Macrophage-mediated trogocytosis can kill cancer cells

Understanding the complex behavior of effector cells such as monocytes or macrophages in regulating cancerous growth is of central importance for cancer immunotherapy. Earlier studies using CD20-specific antibodies have demonstrated that the Fc receptor (FcR)-mediated transfer of the targeted receptors from tumor cells to these effector cells through trogocytosis can enable escape from antibody therapy, leading to the viewpoint that this process is pro-tumorigenic. In the current study we demonstrate that persistent trogocytic attack results in the killing of HER2-overexpressing breast cancer cells. Further, antibody engineering to increase FcR interactions enhances this tumoricidal activity. These studies extend the complex repertoire of activities of macrophages to trogocytic-mediated cell death of HER2-overexpressing target cells and have implications for the development of effective antibody-based therapies.

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Comparison of Eligibility Criteria Between Protocols, Registries, and Publications of Cancer Clinical Trials

Trial registration and public accessibility of appended or published protocols of phase III randomized clinical trials (RCTs) allow comparison of reported research with essential aspects of trial design. We determined how eligibility criteria of participants specified in protocols were described in trial registries and articles of 255 cancer RCTs published in leading journals. The mean proportion of matching eligibility criteria between protocols and publications per trial (the primary endpoint) was 44.0% (95% confidence interval [CI] = 40.8% to 47.3%). Almost all discrepancies in eligibility criteria (96.7%, 95% CI = 96.1% to 97.3%) suggested to readers of articles that a broader study population was included. The mean proportion of matching eligibility criteria between protocols and registries was 72.9% (95% CI = 68.2% to 77.7%, the secondary endpoint). We conclude that there are substantial differences in eligibility criteria between trial protocols, registries and articles. Inaccurate reporting of eligibility criteria may prevent appropriate assessment of the applicability of trial results.

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p110{alpha} inhibition alters PanNETs progression

Purpose: Mutations in the PI3-kinase (PI3K) pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacological intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance to mTOR targeted therapy is emerging partially due to the loss of mTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown Experimental Design: In the present study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110α selective (GDC-0326) inhibitors and isoform specific PI3K kinase-dead mutant mice Results: Human and mouse PanNETs showed enhanced pAKT, pPRAS40 and pS6 positivity compared to normal tissue. While treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110α PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node (LN) metastasis compared to vehicle treated mice. We also demonstrated that tumor and stromal cells are implicated in the anti-tumor activity of GDC-0326 in RIP1-Tag2 tumors Conclusions: Our data provide a rationale for p110α selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis.

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PD-1 Pathway Blockade in EGFR-mutant and ALK-positive NSCLC

Purpose: PD-1 inhibitors are established agents in the management of non-small cell lung cancer (NSCLC); however, only a subset of patients derives clinical benefit. To determine the activity of PD-1/PD-L1 inhibitors within clinically-relevant molecular subgroups, we retrospectively evaluated response patterns among EGFR-mutant, ALK-positive, and EGFR wild-type/ALK-negative patients. Experimental Design: We identified 58 patients treated with PD-1/PD-L1 inhibitors. Objective response rates (ORRs) were assessed using RECIST v1.1. PD-L1 expression and CD8+ tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemistry. Results: Objective responses were observed in 1/28 (3.6%) EGFR-mutant or ALK-positive patients versus 7/30 (23.3%) EGFR wild-type and ALK-negative/unknown patients (P = 0.053). The ORR among never- or light- ({less than or equal to}10 pack years) smokers was 4.2% versus 20.6% among heavy smokers (P = 0.123). In an independent cohort of advanced, EGFR-mutant (N=68) and ALK-positive (N=27) patients, PD-L1 expression was observed in 24%/16%/11% and 63%/47%/26% of pre-tyrosine kinase inhibitor (TKI) biopsies using cutoffs of {greater than or equal to}1%, {greater than or equal to}5% and {greater than or equal to}50% tumor cell staining, respectively. Among EGFR-mutant patients with paired, pre- and post-TKI resistant biopsies (N=57), PD-L1 expression levels changed after resistance in 16 (28%) patients. Concurrent PD-L1 expression ({greater than or equal to}5%) and high levels of CD8+ TILs (grade {greater than or equal to}2) were observed in only 1 pre-treatment (2.1%) and 5 resistant (11.6%) EGFR-mutant specimens, and was not observed in any ALK-positive, pre- or post-TKI specimens. Conclusions: NSCLCs harboring EGFR mutations or ALK rearrangements are associated with low ORRs to PD-1/PD-L1 inhibitors. Low rates of concurrent PD-L1 expression and CD8+ TILs within the tumor microenvironment may underlie these clinical observations.

