scholarly journals High-capacity poly(2-oxazoline) formulation of TLR 7/8 agonist extends survival in a chemo-insensitive, metastatic model of lung adenocarcinoma

2020 ◽  
Vol 6 (25) ◽  
pp. eaba5542 ◽  
Author(s):  
Natasha Vinod ◽  
Duhyeong Hwang ◽  
Salma H. Azam ◽  
Amanda E. D. Van Swearingen ◽  
Elizabeth Wayne ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Treatment Options ◽  
High Capacity ◽  
Stage Iv ◽  
Inhibitory Effect ◽  
Immune Checkpoint Blockade ◽  
Platinum Based Chemotherapy ◽  
Stage Iv Cancer ◽  
Antigen Presenting

About 40% of patients with non–small cell lung cancer (NSCLC) have stage IV cancer at the time of diagnosis. The only viable treatment options for metastatic disease are systemic chemotherapy and immunotherapy. Nonetheless, chemoresistance remains a major cause of chemotherapy failure. New immunotherapeutic modalities such as anti–PD-1 immune checkpoint blockade have shown promise; however, response to such strategies is highly variable across patients. Here, we show that our unique poly(2-oxazoline)–based nanomicellar formulation (PM) of Resiquimod, an imidazoquinoline Toll-like receptor (TLR) 7/8 agonist, had a superior tumor inhibitory effect in a metastatic model of lung adenocarcinoma, relative to anti–PD-1 therapy or platinum-based chemotherapy. Investigation of the in vivo immune status following Resiquimod PM treatment showed that Resiquimod-based stimulation of antigen-presenting cells in the tumor microenvironment resulted in the mobilization of an antitumor CD8+ immune response. Our study demonstrates the promise of poly(2-oxazoline)-formulated Resiquimod for treating metastatic NSCLC.

scholarly journals High Capacity poly(2-oxazoline) formulation of TLR 7/8 agonist extends survival in a chemo-insensitive, metastatic model of Lung Adenocarcinoma

2019 ◽  
Author(s):  
Natasha Vinod ◽  
Duhyeong Hwang ◽  
Salma H. Azam ◽  
Amanda E. D. Van Swearingen ◽  
Elizabeth Wayne ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Treatment Options ◽  
High Capacity ◽  
Stage Iv ◽  
Inhibitory Effect ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Platinum Based Chemotherapy ◽  
Stage Iv Cancer

AbstractAbout 40% of the NSCLC patients have Stage IV cancer at the time of diagnosis. The only viable treatment options for metastatic disease are systemic chemotherapy and immunotherapy. Nonetheless, chemoresistance remains a major cause of chemotherapy failure. New immunotherapeutic modalities such as anti-PD1 checkpoint blockade have shown promise; however, response to such strategies is highly variable across patients. Here, we show that our novel poly(2-oxazoline) (POx) based nanomicellar formulation of Resiquimod, an imidazoquinoline TLR 7/8 agonist, had a superior tumor inhibitory effect in a metastatic model of lung adenocarcinoma, relative to anti-PD1 immune checkpoint blockade therapy as well as platinum-based chemotherapy, which is the mainstay of treatment for NSCLC. Investigation of the in vivo immune status following Resiquimod PM (POx micellar formulation of Resiquimod) treatment showed that Resiquimod-based stimulation of antigen-presenting cells in the tumor microenvironment resulted in the mobilization of anti-tumor CD8+ immune response. Our study demonstrates the promise of optimally delivered and nano-formulated Resiquimod as a new immunomodulating therapeutic strategy for the treatment of metastatic NSCLC.

scholarly journals How Well Do Documented Goals-of-Care Discussions for Patients with Stage IV Cancer Reflect Communication Best Practices?

2021 ◽  
Author(s):  
Natalie C. Ernecoff ◽  
Kathryn L. Wessell ◽  
William A. Wood ◽  
Gary S. Winzelberg ◽  
Frances A. Collichio ◽  
...  
Keyword(s):  
Best Practices ◽  
Cancer Progression ◽  
Treatment Options ◽  
Stage Iv ◽  
Treatment Recommendation ◽  
Treatment Preferences ◽  
Goals Of Care ◽  
Patient Goals ◽  
Stage Iv Cancer

