Immune checkpoint blockade, exemplified by antibodies targeting the PD-1 receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we ...screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T-cell activation, contributing to antitumor effects
, due in part to the derepression of NFAT family proteins and their target genes, critical regulators of T-cell function. Although CDK4/6 inhibitors decrease T-cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel
organotypic tumor spheroid culture system and in multiple
murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies.
Our results define previously unrecognized immunomodulatory functions of CDK4/6 and suggest that combining CDK4/6 inhibitors with immune checkpoint blockade may increase treatment efficacy in patients. Furthermore, our study highlights the critical importance of identifying complementary strategies to improve the efficacy of immunotherapy for patients with cancer.
.
Histone deacetylase (HDAC) overexpression has been documented in various cancers and may be associated with worse outcomes. Data from early-phase studies of advanced non-small cell lung cancer ...(NSCLC) suggest encouraging antitumor activity with the combination of an HDAC inhibitor and either platinum-based chemotherapy or an EGFR inhibitor; however, toxicity is a limiting factor in the use of pan-HDAC inhibitors. Selective inhibition of HDAC6 may represent a potential therapeutic target and preclinical studies revealed immunomodulatory effects with HDAC6 inhibition, suggesting the potential for combination with immune checkpoint inhibitors. This phase Ib, multicenter, single-arm, open-label, dose-escalation study investigated the HDAC6 inhibitor ACY-241 (citarinostat) plus nivolumab in patients with previously treated advanced NSCLC who had not received a prior HDAC or immune checkpoint inhibitor.
The orally administered ACY-241 dose was escalated (180, 360, or 480 mg once daily). Nivolumab was administered at 240 mg (day 15 of cycle 1, then every 2 weeks thereafter). The primary endpoint was to determine the maximum tolerated dose (MTD) of ACY-241 plus nivolumab. Secondary endpoints included safety, tolerability, and preliminary antitumor activity. Pharmacodynamics was an exploratory endpoint.
A total of 18 patients were enrolled, with 17 patients treated. No dose-limiting toxicities (DLTs) occurred with ACY-241 at 180 or 360 mg; 2 DLTs occurred at 480 mg. The MTD of ACY-241 was 360 mg. The most common grade ≥ 3 treatment-emergent adverse events were dyspnea (n = 3; 18%) and pneumonia (n = 3; 18%). At the 180-mg dose, 1 complete response and 2 partial responses (PRs) were observed. At the 360-mg dose, 3 PRs were observed; 1 patient achieved stable disease (SD) and 1 experienced progressive disease (PD). At the 480-mg dose, no responses were observed; 1 patient achieved SD and 3 experienced PD. Acetylation analyses revealed transient increases in histone and tubulin acetylation levels following treatment. An increase in infiltrating total CD3
T cells was observed following treatment.
The study identified an MTD for ACY-241 plus nivolumab and the data suggest that the combination may be feasible in patients with advanced NSCLC. Responses were observed in patients with advanced NSCLC.
https://clinicaltrials.gov/ct2/show/NCT02635061 (identifier, NCT02635061).
Although polar bears (Ursus maritimus) and brown bears (U. arctos) have been exhibited in zoological gardens for centuries, little is known about their nutritional needs. Multiple recent studies on ...both wild and captive polar bears and brown bears have found that they voluntarily select dietary macronutrient proportions resulting in much lower dietary protein and higher fat or digestible carbohydrate concentrations than are currently fed in most zoos. These lower protein concentrations selected by both species maximized growth rates and efficiencies of energy utilization in brown bears and may play a role in reducing kidney, liver, and cardiovascular diseases in both species. Therefore, we propose the need for the development of new dietary regimens for both species in managed care that better reflect their macronutrient needs. We developed a new kibble that is higher in fat and lower in protein than typical diets that have been fed in managed care, has a fatty acid profile more consistent with wild bear diets, and has been readily consumed by both brown bears and polar bears. The kibble can be fed as the sole diet or as part of more complex diets with additional fruits, meats, or vegetables. Because many nutritional deficiencies and related diseases can take months or years to appear, we urge caution and continued long‐term monitoring of bears and their diets to ensure their optimal health.
Wild and captive polar bears and brown bears select diets higher in fats and carbohydrates and lower in protein than those currently fed in zoos. Changing polar bear diets may improve their health by reducing the incidence of kidney and liver disease which are common in the zoo population.
Research Highlights
Captive polar bears are very susceptible to renal failure and liver cancer.
We hypothesized that these diseases are due to improper diets.