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MELK confers radioresistance in TNBC

Purpose: While effective targeted therapies exist for estrogen receptor-positive and HER2-positive breast cancer, no such effective therapies exist for triple-negative breast cancer (TNBC), thus it is clear that additional targets for radiosensitization and treatment are critically needed. Experimental Design: Expression microarrays, qRT-PCR, and western blotting were used to assess MELK RNA and protein expression levels. Clonogenic survival assays were used to quantitate the radiosensitivity of cell lines at baseline and after MELK inhibition. The effect of MELK knockdown on DNA damage repair kinetics was determined using H2AX staining. The in vivo effect of MELK knockdown on radiosensitivity was performed using mouse xenograft models. Kaplan-Meier analysis was used to estimate local control and survival information and a Cox proportional hazards model was constructed to identify potential factors impacting local recurrence-free survival. Results: : MELK expression is significantly elevated in breast cancer tissues compared to normal tissue as well as in TNBC compared to non-TNBC. MELK RNA and protein expression is significantly correlated with radioresistance in breast cancer cell lines. Inhibition of MELK (genetically and pharmacologically) induces radiation sensitivity in vitro and significantly delayed tumor growth in vivo in multiple models. Kaplan-Meier survival and multivariable analyses identify increasing MELK expression as being the strongest predictor of radioresistance and increased local recurrence in multiple independent datasets. Conclusions: Here, we identify MELK as a potential biomarker of radioresistance and target for radiosensitization in TNBC. Our results support the rationale for developing clinical strategies to inhibit MELK as a novel target in TNBC.

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IMA950 Phase I Trial Final Results

PURPOSE: To perform a two-cohort, phase 1 safety and immunogenicity study of IMA950 in addition to standard chemo-radiotherapy (CRT) and adjuvant temozolomide in patients with newly diagnosed glioblastoma (GBM). IMA950 is a novel GBM specific therapeutic vaccine containing 11 tumor-associated peptides (TUMAPs), identified on human leukocyte antigen (HLA) surface receptors in primary human GBM tissue. EXPERIMENTAL DESIGN: Patients were HLA A*02 positive and had undergone tumor resection. Vaccination comprised 11 intradermal injections with IMA950 plus GM-CSF over a 24 week period, beginning 7-14 days prior to initiation of CRT (Cohort 1) or 7 days post CRT (Cohort 2). Safety was assessed according to NCI CTCAE Version 4.0 and TUMAP specific T cell immune responses determined. Secondary observations included progression-free survival (PFS), pre-treatment regulatory T-cell (Treg) levels and the effect of steroids on T-cell responses. RESULTS: Forty five patients were recruited. Related adverse events included minor injection site reactions, rash, pruritus, fatigue, neutropenia and single cases of allergic reaction, anemia and anaphylaxis. Two patients experienced Grade 3 dose limiting toxicity of fatigue and anaphylaxis. Of 40 evaluable patients, 36 were TUMAP responders and 20 were multi-TUMAP responders, with no important differences between cohorts. No effect of pre-treatment Treg levels on IMA950 immunogenicity was observed and steroids did not affect TUMAP responses. PFS was 74% at 6 months and 31% at 9 months. CONCLUSION: IMA950 plus GM-CSF was well tolerated with the primary immunogenicity endpoint of observing multi-TUMAP responses in at least 30% of patients exceeded. Further development of IMA950 is encouraged.

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Characteristics and Prognostic Analysis of 69 Patients With Pulmonary Sarcomatoid Carcinoma

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare malignancy. Methods: A total of 69 patients with PSC treated at a single institution in southern China with long-term follow-up were evaluated in this study. We analyzed the clinical characteristics, immunohistochemical profiles, epidermal growth factor receptor mutation status, K-RAS mutation status, treatments, and prognosis. Results: PSC mainly occurred in young male patients with a history of smoking. Most patients received multimodality treatments and the majority had early-stage disease. The median survival time was 19.1 months, and the 5-year survival rate was 17.4%. The patients without distant metastasis, with normal or higher body mass index (≥18.5), with normal hemoglobin, with smaller tumor size (≤4 cm), and those who received complete resection had significantly better overall survival (P

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