Purpose: Pancreatic ductal adenocarcinoma (PDA) is rarely cured, and single-agent immune checkpoint inhibition has not demonstrated clinical benefit despite the presence of large numbers of CD8+T cells. We hypothesized that tumor-infiltrating CD8+T cells harbor latent anti-tumor activity that can be reactivated using combination immunotherapy. Experimental Design: Preserved human PDA specimens were analyzed using multiplex immunohistochemistry (IHC) and T cell receptor (TCR) sequencing. Fresh...
Tue Apr 02, 2019 16:48
Purpose: Radio-sensitivity of normal intestinal epithelium is the major limiting factor for definitive radio therapy (RT) against abdominal malignancies. Radiosensitizers which can be used without augmenting radiation toxicity to normal tissue is still an unmet need. Inhibition of proteosomal degradation is developing as major therapeutic strategy for anticancer therapy as cancer cells are more susceptible to proteasomal inhibition induced cytotoxicity compared to normal cells. Auranofin a gold-containing...
Tue Apr 02, 2019 16:48
Targeting CD38 enhances the antileukemic activity of ibrutinib in chronic lymphocytic leukemia (CLL)
Purpose: CD38 has emerged as a high-impact therapeutic target in multiple myeloma, with the approval of daratumumab (anti-CD38 monoclonal antibody). The clinical importance of CD38 in chronic lymphocytic leukemia (CLL) patients has been known for over two decades, though it's relevance as a therapeutic target in CLL remains understudied. Experimental Design: We investigated the biological effects and anti-tumor mechanisms engaged by daratumumab in primary CLL cells. Besides its known immune-effector...
Tue Apr 02, 2019 16:48
Purpose: Acute myeloid leukemia (AML) is a hematological malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional chemotherapy and a diagnosis of AML is usually fatal. More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. These studies were directed at determining the effects of glutaminase inhibition on metabolism in AML and...
Tue Apr 02, 2019 16:48
Purpose: Patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer have a high incidence of brain metastases, and trastuzumab emtansine (T-DM1) is often employed. Stereotactic radiosurgery (SRS) is frequently utilized, and case series report increased toxicity with combination SRS and T-DM1. We provide an update of our experience of T-DM1 and SRS evaluating risk of clinically significant radionecrosis (CSRN) and propose a mechanism for this toxicity. Methods: Patients...
Tue Apr 02, 2019 16:48
Purpose:Immune checkpoint blockade (ICB) therapy induces durable tumor regressions in a minority of cancer patients. In this study, we aimed to identify kinase inhibitors that were capable of increasing the anti-melanoma immunity. Experimental Design:Flow cytometry-based screening was performed to identify kinase inhibitors that can block the IFN- induced PD-L1 expression in melanoma cells. The pharmacologic activities of regorafenib alone or in combination with immunotherapy in vitro and in vivo...
Tue Apr 02, 2019 16:48
Purpose: The detection of pre-existing EGFRT790M subclones and the assessment of their clinical significance in the pretreatment of EGFRT790M non-small cell lung cancer (NSCLC) patients remain unclear. Experimental Design: A total of 179 tumor samples from patients treated or not with a first-generation Tyrosine Kinase Inhibitor (TKI) was analyzed. The presence of ultra-low levels of pre-existing EGFRT790M mutation was evaluated using ultra-sensitive droplet digital PCR (ddPCR) and the clinical implication...
Mon Apr 01, 2019 17:27
Macrophages are a key component of the tumor microenvironment. Blocking Clever-1, a molecule expressed in M2-like macrophages, unleashed macrophage and T cell mediated antitumor immunity. Myeloid checkpoints including Clever-1 hold promise as alternative or complementary immunotherapy strategies.
Mon Apr 01, 2019 17:27
Background: Regarding CA-125 longitudinal kinetics during chemotherapy, the actual predictive value of the Gynecology Cancer InterGroup (GCIG) CA-125 response criterion is questioned. The modeled CA-125 elimination rate constant KELIM exhibited higher prognostic value in recurrent ovarian cancer patients enrolled in CALYPSO trial. The objective was to validate the higher predictive & prognostic values of KELIM during first line treatments. Experimental design: Data from 3 large phase III trials...
Mon Apr 01, 2019 17:27
Purpose: In Neurofibromatosis Type 1 (NF1) and in highly aggressive malignant peripheral nerve sheath tumors (MPNSTs), constitutively active RAS-GTP and increased MAPK signaling are important in tumorigenesis. Dual specificity phosphatases (DUSPs) are negative regulators of MAPK signaling that dephosphorylate p38, JNK and ERK in different settings. While often acting as tumor suppressors, DUSPs may also act as oncogenes, helping tumor cells adapt to high levels of MAPK signaling. We hypothesized...
Mon Apr 01, 2019 17:27
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