Abstract Background: Written clinical communication regarding patients’ disease understanding and values may facilitate goal-concordant care, yet little is known about electronic health record (EHR) goals-of-care documentation. We sought to (1) describe frequency of communication best practices in EHR-documented goals-of-care discussions, and (2) assess whether templated notes improve quality of documentation.Methods: We abstracted all EHR-documented goals-of-care discussions for hospitalized patients with Stage IV cancer from admission to 60-days follow-up. Goals-of-care documentation was operationalized to include discussion of: (a) prognosis and/or illness understanding; and (b) goals and/or treatment options. Investigators qualitatively coded text based on conceptual frameworks for communication best practices, including decision making documentation, and noted if a health system template was used. Results: Among 206 of 492 (42%) patients with documented goals-of-care discussions, clinicians frequently communicated cancer progression or incurability (89%), but rarely addressed prognosis for life expectancy (22%). Goals and values were documented for 83%, and a treatment decision for 82% of patients. Treatment preferences were assessed for 98% of patients; options discussed included cancer treatment (62%), hospice (62%), resuscitation (51%), or intensive care (38%). Clinicians made a treatment recommendation for 40% of patients. Attention to emotional and spiritual concerns was uncommon (15%). Use of a template increased documentation of patient goals and values (80% vs. 61%, p<0.01), but did not enhance other communication best practices.Conclusion: Insights from the study can be used to guide future training and research to study and improve the quality of written communication about goal of care, and its impact on goal-concordant care.

scholarly journals O81 IMpower110: interim overall survival (OS) analysis of a phase III study of atezolizumab (ATEZO) monotherapy vs platinum-based chemotherapy (CHEMO) as first-line (1L) treatment in PD-L1–selected NSCLC

2020 ◽  
Vol 8 (Suppl 1) ◽  
pp. A1.1-A1
Author(s):  
Roy Herbst ◽  
Filippo De Marinis ◽  
Giuseppe Giaccone ◽  
Niels Reinmuth ◽  
Alain Vergnenegre ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Treatment Options ◽  
Stage Iv ◽  
Ethics Committees ◽  
Phase Iii ◽  
Meaningful Improvement ◽  
Platinum Based Chemotherapy ◽  
In The Wild ◽  
Grade 3 ◽  
Ecog Ps

BackgroundPD-L1/PD-1 inhibitors (CPI) as monotherapy or in combination with platinum-based doublet chemo (± bevacizumab) are 1L treatment options in metastatic NSCLC, with choice of agent(s) determined by PD-L1 expression. For patients (pts) who may be ineligible for combination therapy, CPI monotherapy remains an attractive treatment choice. IMpower110 evaluated atezo as 1L treatment in PD-L1–selected pts independent of tumor histology.MethodsIMpower110 enrolled 572 chemo-naive pts with stage IV nonsquamous (nsq) or squamous (sq) NSCLC, PD-L1 expression ≥ 1% on TC or IC, measurable disease by RECIST 1.1 and ECOG PS 0-1. Pts were randomized 1:1 to receive atezo 1200 mg IV q3w (Arm A) or platinum-based chemo (Arm B; 4 or 6 21-day cycles). Arm B nsq pts received cisplatin (cis) 75 mg/m2 or carboplatin (carbo) AUC 6 + pemetrexed 500 mg/m2 IV q3w; Arm B sq pts received cis 75 mg/m2 + gemcitabine (gem) 1250 mg/m2 or carbo AUC 5 + gem 1000 mg/m2 IV q3w. Stratification factors were sex, ECOG PS, histology and tumor PD-L1 status (TC1/2/3 and any IC vs TC0 and IC1/2/3). The primary endpoint of OS is tested hierarchically in the wild-type (WT; EGFR/ALK-negative) population (TC3 or IC3 then TC2/3 or IC2/3 then TC1/2/3 or IC1/2/3).ResultsThe 3 primary efficacy populations included 554 TC1/2/3 or IC1/2/3 WT pts, 328 TC2/3 or IC2/3 WT pts and 205 TC3 or IC3 WT pts. Median follow-up was 15.7 months (range, 0-35) in TC3 or IC3 WT pts. In the TC3 or IC3 WT population, atezo monotherapy improved median OS by 7.1 months (HR, 0.595; P = 0.0106) compared with chemo (table 1). The safety population comprised 286 pts in Arm A and 263 in Arm B. Treatment-related AEs (TRAEs) and Grade 3-4 TRAEs occurred in 60.5% (Arm A) and 85.2% (Arm B), and 12.9% (Arm A) and 44.1% (Arm B), respectively.Abstract 081 Table 1ConclusionsAt this interim analysis, IMpower110 met the primary endpoint of OS with statistically significant and clinically meaningful improvement in the TC3 or IC3 WT population. The safety profile favored Arm A, with no new or unexpected safety signals identified.Trial RegistrationNCT02409342Ethics ApprovalThe trial was conducted according to the principles of the Declaration of Helsinki. All patients provided written informed consent. Protocol approval was obtained from independent review boards or ethics committees at each site.

scholarly journals How well do documented goals-of-care discussions for patients with stage IV cancer reflect communication best practices?

