Abstract A040: Gene and protein expression of MAGE, PD-L1, and associated immune landscape elements in non-small cell lung carcinoma (NSCLC), urothelial carcinoma (UC), squamous cell cancer of the head and neck (SCCHN), and cervical carcinoma (CC)
| العنوان: | Abstract A040: Gene and protein expression of MAGE, PD-L1, and associated immune landscape elements in non-small cell lung carcinoma (NSCLC), urothelial carcinoma (UC), squamous cell cancer of the head and neck (SCCHN), and cervical carcinoma (CC) |
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| المؤلفون: | Clark C. Fjeld, Alexandra Drakaki, Adrian Bot, Jin Li, Wesley Chang, Rajul K. Jain, Stephanie H. Astrow, Izak Faiena |
| المصدر: | Molecular Cancer Therapeutics. 17:A040-A040 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | endocrine system, Cancer Research, Tumor microenvironment, biology, business.industry, Cancer, medicine.disease, Immune system, Oncology, Antigen, PD-L1, Cancer research, medicine, biology.protein, Carcinoma, Immunohistochemistry, Cancer/testis antigens, business, neoplasms |
| الوصف: | Purpose: Therapeutic options are limited for patients with advanced solid tumors failing conventional chemotherapy. Clinical responses have been observed with adoptively transferred tumor-specific T cells, including a T-cell receptor (TCR)-based therapy targeting the Cancer Testis Antigens MAGE-A3 and MAGE-A6 (Lu et al., J Immunother Cancer 2015;3(Suppl 2) P158). A T-cell product comprising this TCR is currently being tested in a novel phase 1 multicenter trial (NCT03139370). The programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) pathway may interfere with antitumor immune mechanisms. Several inhibitors of PD-1/PD-L1 signaling have shown activity and acceptable safety in multiple advanced cancer histologies. The expression of MAGE A antigens is prevalent in diverse solid tumors (Kerkar et al., J Immunother 2016;39(4):181-7). The prevalence of MAGE A3/A6 expression among MAGE A-positive tumors, and the rate and pattern of PD-L1 expression in relation to MAGE expression, are of interest as they may create a rationale for MAGE A3/A6 directed TCR therapy, alone or in conjunction with PD1/PD-L1 inhibition. Here, we describe the development and analytical validation of a two-part assay system combining immunohistochemistry (IHC) and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) for the detection of MAGE A3/A6 expression, and examine its performance in NSCLC, UC, SCCHN and CC. We also assess the coexpression of PD-L1 and other immune-related genes (e.g., HLAs) in tumor cells and/or immune cells to better understand the tumor microenvironment. Methods: Sections from approximately 200 formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens were screened by IHC for MAGE-A (mAb 6C1; recognizes MAGE A1, A2, A3, A4, A6, A10, A12) and PD-L1 (mAb E1L3N) expression. Gene expression analyses (RT-qPCR and RNA sequencing) were carried out on RNA extracted from adjacent tissue sections. Results: Analytical validation of the MAGE A3/A6 assay system successfully met predefined acceptance criteria appropriate for clinical sample testing. 75-80% of MAGE A IHC+ tumors were positive for MAGE A3/A6 mRNA. The rate of PD-L1 expression in tumor cells and/or immune cells in MAGE+ tumors was 89% for NSCLC (n=37), 41% for UC (n=32), 95% for SCCHN (n=19), and 100% for CC (n=7). Distinct tumor cell staining patterns were identified including samples in which PD-L1 and MAGE-A staining overlapped extensively, partially, or were nearly mutually exclusive. In some tumors, diffuse PD-L1+ immune cells were observed in the tumor bed; in other samples, PD-L1+ immune cells appeared to surround the tumor bed, while others showed lack of PD-L1+ immune cells. Conclusions: The results support clinical evaluation of a MAGE A3/A6 TCR T-cell product across these major histologies. This two-part MAGE A3/A6 screening assay may reduce the potential for false-positive results obtained using the 6c1 IHC assay alone , and be useful in screening subjects for anti-MAGE A3/A6 T-cell therapy. While the significance of staining patterns remains to be determined, the presence of PD-L1 positive TC and IC in MAGE A3/A6+ tumors supports the concept of checkpoint blockade in combination with T-cell therapy to treat advanced solid tumors. Citation Format: Stephanie H. Astrow, Izak Faiena, Rajul Jain, Alexandra Drakaki, Wesley S. Chang, Clark C. Fjeld, Jin Li, Adrian Bot. Gene and protein expression of MAGE, PD-L1, and associated immune landscape elements in non-small cell lung carcinoma (NSCLC), urothelial carcinoma (UC), squamous cell cancer of the head and neck (SCCHN), and cervical carcinoma (CC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A040. |
| تدمد: | 1538-8514 1535-7163 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::fb2ca9b2165d46cbcef9c809fcb50bd9Test https://doi.org/10.1158/1535-7163.targ-17-a040Test |
| رقم الانضمام: | edsair.doi...........fb2ca9b2165d46cbcef9c809fcb50bd9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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