Inflammatory bowel disease (IBD) results from a dysregulated interaction between the microbiota and a genetically susceptible host. Genetic studies have linked TNFSF15 polymorphisms and its protein ...TNF-like ligand 1A (TL1A) with IBD, but the functional role of TL1A is not known. Here, we found that adherent IBD-associated microbiota induced TL1A release from CX3CR1+ mononuclear phagocytes (MNPs). Using cell-specific genetic deletion models, we identified an essential role for CX3CR1+MNP-derived TL1A in driving group 3 innate lymphoid cell (ILC3) production of interleukin-22 and mucosal healing during acute colitis. In contrast to this protective role in acute colitis, TL1A-dependent expression of co-stimulatory molecule OX40L in MHCII+ ILC3s during colitis led to co-stimulation of antigen-specific T cells that was required for chronic T cell colitis. These results identify a role for ILC3s in activating intestinal T cells and reveal a central role for TL1A in promoting ILC3 barrier immunity during colitis.
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•IBD-associated adherent microbiota induce MNP-derived TL1A•MNP-derived TL1A promotes the ILC3-IL-22 axis and protects against acute colitis•TL1A induces ILC3 expression of OX40L during colitis in vivo•OX40L on ILC3s stimulates T cell activation and is required for T cell-driven colitis
Inflammatory bowel disease (IBD) results from a dysregulated interaction between the microbiota and a genetically susceptible host. Castellanos et al. show a protective role for microbial induction of the IBD-linked protein TL1A in promoting ILC3 barrier immunity and uncover a pathogenic role for TL1A-induced expression of OX40L on ILC3s in driving chronic T cell colitis.
The MAP-kinase pathway, consisting of the kinases RAS, RAF, MEK, and ERK, is crucial for cell proliferation, inhibition of apoptosis, and migration of cells. Direct inhibition of RAS is not yet ...possible, whereas inhibition of RAF is already established in malignant melanoma and under investigation in non-small-cell lung cancer (NSCLC). Due to their structure and function, the MEK proteins are attractive targets for cancer therapy and are also under investigation in NSCLC. We discuss strategies of targeting the RAS-RAF-MEK-ERK pathway with emphasis on MEK inhibition, either alone or in combination with other targets or conventional chemotherapy.
•OAK subgroup analysis compared SP142 and 22C3 assays at defined programmed death ligand 1 thresholds.•Survival benefit of atezolizumab over docetaxel across non–small cell lung cancer programmed ...death ligand 1–positive/negative subgroups.•Despite assay differences, SP142 and 22C3 similarly predicted atezolizumab efficacy.
This phase III OAK trial (NCT02008227) subgroup analysis (data cutoff, January 9, 2019) evaluated the predictive value of 2 PD-L1 IHC tests (VENTANA SP142 and Dako 22C3) for benefit from atezolizumab versus docetaxel by programmed death ligand 1 (PD-L1) status in patients with previously treated metastatic non–small cell lung cancer.
PD-L1 expression was assessed prospectively with SP142 on tumor cells (TC) and tumor-infiltrating immune cells (IC) and retrospectively with 22C3 using a tumor proportion score (TPS) based on TC membrane staining. Efficacy was assessed in the 22C3 biomarker-evaluable population (22C3-BEP) (n = 577; 47.1% of SP142-intention-to-treat population) and non–22C3-BEP (n = 648) in PD-L1 subgroups (high, low, and negative) and according to selection by 1 or both assays.
In the 22C3-BEP, overall survival benefits with atezolizumab versus docetaxel were observed across PD-L1 subgroups; benefits were greatest in SP142-defined PD-L1–high (TC3 or IC3: hazard ratio HR, 0.39 95% confidence interval (CI), 0.25-0.63) and 22C3-defined PD-L1–high (TPS ≥ 50%: HR, 0.56 95% CI, 0.38-0.82) and low (TPS, 1% to < 50%: HR, 0.55 95% CI, 0.37-0.82) groups. Progression-free survival improved with increasing PD-L1 expression for both assays. SP142 and 22C3 assays identified overlapping and unique patient populations in PD-L1–high, positive, and negative subgroups. Overall survival and progression-free survival benefits favored atezolizumab over docetaxel in double PD-L1–positive and negative groups; patients with both SP142- and 22C3-positive tumors derived the greatest benefit.
Despite different scoring algorithms and differing sensitivity levels, the SP142 and 22C3 assays similarly predicted atezolizumab benefit at validated PD-L1 thresholds in patients with non–small cell lung cancer.