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Natalie C. Ernecoff ◽  
Kathryn L. Wessell ◽  
William A. Wood ◽  
Gary S. Winzelberg ◽  
Frances A. Collichio ◽  
...  
Keyword(s):  
Best Practices ◽  
Cancer Progression ◽  
Treatment Options ◽  
Specific Treatment ◽  
Stage Iv ◽  
Treatment Decision ◽  
Free Text ◽  
Goals Of Care ◽  
Stage Iv Cancer

Abstract Background Written clinical communication regarding patients’ disease understanding and values may facilitate goal-concordant care, yet little is known about the quality of electronic health record (EHR) documentation. We sought to (1) describe frequency of communication best practices in EHR-documented goals-of-care discussions, and (2) assess whether templated notes improve quality of documentation. Methods Researchers pulled text of EHR-documented goals-of-care discussions for hospitalized patients with Stage IV cancer from admission to 60-days follow-up. Text was included when in a single encounter the clinician addressed: (a) prognosis and/or illness understanding; and (b) goals and/or treatment options. Researchers qualitatively coded text based on guidelines for communication best practices, and noted if an EHR template was used. Results Forty-two percent (206/492) of patients had EHR-documented goals-of-care discussions. Text frequently described communication of cancer progression (89%), though rarely included prognosis (22%). Text often included patients’ goals and values (83%), and at least on specific treatment decision (82%). Communication about treatments was included for 98% of patients; common examples included cancer treatment (62%), hospice (62%), resuscitation (51%), or intensive care (38%). Clinicians documented making recommendations for 40% of patients. Text addressing patient emotional and spiritual concerns was uncommon (15%). Compared to free text, use of a template was associated with increased documentation of goals and values (80% vs. 61%, p < 0.01), but not other best practices. Conclusion Insights from the study can be used to guide future training and research to study and improve the quality of documentation about goal of care, and its impact on goal-concordant care.

scholarly journals Inhibition of TMEM16A by Natural Product Silibinin: Potential Lead Compounds for Treatment of Lung Adenocarcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuai Guo ◽  
Xue Bai ◽  
Yufei Liu ◽  
Sai Shi ◽  
Xuzhao Wang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Binding Sites ◽  
Drug Targets ◽  
Inhibitory Effect ◽  
New Drugs ◽  
Site Directed Mutagenesis ◽  
Tumor Xenograft ◽  
Whole Cell ◽  
Xenograft Mice

Background: Effective anticancer therapy can be achieved by identifying novel tumor-specific drug targets and screening of new drugs. Recently, TMEM16A has been identified to be overexpressed in lung adenocarcinoma, and inhibitors of TMEM16A showed obvious antitumor efficacy.Methods: YFP fluorescence quenching and whole-cell patch clamp experiments were used to explore the inhibitory effect of silibinin on TMEM16A. Molecular docking and site-directed mutagenesis were performed to confirm the binding sites of silibinin and TMEM16A. MTT assay, wound healing assay, and annexin-V assay were used to detect the effect of silibinin on cancer cell proliferation, migration, and apoptosis. shRNA was transfected into LA795 cells to knock down the expression of endogenous TMEM16A. Tumor xenograft mice combined with Western blot experiments reveal the inhibitory effect and mechanism of silibinin in vivo.Results: Silibinin concentration dependently inhibited the whole-cell current of TMEM16A with an IC50 of 30.90 ± 2.10 μM. The putative binding sites of silibinin in TMEM16A were K384, R515, and R535. The proliferation and migration of LA795 cells were downregulated by silibinin, and the inhibition effect can be abolished by knockdown of the endogenous TMEM16A. Further, silibinin was injected to tumor xenograft mice which exhibited significant antitumor activity without weight loss. Finally, Western blotting results showed the mechanism of silibinin inhibiting lung adenocarcinoma was through apoptosis and downregulation of cyclin D1.Conclusion: Silibinin is a novel TMEM16A inhibitor, and it can be used as a lead compound for the development of lung adenocarcinoma therapy drugs.

