The success of adoptive T cell-based immunotherapy (ACT) in cancer is limited in part by the accumulation of myeloid-derived suppressor cells (MDSC), which block several T cell functions, including T cell proliferation and the expression of various cytotoxic mediators. Paradoxically, the inhibition of CD8+ T cell differentiation into cytotoxic populations increased their efficacy after ACT into tumor-bearing hosts. Therefore, we aimed to test the impact of conditioning CD8+ T cells with MDSC on their differentiation potential and ACT efficacy. Our results indicate that MDSC impaired the progression of CD8+ T cells into effector populations, without altering their activation status, production of IL-2, or signaling through the T cell receptor. In addition, culture of CD8+ T cells with MDSC resulted in an increased ACT anti-tumor efficacy, which correlated with a higher frequency of the transferred T cells and elevated IFNγ production. Interestingly, activated CD62L+ CD8+ Tcells were responsible for the enhanced anti-tumor activity showed by MDSC-exposed T cells. Additional results showed a decreased protein synthesis rate and lower activity of the mammalian/mechanistic target of rapamycin (mTOR) in T cells conditioned with MDSC. Silencing of the negative mTOR regulator tuberous sclerosis complex-2 in T cells co-cultured with MDSC restored mTOR activity, but resulted in T cell apoptosis. These results indicate that conditioning of T cells with MDSC induces stress survival pathways mediated by a blunted mTOR signaling, which regulated T cell differentiation and ACT efficacy. Continuation of this research will enable the development of better strategies to increase ACT responses in cancer.

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Recent years have seen major breakthroughs in genome-engineering systems, such as transposon-mediated gene delivery systems and CRISPR-Cas9-mediated genome-editing tools. In these systems, transient expression of auxiliary genes is responsible for permanent genomic modification. For both systems, it would be valuable to select for cells that are likely to undergo stable genome modification. Importantly, in particular for clinical applications of genome-engineered cell products, it will also be of importance to remove those cells that, due to random vector integration, display an unwanted stable expression of the auxiliary gene. Here, we develop a traceless selection system that on the one hand allows efficient enrichment of modified cells, and on the other hand can be used to select against cells that retain expression of the auxiliary gene. The value of this system to produce highly enriched-auxiliary gene-free cell products is demonstrated.

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This chapter introduces methods to synthesize experimental results from independent high-throughput genomic experiments, with a focus on adaptation of traditional methods from systematic review of clinical trials and epidemiological studies. First, it reviews methods for identifying, acquiring, and preparing individual patient data for meta-analysis. It then reviews methodology for synthesizing results across studies and assessing heterogeneity, first through outlining of methods and then through a step-by-step case study in identifying genes associated with survival in high-grade serous ovarian cancer.

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Like Chinese boxes nesting inside each other, the classification of non-small cell lung cancer (NSCLC) is subdivided into smaller and smaller subtypes on the basis of histological and molecular attributes. The latter characterizes NSCLC by its molecular alterations and the identification of inhibitors that target these cancer-specific "driver" mutations. Despite the initial promise of precision-guided therapies to inhibit a finer and finer array of molecular subcategories, despite even the curative potential of immunotherapeutic checkpoint blockade, in particular, casualties still abound and true clinical success stories are few and far between; the ever-present, if sometimes unmentioned, "elephant in the room", is the acquisition of resistance, which, sooner or later, rears its ugly head to undermine treatment success and shorten survival. Emerging data suggests that epigenetic therapies are able to reprogram the aberrant tumor-associated epigenome and ‘tame the beast of resistance’, thereby prolonging survival. This article reviews the role of epigenetic dysregulation in NSCLC, explores PFS2 as a possible surrogate endpoint, briefly mentions possible biomarkers and highlights combinatorial treatment epigenetic strategies to "prime" tumors and reverse resistance.

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In a phase 3, randomized, open-label trial (Pazopanib versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma, COMPARZ; NCT00720941), pazopanib was found to be noninferior to sunitinib in terms of progression-free survival in patients with metastatic renal cell carcinoma with no prior therapy. Overall treatment differences were evaluated in a post hoc analysis with a quality-adjusted time without symptoms or toxicity (Q-TWiST) methodology.
Each patient’s overall survival was partitioned into 3 mutually exclusive health states: time with grade 3 or 4 toxicity (TOX), time without symptoms of disease or grade 3/4 toxicity of treatment, and time after tumor progression or relapse (REL). The time spent in each state was weighted by a health-state utility associated with that state and summed to calculate the Q-TWiST. A threshold utility analysis was used, and utilities were applied across the range of 0 (similar to death) to 1 (perfect health).
A total of 1110 patients were enrolled (557 on pazopanib and 553 on sunitinib). The mean TOX was 31 days (95% confidence interval, 13-48 days) longer for sunitinib versus pazopanib. In the threshold utility analysis, the difference in the Q-TWiST ranged from -11 days (utility for TOX, 1; utility for REL, 0) to 43 days (utility for TOX, 0; utility for REL, 1) in favor of pazopanib across most utility combinations. Differences were significant in less than half of the utility combinations examined, and this typically occurred when the utility for TOX was lower than the utility for REL.
Patients randomized to pazopanib had a slightly longer Q-TWiST in comparison with sunitinib patients, and this was primarily due to the reduced length of TOX. Cancer 2016;122:1108-1115. © 2016 American Cancer Society.
© 2016 American Cancer Society.

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