Wild and captive polar bears and brown bears seek low protein:nonprotein energy ratios, whereas captive bears currently are fed high protein ratios.
We recommend new diets that more closely match the preferred macronutrient ratios.
BackgroundImmune checkpoint inhibitors have revolutionized cancer treatment, but the benefits in refractory patients with esophageal cancer have been modest. Predictors of response as well as new ...targets for novel therapeutic combinations are needed. In this phase 2 clinical trial, we tested single-agent pembrolizumab in patients with advanced esophageal cancer, who received at least one prior line of therapy.MethodsPembrolizumab 200 mg every 3 weeks was tested in 49 patients with refractory esophageal cancer: 39 with adenocarcinoma and 10 with esophageal squamous cell carcinoma. Major endpoints were radiological response by Immune-related Response Evaluation Criteria In Solid Tumors and survival. Tumor samples were evaluated for programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and immune contexture by both NanoString mRNA expression analysis and flow cytometry. Peripheral blood mononuclear cells and a panel of circulating chemokines were also analyzed.ResultsThe overall response rate (ORR) was 8% (4 of 49 patients; 95% CI 2.3% to 19.6%). Median overall survival (OS) was 5.8 months (95% CI 4.0 to 9.5). ORR and OS were not associated with histology. For PD-L1-positive patients, ORR was 13.3% (95% CI 1.7% to 40.5%) and median OS was 7.9 months (95% CI 4.7 to 15.5). A trend toward improved OS was observed in seven patients with a TMB ≥10 mut/Mb (p=0.086). Tumors with a PD-L1 Combined Positive Score ≥1 showed enrichment of LAG3 (p=0.005) and IDO1 (p=0.04) gene expression. Baseline levels of circulating CXCL10, interleukin 2 (IL2) receptor α (IL2RA) and IL6 were associated with survival: CXCL10 favorably, (HR 0.37, p=0.002 (progression-free survival); HR 0.55, p=0.018 (OS)); IL2RA and IL6 unfavorably (HR 1.57, p=0.020 for IL6 (OS); HR 2.36, p=0.025 for IL2RA (OS)).ConclusionsPembrolizumab monotherapy was modestly effective in refractory esophageal cancer. Circulating CXCL10 at baseline appeared to be a robust predictor of response. Other T cell exhaustion markers are upregulated in PD-L1-positive patients, suggesting that immunotherapy combinations such as anti-LAG3/programmed cell death protein 1 (PD-1) or anti-IDO1/PD-1 may be of promise in refractory esophageal cancer.
Highlights • We identified a group of R/M SCCHN tumors with an inflamed immunophenotype. • We identified a non-inflamed tumor immunophenotype in the same population. • Patients with the inflamed ...tumor phenotype had improved survival. • Patients with the inflamed tumor phenotype may benefit from checkpoint blockade.
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Background: Defactinib is an oral Focal Adhesion Kinase (FAK) inhibitor with preclinical activity in MPM. We assessed responses to defactinib treatment prior to planned surgical ...resection in naive patients with MPM. Methods: Three cohorts of 10 participants each received defactinib 400mg BID for 12, 35 and 21 days. Pre- and post-treatment blood, tumor biopsies and imaging were obtained for biomarker, immune cell and tumor response (modified RECIST, Tumor volume and SUV max) assessment. Toxicity was monitored for 30 days post treatment. Results: Between 12/2013 and 12/2017, 31 participants were registered at our center; 1 withdrew prior to intervention. Among 30 treated, 24 (80%) were male; median age 70 (47-83) years; surgery was EPP 7%, complete pleurectomy decortication (PD) 10%, extended PD 60%, partial PD 10%, unresectable 13%; MPM subtype was epithelioid 67%, biphasic 17%, sarcomatoid 17%. Expected complications of FAK inhibition, diagnostic/staging/operative procedures occurred in 83% (grade 1, 30%; grade 2, 43%; grade 3, 10%). Unexpected adverse events occurred in 77% (grade 1, 63%; grade 2, 20%; grade 3, 17% wound-infection, prolonged QT interval, and hyperglycemia in 3% each; increased INR in 7%; grade 5, 7% due to progressive disease in 3%, intraoperative anaphylactoid reaction unrelated to the drug in 3%). Objective partial response was observed in 13%, stable disease in 67%, progression in 17%. Tumor volume decreased 3-72% in 47% patients and increased 1-82% in 53%. SUV max decreased 3-69% in 50% and increased 1-61% in 50%. Biological correlates of treatment included target inhibition (75% pFAK reduction); tumor immune microenvironment changes: increased naïve (CD45RA+PD-1+CD69+) CD4 and CD8 T cells, reduced myeloid and Treg immuno-suppressive cells, reduced exhausted T cells (PD-1+CD69+), reduced peripheral MDSCs; and histological subtype change (pleomorphic or biphasic to epithelioid) in 13% of cases. Conclusions: Brief preoperative defactinib exposure was well tolerated, did not alter resectability or mortality compared to prior series, and showed evidence of therapeutic and immunomodulatory effects. Clinical trial information: NCT02004028.