It is unclear whether PD-L1 assays differ in their ability to predict clinical outcomes with checkpoint immunotherapy. This OAK analysis indicated greater survival with atezolizumab than docetaxel regardless of the assay used to determine tumor PD-L1 status (SP142 or 22C3) in a second-/third-line metastatic NSCLC population. The SP142 and 22C3 assays similarly predict atezolizumab efficacy at validated PD-L1 thresholds.
The PI3K/Akt/mammalian target of rapamycin pathway is activated in a majority of malignant pleural mesotheliomas (MPM). We evaluated the activity of everolimus, an oral mammalian target of rapamycin ...inhibitor, in patients with unresectable MPM.
MPM patients who had received at least one but no more than two prior chemotherapy regimens, which must have been platinum-based, were treated with 10 mg of everolimus daily. The primary endpoint was 4-month progression-free survival (PFS) by RECIST 1.1.
A total of 59 evaluable patients were included in the analysis. The median duration of treatment was 2 cycles (56 days). Overall response rate was 2% 95% confidence interval (CI): 0–12% by RECIST 1.1 and 0% (0–10%) by modified RECIST for MPM. The 4-month PFS rate was 29% (95% CI: 17–41%) by RECIST 1.1, and 27% (95% CI: 16–39%) by modified RECIST. The median PFS was 2.8 months (95% CI: 1.8–3.4) by RECIST 1.1. The median overall survival was 6.3 months (95% CI: 4.0–8.0). There was no difference in PFS among patients who received one or two prior chemotherapy regimens (p = 0.74). There was no difference in overall survival between patients with epithelioid histology versus other types (p = 0.47). The most common toxicities were fatigue (59%), hypertriglyceridemia (44%), anemia (42%), oral mucositis (34%), nausea (32%), and anorexia (32%). The most common grade 3 to 4 toxicities were fatigue (10.2%), anemia (6.8%), and lung infection (6.8%).
Everolimus has limited clinical activity in advanced MPM patients. Additional studies of single-agent everolimus in advanced MPM are not warranted.
To determine the changes in clinical trials and outcomes of patients with advanced-stage non-small-cell lung cancer (NSCLC) treated on phase III randomized trials initiated in North America from 1973 ...to 1994.
Phase III trials for patients with advanced-stage NSCLC were identified through a search of the National Cancer Institute's Cancer Therapy Evaluation Program database from 1973 to 1994, contact with Cooperative Groups, and by literature search of MEDLINE. Patients with advanced NSCLC treated during a similar time interval were also examined in the SEER database. Trends were tested in the number of trials, in the number and sex of patients entered on the trials, and in survival over time.
Thirty-three phase III trials were initiated between 1973 and 1994. Twenty-four trials (73%) were initiated within the first half of this period (1973 to 1983) and accounted for 5,359 (64%) of the 8,434 eligible patients. The median number of patients treated per arm of the trials rose from 77 (1973 to 1983) to 121 (1984 to 1994) (P <.001). Five trials (15%) showed a statistically significant difference in survival between treatment arms, with a median prolongation of the median survival of 2 months (range, 0.7 to 2.7 months).
Analysis of past trials in North America shows that the prolongation in median survival between two arms of a randomized study was rarely in excess of 2 months. Techniques for improved use of patient resources and appropriate trial design for phase III randomized therapeutic trials with patients with advanced NSCLC need to be developed.
Well-conducted cancer clinical trials are essential for improving patient outcomes. Unfortunately, only 3% of new cancer patients participate in clinical trials. Barriers to patient accrual in cancer ...clinical trials must be identified and overcome to increase patient participation.
We prospectively tracked factors that potentially affected patient accrual into cancer clinical trials at the University of California Davis Cancer Center. Oncologists seeing new outpatients were asked to complete questionnaires regarding patient characteristics and the physician's decision-making on patient eligibility, protocol availability, and patient opinions on participation. Statistical analysis was performed to correlate these parameters with subsequent protocol accrual.