Opsalin: A phase II placebo (Pbo)-controlled randomized study of ombrabulin in patients with platinum-sensitive recurrent ovarian cancer (OC) treated with carboplatin (Cb) and paclitaxel (P).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5516-5516 ◽  
Author(s):  
Michael J. Birrer ◽  
Igor Bondarenko ◽  
Sergei Tjulandin ◽  
Ignace Vergote ◽  
David Cibula ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Treatment Options ◽  
Randomized Study ◽  
Progression Free Survival ◽  
Disease Recurrence ◽  
Vascular Disrupting Agent ◽  
Primary Tumors ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy

5516 Background: Patients with platinum-sensitive recurrent OC are often retreated with CbP due to limited treatment options. Ombrabulin (AVE8062), a combretastatin A4 analog, is a vascular disrupting agent that damages established tumor vasculature causing tumor necrosis and has synergistic antitumor activity with platinum agents in vivo (Cancer Sci. 2003;94:200). OPSALIN evaluated whether adding ombrabulin to CbP improves outcomes in patients with platinum-sensitive recurrent OC (NCT01332656; EFC10260). Methods: Patients (aged ≥18 yrs, ECOG PS ≤2) with platinum-sensitive measurable ovarian, fallopian tube, or primary peritoneum carcinoma after completion of one line of platinum-based chemotherapy received ombrabulin 35 mg/m² or Pbo plus CbP (AUC 5–6, 175 mg/m²) every 3 weeks. Randomization (1:1) was stratified by time of first disease recurrence (6–12 or >12 months). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate (RR), and safety. An interim analysis after ~54 PFS events (60% of the target 90 PFS events) was planned. Results: From May 2011 to August 2012, 154 patients were randomized (n=77 in each group). Groups were balanced in terms of baseline characteristics. Overall, the median age was 56 yrs (range 34–79), 93% had ovarian primary tumors, and 54% had first disease recurrence >12 months. Planned interim analysis was performed after 53 PFS events (27 ombrabulin; 26 Pbo); median follow-up was 6.8 months. Ombrabulin did not improve PFS vs Pbo in any subgroup (global median 8.4 vs 10.4 months, respectively; HR 1.33; 60%CI 1.06–1.69). Overall, RR was 65% for ombrabulin and 71% for Pbo. Safety profiles were comparable; rates of grade 3–4 adverse events were 51% for ombrabulin and 41% for Pbo, with no particular safety signals. Conclusions: This interim analysis has suggested no safety concerns or efficacy advantage of adding ombrabulin to CbP in patients with platinum-sensitive recurrent OC. The study was discontinued due to limited probability of the ombrabulin arm showing PFS superiority at the final analysis. Study sponsored by Sanofi. Clinical trial information: NCT01332656.

scholarly journals How Well Do Documented Goals-of-care Discussions for Patients With Stage IV Cancer Reflect Communication Best Practices?

2020 ◽  
Author(s):  
Natalie C. Ernecoff ◽  
Kathryn L. Wessell ◽  
William A. Wood ◽  
Gary S. Winzelberg ◽  
Frances A. Collichio ◽  
...  
Keyword(s):  
Best Practices ◽  
Cancer Progression ◽  
Treatment Options ◽  
Stage Iv ◽  
Treatment Recommendation ◽  
Treatment Preferences ◽  
Goals Of Care ◽  
Patient Goals ◽  
Stage Iv Cancer

Abstract Background: Written clinical communication regarding patients’ disease understanding and values may facilitate goal-concordant care, yet little is known about electronic health record (EHR) goals-of-care documentation. We sought to (1) describe frequency of communication best practices in EHR-documented goals-of-care discussions, and (2) assess whether templated notes improve quality of documentation.Methods: We abstracted all EHR-documented goals-of-care discussions for hospitalized patients with Stage IV cancer from admission to 60-days follow-up. Goals-of-care documentation was operationalized to include discussion of: (1) prognosis or illness understanding; and (2) goals or treatment options. Investigators qualitatively coded text based on conceptual frameworks for communication best practices, and noted if a health system template was used. Results: Among 206 of 492 (42%) patients with documented goals-of-care discussions, clinicians frequently communicated cancer progression or incurability (89%), but rarely addressed prognosis for life expectancy (22%). Goals and values were documented for 83%, and a treatment decision for 82% of patients. Treatment preferences were assessed for 98% of patients; options discussed included cancer treatment (62%), hospice (62%), resuscitation (51%), or intensive care (38%). Clinicians made a treatment recommendation for 40% of patients. Attention to emotional and spiritual concerns was uncommon (15%). Use of a template increased documentation of patient goals and values (80% vs. 61%, p<0.01), but did not enhance other communication best practices.Conclusion: Insights from the study can be used to guide future training and research to study and improve the quality of written communication about goal of care, and its impact on goal-concordant care.

scholarly journals Genomic Landscape of Vinflunine Response in Metastatic Urothelial Cancer

