with important roles in neoplasia. Recently, a very high frequency of somatic mutations in PIK3CA has been reported among a large series of colorectal cancers. However, the relevance of PIK3CA mutation in other cancer types remains unclear because of the limited number of tumors investigated. We have screened a total of 284 primary human tumors for mutations in all coding exons of PIK3CA using a combination of single stranded conformational polymorphism and denaturing high-performance liquid chromatography analysis. Among 70 primary breast cancers, 40% (28 of 70) harbored mutations in PIK3CA, making it the most common mutation described to date in this cancer type. Mutations were not associated with histologic subtype, estrogen receptor status, grade or presence of tumor in lymph nodes. Among the primary epithelial ovarian cancers only 11 of 167 (6.6%) contain somatic mutations, but there was a clear histologic subtype bias in their distribution. Only 2 of 88 (2.3%) of serous carcinomas had PIK3CA mutations compared with 8 of 40 (20.0%) endometrioid and clear cell cancers, which was highly significant (P = 0.001). In contrast, PIK3CA gene amplification (>7-fold) was common among all histologic subtypes (24.5%) and was inversely associated with the presence of mutations. Overall, PIK3CA mutation or gene amplification was detected in 30.5% of all ovarian cancers and 45% of the endometrioid and clear cell subtypes. Our study is the first direct evidence that PIK3CA is an oncogene in ovarian cancer and greatly extends recent findings in breast cancer.
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            Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type.

            Cancer cells expressing PD-1 ligands (PD-L1/PD-L2) inhibit immune-modulatory T-cell activation facilitating disease progression. Preliminary clinical trials exploring interruption of PD-1/PD-L1 signaling showed benefit in several cancer types. We analyzed the distribution of PD-1-positive tumor-infiltrating lymphocytes (TIL) and cancer cells' expression of PD-L1 in a molecularly profiled cohort of 437 malignancies (380 carcinomas, 33 sarcomas, and 24 melanomas). We showed that the presence of PD-1(+) TILs significantly varied among cancer types (from 0% in extraskeletal myxoid chondrosarcomas to 93% in ovarian cancer), and was generally associated with the increased number of mutations in tumor cells (P = 0.029). Cancer cell expression of PD-L1 varied from absent (in Merkel cell carcinomas) to 100% (in chondro- and liposarcomas), but showed the inverse association with the number of detected mutations (P = 0.004). Both PD-1 and PD-L1 expression were significantly higher in triple-negative breast cancers (TNBC) than in non-TNBC (P < 0.001 and 0.017, respectively). Similarly, MSI-H colon cancers had higher PD-1 and PD-L1 expression than the microsatellite stable tumors (P = 0.002 and 0.02, respectively). TP53-mutated breast cancers had significantly higher PD-1 positivity than those harboring other driver mutations (e.g., PIK3CA; P = 0.002). In non-small cell lung cancer, PD-1/PD-L1 coexpression was identified in 8 cases (19%), which lacked any other targetable alterations (e.g., EGFR, ALK, or ROS1). Our study demonstrated the utility of exploring the expression of two potentially targetable immune checkpoint proteins (PD-1/PD-L1) in a substantial proportion of solid tumors, including some aggressive subtypes that lack other targeted treatment modalities.
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              Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial.

              Endogenous or iatrogenic antitumour immune responses can improve the course of follicular lymphoma, but might be diminished by immune checkpoints in the tumour microenvironment. These checkpoints might include effects of programmed cell death 1 (PD1), a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. We did this phase 2 trial to investigate the activity of pidilizumab, a humanised anti-PD1 monoclonal antibody, with rituximab in patients with relapsed follicular lymphoma. We did this open-label, non-randomised trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Adult (≥18 years) patients with rituximab-sensitive follicular lymphoma relapsing after one to four previous therapies were eligible. Pidilizumab was administered at 3 mg/kg intravenously every 4 weeks for four infusions, plus eight optional infusions every 4 weeks for patients with stable disease or better. Starting 17 days after the first infusion of pidilizumab, rituximab was given at 375 mg/m(2) intravenously weekly for 4 weeks. The primary endpoint was the proportion of patients who achieved an objective response (complete response plus partial response according to Revised Response Criteria for Malignant Lymphoma). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00904722. We enrolled 32 patients between Jan 13, 2010, and Jan 20, 2012. Median follow-up was 15.4 months (IQR 10.1-21.0). The combination of pidilizumab and rituximab was well tolerated, with no autoimmune or treatment-related adverse events of grade 3 or 4. The most common adverse events of grade 1 were anaemia (14 patients) and fatigue (13 patients), and the most common adverse event of grade 2 was respiratory infection (five patients). Of the 29 patients evaluable for activity, 19 (66%) achieved an objective response: complete responses were noted in 15 (52%) patients and partial responses in four (14%). The combination of pidilizumab plus rituximab is well tolerated and active in patients with relapsed follicular lymphoma. Our results suggest that immune checkpoint blockade is worthy of further study in follicular lymphoma. National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech, and University of Texas MD Anderson Cancer Center. Copyright © 2014 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Neuro-Oncology
                Oxford University Press (OUP)
                1522-8517
                1523-5866
                August 01 2017
                August 01 2017
                : 19
                : 8
                : 1047-1057
                Article
                10.1093/neuonc/nox026
                5570198
                28371827
                fe33e97d-2f1f-4929-bf04-a3aec1af47df
                © 2017
                History

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