There were 276 assessable patients. At the initial visits, physicians did not consider clinical trials in 38% (105/276) of patients principally because of a perception of protocol unavailability and poor performance status. Physicians considered 62% (171/276) of patients for participation in clinical trials. Of these, only 53% (91/171) had an appropriate protocol available for site and stage of disease. Seventy-six of 90 patients (84%) with available protocols met eligibility criteria for a particular study. Only 39 of 76 patients (51%) agreed to participate in cancer clinical trials, for an overall accrual rate of 14% (39/276). The remainder (37/76, 49%) declined trial participation despite meeting eligibility criteria. The most common reasons were a desire for other treatment (34%), distance from the cancer center (13%), patient refusal to disclose reason (11%), and insurance denial (8%). Patients with private insurance were less likely to enroll in clinical trials compared to those with government-funded insurance (OR, 0.34; P =.03; 95% CI, 0.13 to 0.9).
Barriers to cancer clinical trial accrual can be prospectively identified and addressed in the development and conduct of future studies, which may potentially lead to more robust clinical trials enrollment. Investigation of patient perceptions regarding the clinical trials process and the role of third party-payers is warranted.
Dynamic changes in circulating tumor DNA (ctDNA) are under investigation as an early indicator of treatment outcome.
Serial plasma ctDNA (baseline, 8 weeks, and at progression) was prospectively ...incorporated into the SWOG S1403 clinical trial of afatinib ± cetuximab in tyrosine kinase inhibitor-naïve, EGFR mutation tissue-positive non-small cell lung cancer.
EGFR mutations were detected in baseline ctDNA in 77% (82/106) of patients, associated with the presence of brain and/or liver metastases and M1B stage. Complete clearance of EGFR mutations in ctDNA by 8 weeks was associated with a significantly decreased risk of progression, compared with those with persistent ctDNA at Cycle 3 Day 1 HR, 0.23; 95% confidence interval (CI), 0.12-0.45; P < 0.0001, with a median progression-free survival (PFS) of 15.1 (95% CI, 10.6-17.5) months in the group with clearance of ctDNA versus 4.6 (1.7-7.5) months in the group with persistent ctDNA. Clearance was also associated with a decreased risk of death (HR, 0.44; 95% CI, 0.21-0.90), P = 0.02; median overall survival (OS): 32.6 (23.5-not estimable) versus 15.6 (4.9-28.3) months.
Plasma clearance of mutant EGFR ctDNA at 8 weeks was highly and significantly predictive of PFS and OS, outperforming RECIST response for predicting long-term benefit.
Lung cancer remains the leading cause of cancer-related death worldwide. NSCLC accounts for more than 85% of all lung cancers, and the prognosis for advanced-stage disease is typically poor. In ...recent years, the importance of histologic subtypes of NSCLC has been recognized, and the distinction between squamous and other NSCLC histologic subtypes is now critical to patient management. Squamous cell lung cancer (sqCLC) represents approximately 25% to 30% of NSCLC. The prognosis for patients with advanced NSCLC is poorer for those with sqCLC than for those with adenocarcinoma. This is partly due to a number of clinical characteristics that distinguish sqCLC from other NSCLC histologic subtypes, such as smoking history, comorbid diseases, age, and molecular profile. Together, these factors make sqCLC an especially challenging disease to manage. Herein, we review some of the key clinicopathologic features of sqCLC. Understanding these features to optimally address many of the unique therapeutic challenges of this disease is likely to be central to ultimately improving outcomes for patients with squamous NSCLC.
Lung cancer is the most common cause of cancer deaths. Most patients present with advanced-stage disease, and the prognosis is generally poor. However, with the understanding of lung cancer biology, ...and development of molecular targeted agents, there have been improvements in treatment outcomes for selected subsets of patients with non–small-cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated significantly improved tumor responses and progression-free survival in subsets of patients with advanced NSCLC, particularly those with tumors harboring activating EGFR mutations. Testing for EGFR mutations is a standard procedure for identification of patients who will benefit from first-line EGFR TKIs. For patients with advanced NSCLC and no activating EGFR mutations (EGFR wild-type) or no other driving oncogenes such as ALK-gene rearrangement, chemotherapy is still the standard of care. A new generation of EGFR TKIs, targeting multiple receptors and with irreversible bindings to the receptors, are in clinical trials and have shown encouraging effects. Research on primary and acquired resistant mechanisms to EGFR TKIs are ongoing. Monoclonal antibodies (e.g. cetuximab), in combination with chemotherapy, have demonstrated improved outcomes, particularly for subsets of NSCLC patients, but further validations are needed. Novel monoclonal antibodies are combined with chemotherapy, and randomized comparative studies are ongoing. This review summarizes the current status of EGFR inhibitors in NSCLC in 2012 and some of the major challenges we are facing.
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