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 378
Author(s):  
Alejandra Bernardini ◽  
Marta Dueñas ◽  
María Cruz Martín-Soberon ◽  
Carolina Rubio ◽  
Cristian Suarez-Cabrera ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Treatment Options ◽  
Immune Checkpoint Blockade ◽  
University Hospitals ◽  
Genomic Biomarkers ◽  
Synonymous Mutations ◽  
Potential Biomarker ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy ◽  
Significant Difference

Background and Aims: Metastatic urothelial carcinoma (mUC) remains an incurable disease with limited treatment options after platinum-based chemotherapy and immune checkpoint blockade (ICB). Vinflunine has shown a modest increase in overall survival and remains a therapeutic option for chemo- and immunotherapy refractory tumours. However, biomarkers that could identify responding patients to vinflunine and possible alternative therapies after failure to treatment are still missing. In this study, we aimed to identify potential genomic biomarkers of vinflunine response in mUC patient samples and potential management alternatives. Methods: Formalin-fixed paraffin-embedded samples of mUC patients (n = 23) from three university hospitals in Spain were used for genomic targeted-sequencing and transcriptome (using the Immune Profile panel by NanoString) analyses. Patients who received vinflunine after platinum-based chemotherapy failure were classified in non-responders (NR: progressive disease ≤ 3 months; n= 11) or responders (R: response ≥ 6 months; n = 12). Results: Genomic characterization revealed that the most common alteration, TP53 mutations, had comparable frequency in R (6/12; 50%) and NR (4/11; 36%). Non-synonymous mutations in KTM2C (4/12; 33.3%), PIK3CA (3/12; 25%) and ARID2 (3/12; 25%) were predominantly associated with response. No significant difference was observed in tumour mutational burden (TMB) between R and NR patients. The NR tumours showed increased expression of diverse immune-related genes and pathways, including various interferon gamma-related genes. We also identified increased MAGEA4 expression as a potential biomarker of non-responding tumours to vinflunine treatment. Conclusions: Our data may help to identify potential genomic biomarkers of response to vinflunine. Moreover, tumours refractory to vinflunine showed immune signatures potentially associated with response to ICB. Extensive validation studies, including longitudinal series, are needed to corroborate these findings.

Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): First report of a randomized expansion cohort from CheckMate 032.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8503-8503 ◽  
Author(s):  
Matthew David Hellmann ◽  
Patrick Alexander Ott ◽  
Jon Zugazagoitia ◽  
Neal E. Ready ◽  
Christine L. Hann ◽  
...  
Keyword(s):  
Initial Treatment ◽  
Treatment Options ◽  
Objective Response ◽  
Immune Checkpoint Blockade ◽  
First Report ◽  
Randomized Evaluation ◽  
Early Results ◽  
Platinum Based Chemotherapy ◽  
Expansion Cohort

8503 Background: Patients (pts) with advanced SCLC after first-line platinum-based chemotherapy (PLT-CT) have a poor prognosis and limited treatment options. CheckMate 032 is a phase I/II trial evaluating multiple regimens of nivo ± ipi in solid tumors, including advanced SCLC. Tolerability and efficacy of nivo ± ipi were demonstrated in early results from the initial treatment arms (Antonia, Lancet Oncol 2016), prompting long-term follow-up and the addition of a randomized expansion cohort to further evaluate nivo ± ipi in advanced SCLC. Methods: In the initial treatment arms, pts with advanced SCLC and disease progression after prior PLT-CT were assigned to nivo (3 mg/kg Q2W; n = 98) or nivo 1 + ipi 3 (1 mg/kg and 3 mg/kg Q3W x 4, then nivo 3 Q2W; n = 61); safety/efficacy was assessed with a follow-up of ~18 mo. In the subsequent SCLC expansion cohort, pts were randomized 3:2 to nivo vs nivo 1 + ipi 3 and stratified by number of prior therapies. The primary endpoint was objective response rate (ORR). Results: Updated efficacy/safety results from the initial (non-randomized) nivo and nivo 1 + ipi 3 arms are summarized in the table. Responses were durable and occurred regardless of PD-L1 expression or PLT-sensitivity; safety was consistent with prior nivo ± ipi studies. In the expansion cohort, 247 pts were randomized to nivo or nivo 1 + ipi 3. The presentation will contain the first report of efficacy/safety results and subgroup analyses from this randomized expansion cohort. Conclusions: Durable responses are observed with nivo and nivo + ipi in pts with previously treated SCLC. The expansion cohort represents the first randomized evaluation of combined immune checkpoint blockade in SCLC. Clinical trial information: NCT01928394. [Table: see text]

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