Clin Cancer Res
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Purpose: Multiple myeloma remains an incurable malignancy of plasma cells despite considerable advances in treatment. The purpose of the study was to develop novel chimeric antigen receptors (CAR) for the treatment of multiple myeloma and explore combinatorial therapy using CAR T cells and immunomodulatory drugs such as lenalidomide for increasing treatment efficacy. Experimental Design: We redirected central memory T cells to express second-generation CAR-specific for CS1 and adoptively transferred them into multiple myeloma tumor-bearing mice to test their anti-multiple myeloma activity. ⋯ Mechanistic studies indicated that the addition of lenalidomide during CS1 CAR T-cell expansion in vitro enhanced the immune functions of CS1 CAR T cells, including cytotoxicity, memory maintenance, Th1 cytokine production, and immune synapse formation. Furthermore, lenalidomide enhanced the antitumor activity and persistence of adoptively transferred CS1 CAR T cells in vivoConclusions: The study demonstrates that lenalidomide improves the anti-multiple myeloma properties of CS1-directed CAR T cells and provides a basis for a planned clinical trial using the combination of lenalidomide with engineered T cells against CS1 in relapsed myeloma. Clin Cancer Res; 24(1); 106-19. ©2017 AACR.
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Purpose: Daratumumab treatment results in a marked reduction of CD38 expression on multiple myeloma cells. The aim of this study was to investigate the clinical implications and the underlying mechanisms of daratumumab-mediated CD38 reduction. Experimental Design: We evaluated the effect of daratumumab alone or in combination with lenalidomide-dexamethasone, on CD38 levels of multiple myeloma cells and nontumor immune cells in the GEN501 study (daratumumab monotherapy) and the GEN503 study (daratumumab combined with lenalidomide-dexamethasone). ⋯ Importantly, all these effects also occurred in patients with deep and durable responses, thus excluding CD38 reduction alone as a mechanism of daratumumab resistance. The trials were registered at www.clinicaltrials.gov as NCT00574288 (GEN501) and NCT1615029 (GEN503). Clin Cancer Res; 23(24); 7498-511. ©2017 AACR.
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Purpose: To develop and validate a radiomics nomogram for the preoperative prediction of lymph node (LN) metastasis in bladder cancer. Experimental Design: A total of 118 eligible bladder cancer patients were divided into a training set (n = 80) and a validation set (n = 38). Radiomics features were extracted from arterial-phase CT images of each patient. ⋯ Conclusions: The presented radiomics nomogram, a noninvasive preoperative prediction tool that incorporates the radiomics signature and CT-reported LN status, shows favorable predictive accuracy for LN metastasis in patients with bladder cancer. Multicenter validation is needed to acquire high-level evidence for its clinical application. Clin Cancer Res; 23(22); 6904-11. ©2017 AACR.
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Purpose: The prevalence of mutations in cancer susceptibility genes such as BRCA1 and BRCA2 and other cancer susceptibility genes and their clinical relevance are largely unknown among a large series of unselected breast cancer patients in the Chinese population. Experimental Design: A total of 8,085 consecutive unselected Chinese breast cancer patients were enrolled. Germline mutations in 46 cancer susceptibility genes were detected using a 62-gene panel. ⋯ Conclusions: 9.2% of breast cancer patients carry a pathogenic mutation in cancer susceptibility genes in this large unselected series. Triple-negative breast cancers have the highest prevalence of mutations in BRCA1 /2 and other breast cancer susceptibility genes among the four molecular subgroups, whereas ER-/PR-HER2+ breast cancers had the lowest mutations in these genes. Clin Cancer Res; 23(20); 6113-9. ©2017 AACR.
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Purpose: Ethnic differences are conspicuous in melanoma. This study is to obtain a comprehensive view of a genomic landscape and a better understanding of the correlations of gene mutation status with clinicopathologic characteristics and disease prognosis in the Asian population. Experimental Design: A total of 2,793 melanoma patient samples were retrospectively collected and analyzed for mutations in C-KIT, BRAF, NRAS, and PDGFRA coding regions and telomerase reverse transcriptase (TERT) promoter region by Sanger sequencing. ⋯ Mutations in BRAF, C-KIT, and NRAS have prognostic values that vary by melanoma subtypes. Clinical treatment targeting these critical pathways should be aimed directly at these poor-prognosis subpopulations for maximum potential impact. Clin Cancer Res; 23(20); 6120-7. ©2017 AACR.