Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

The MMS22L-TONSL Complex Mediates Recovery from Replication Stress and Homologous Recombination

Genome integrity is jeopardized each time DNA replication forks stall or collapse. Here we report the identification of a complex composed of MMS22L (C6ORF167) and TONSL (NFKBIL2) that participates in the recovery from replication stress. MMS22L and TONSL are homologous to yeast Mms22 and plant Tonsoku/Brushy1, respectively. MMS22L-TONSL accumulates at regions of ssDNA associated with distressed replication forks or at processed DNA breaks, and its depletion results in high levels of endogenous DNA double-strand breaks caused by an inability to complete DNA synthesis after replication fork collapse. Moreover, cells depleted of MMS22L are highly sensitive to camptothecin, a topoisomerase I poison that impairs DNA replication progression. Finally, MMS22L and TONSL are necessary for the efficient formation of RAD51 foci after DNA damage, and their depletion impairs homologous recombination. These results indicate that MMS22L and TONSL are genome caretakers that stimulate the recombination-dependent repair of stalled or collapsed replication forks

Supplementary Material for: Asymptomatic Carotid Artery Stenosis Treated with Medical Therapy Alone: Temporal Trends and Implications for Risk Assessment and the Design of Future Studies

<p><b><i>Background:</i></b> The rate of adverse clinical outcomes among patients with asymptomatic carotid stenosis receiving medical therapy alone can be used to guide clinical decision-making and to inform future research. We aimed to investigate temporal changes in the incidence rate of clinical outcomes among patients with asymptomatic carotid stenosis receiving medical therapy alone and to explore the implications of these changes for the design of future comparative studies. <b><i>Summary:</i></b> We searched MEDLINE, the Cochrane Central Register of Controlled Trials, US Food and Drug Administration documents, and reference lists of included studies (last search: December 31, 2012). We selected prospective cohort studies of medical therapy for asymptomatic carotid artery stenosis and we extracted information on study characteristics, risk of bias, and outcomes. We performed meta-analyses to estimate summary incidence rates, meta-regressions to assess trends over time, and simulations to explore sample size requirements for the design of future studies comparing new treatments against medical therapy. The main outcomes of interest were ipsilateral stroke, any stroke, cardiovascular death, death, and myocardial infarction. We identified 41 studies of medical therapy for patients with asymptomatic carotid stenosis (last recruitment year: 1978-2009). The summary incidence rate of ipsilateral carotid territory stroke (25 studies) was 1.7 per 100 person-years. This incidence rate was significantly lower in recent studies (last recruitment year from 2000 onwards) as compared to studies that ended recruitment earlier (1.0 vs. 2.3 events per 100 person-years; p < 0.001). The incidence rates of any territory stroke (17 studies), cardiovascular death (6 studies), death (13 studies), and myocardial infarction (5 studies) were 2.7, 4.1, 4.6, and 1.8 per 100 person-years, respectively. Simulations showed that future studies would need to enroll large numbers of patients with a relatively high incidence rate under medical therapy, and evaluate interventions with large effect sizes, to have adequate power to reliably detect treatment effects. <b><i>Key Messages:</i></b> Improved prognosis under medical therapy alone has narrowed the potential range of risk reduction attainable with new treatments for asymptomatic carotid stenosis. Future comparative studies will need to enroll large numbers of patients to assess treatment effectiveness.</p

Salt and cardiovascular disease: insufficient evidence to recommend low sodium intake

Several blood pressure guidelines recommend low sodium intake (5 g/day, while awaiting the results of large randomized controlled trials of sodium reduction on incidence of cardiovascular events and mortality