Immune checkpoint blockade, exemplified by antibodies targeting the programmed death-1 (PD-1) receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing ...immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T cell activation, contributing to anti-tumor effects
in vivo
, due in part to de-repression of Nuclear Factor of Activated T cell (NFAT) family proteins and their target genes, critical regulators of T cell function. Although CDK4/6 inhibitors decrease T cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel
ex vivo
organotypic tumor spheroid culture system and in multiple
in vivo
murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies.
The objective of this research was to investigate the influence of beef hot carcass weight (HCW) on consumer sensory attributes. Beef carcasses (n = 116) were selected based on the USDA quality grade ...and HCW. Lightweight (LW; 296-341 kg), middleweight (MW; 386-432 kg), or heavyweight (HW; 466-524 kg) carcasses with USDA Choice (LC) or USDA Select (SEL) quality grades were used in this study. Carcasses were tracked through fabrication and the semitendinosus, chuck roll, and strip loin were collected and fabricated into eye of round, Denver cut, and strip loin steaks, respectively, for consumer sensory evaluation. USDA Select MW Denver cut steaks had increased overall liking and texture liking scores and were more tender and juicier than the SEL LW steaks (
≤ 0.02). USDA Select MW strip loin steaks had increased overall and flavor liking scores and were more tender than the SEL LW steaks (
≤ 0.02). USDA Choice MW eye of round steaks had increased overall, flavor, and texture liking scores and were juicier than the LW eye of round steaks (
≤ 0.04). The steaks evaluated in this study were differentially impacted by HCW and little to no clear pattern of effects could be determined across cut or quality grade. Additional research is needed to determine the most acceptable HCW from a consumer perspective.
Background.
Several antiretroviral agents (ARVs) are associated with chronic renal impairment, but the extent of such adverse events among human immunodeficiency virus (HIV)–positive persons with ...initially normal renal function is unknown.
Methods.
D:A:D study participants with an estimated glomerular filtration rate (eGFR) of ≥90 mL/min after 1 January 2004 were followed until they had a confirmed eGFR of ≤70 mL/min (the threshold below which we hypothesized that renal interventions may begin to occur) or ≤60 mL/min (a value indicative of moderately severe chronic kidney disease CKD) or until the last eGFR measurement during follow-up. An eGFR was considered confirmed if it was detected at 2 consecutive measurements ≥3 months apart. Predictors and eGFR-related ARV discontinuations were identified using Poisson regression.
Results.
Of 22 603 persons, 468 (2.1%) experienced a confirmed eGFR of ≤70 mL/min (incidence rate, 4.78 cases/1000 person-years of follow-up 95% confidence interval {CI}, 4.35–5.22) and 131 (0.6%) experienced CKD (incidence rate, 1.33 cases/1000 person-years of follow-up 95% CI, 1.10–1.56) during a median follow-up duration of 4.5 years (interquartile range IQR, 2.7–6.1 years). A current eGFR of 60–70 mL/min caused significantly higher rates of discontinuation of tenofovir (adjusted incidence rate ratio aIRR, 1.72 95% CI, 1.38–2.14) but not other ARVs compared with a current eGFR of ≥90 mL/min. Cumulative tenofovir use (aIRR, 1.18/year 95% CI, 1.12–1.25) and ritonavir-boosted atazanavir use (aIRR, 1.19/year 95% CI, 1.09–1.32) were independent predictors of a confirmed eGFR of ≤70 but were not significant predictors of CKD whereas ritonavir-boosted lopinavir use was a significant predictor for both end points (aIRR, 1.11/year 95% CI, 1.05–1.17 and 1.22/year 95% CI, 1.16–1.28, respectively). Associations were unaffected by censoring for concomitant ARV use but diminished after discontinuation of these ARVs.
Conclusions.
Tenofovir, ritonavir-boosted atazanavir, and ritonavir-boosted lopinavir use were independent predictors of chronic renal impairment in HIV-positive persons without preexisting renal impairment. Increased tenofovir discontinuation rates with decreasing eGFR may have prevented further deteriorations. After discontinuation, the ARV-associated incidence rates decreased.
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