tbuckley/cabot-search huggingface dataset:
Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules
Authors: Jeffrey Yang, Longqin Hu
Journal: Medicinal Research Reviews (2018)

Cancer immunotherapy has made great strides in the recent decade, especially in the area of immune checkpoint blockade. The outstanding efficacy, prolonged durability of effect, and rapid assimilation of anti-PD-1 and anti-PD-L1 monoclonal antibodies in clinical practice have been nothing short of a medical breakthrough in the treatment of numerous malignancies. The major advantages of these therapeutic antibodies over their small molecule counterparts have been their high binding affinity and target specificity. However, antibodies do have their flaws including immune-related toxicities, inadequate pharmacokinetics and tumor penetration, and high cost burden to manufacturers and consumers. These limitations hinder broader clinical applications of the antibodies and have heightened interests in developing the alternative small molecule platform that includes peptidomimetics and peptides to target the PD-1/PD-L1 immune checkpoint system. The progress on these small molecule alternatives has been relatively slow compared to that of the antibodies. Fortunately, recent structural studies of the interactions among PD-1, PD-L1, and their respective antibodies have revealed key hotspots on PD-1 and PD-L1 that may facilitate drug discovery efforts for small molecule immunotherapeutics. This review is intended to discuss key concepts in immuno-oncology, describe the successes and shortcomings of PD-1/PD-L1 antibody-based therapies, and to highlight the recent development of small molecule inhibitors of the PD-1/PD-L1 protein-protein interaction.
Readability of informed consent forms for cancer patients undergoing radiation therapy: A nationwide survey.
Authors: Subha Perni, Andrew J Einstein, David Paul Horowitz, Michael Rooney, Daniel William Golden, Anne Ritke McCall, Reshma Jagsi
Journal: Journal of Clinical Oncology (2018)

e22152 Background: Given the importance of informed consent in cancer care, we sought to characterize readability and specificity of consent forms for radiation therapy, hypothesizing that readability would be above the 8th grade level recommended by NCI. Methods: An IRB approved e-mail survey of 89 ERAS-listed academic radiation oncology programs in 2016 was conducted. Departments were queried regarding consent process. They were asked to provide general consent forms, and brain and breast forms if utilized. Forms were analyzed for included elements and readability. Readability was analyzed with Readable.io (Added Bytes, UK) using established metrics: Simple Measure of Gobbledygook (SMOG), Flesch-Kincaid Reading Grade Level (FK-RGL) and Automated Readability Index (ARI), all of which characterize grade level, and Flesch-Kincaid Reading Ease (FK-RE), using a 0-100 scale. Results: Of 89 programs contacted, 60 (67%) responded; 56 (93%) used general forms, of which 31 also used site-specific. The remaining 4 (7%) used only site-specific. 49 institutions submitted 98 forms (39 general, 30 brain-specific, and 29 breast-specific). 7 forms were not radiation-specific; 17 added radiation-specific elements to a general template that appeared to be used in other settings. Only 2 (3%) routinely sent forms home with patients prior to signature, and 23 (38%) after signature. Readability averaged a college grade level (Table) with no significant differences between different form types. Midwestern programs had FK-RE scores averaging 6.5 higher (more readable) than Northeastern programs (95% CI: 0.9 – 12.2, p = 0.02). There were no significant regional differences in other indices. Conclusions: The vast majority of US academic radiation oncology facilities use informed consent forms that are far above readability recommendations. Consensus guidelines from professional societies would be useful to standardize and improve consent documents in cancer care. SMOG FK-RGL ARI FK-RE Average 14.5 ± 2.0 12.2 ± 2.4 12.1 ± 3.0 40.3 ± 8.3 (college) Median 14.3 11.8 11.7 40.6 (college) Range 9.2 - 19.2 8.1 - 18.1 6.8 - 19.8 20.4 (college graduate) - 57.8 (10th - 12th grade) % forms at 8th grade level 0% 6.7% 14.6% 0% Readability scores.
Glucocorticoid receptor PROTACs for the treatment of prostate cancer and other malignancies.
Authors: James Thomas Link, Yonathan Lissanu Deribe, Philip Jones
Journal: Journal of Clinical Oncology (2018)

e14545 Background: Many proteins are difficult to drug, limiting the approaches to treat malignancy. To address the problem, technologies were invented that are not clinically relevant. Proteolysis targeting chimeras (PROTACs) address this unmet medical need. PROTACs are conjugates of small molecule ligands tethered to E3 ligase binders. The heterobifunctional conjugates catalyze the formation of a ternary complex that allows the E3 ligase to tag the protein target for destruction by the proteasome by ubiquitination. Glucocorticoid receptor (GR) antagonists are under clinical evaluation to treat castrate resistant prostate, triple negative breast, and drug resistant cancers. When standard therapies are utilized against prostate and breast cancer, GR expression is a resistance mechanism. GR antagonists are being studied with cytotoxic chemotherapy in clinical trials and preclinical data with immunotherapy is emerging. GR PROTACs are anticipated to have greater efficacy and fewer side effects due to their catalytic activity and the superiority of degradation over inhibition. Methods: GR PROTACS were prepared utilizing novel linkers. Their cellular activity has been evaluated in castration resistant prostate and breast cancer cell lines and their in vivo protein degradation activity and safety assessed in rodent models. An efficacy study is being conducted in a prostate cancer rodent model. Results: GR PROTACs have been discovered that degrade the GR in cancer cell lines They retard the proliferation of castration resistant prostate (DU-145, PC3, and LNCaP R1 + R2) and triple negative breast (CAL-120) cancer cell lines. GR PROTACS have been identified that potently degrade GR without a “hook” effect. An IP dosed GR PROTAC has demonstrated in vivo knockdown of the GR in a mouse model. Sequential dosing is safe and effective enabling an efficacy evaluation in a prostate cancer rodent model. Conclusions: GR antagonists are being studied as anticancer agents. They are being evaluated as monotherapies against prostate and breast cancer; co-therapy with cytotoxic chemotherapy against drug resistant tumors; and in conjunction with immunotherapy. GR PROTACs may offer superior efficacy and safety than antagonists.
Safety and efficacy of durvalumab in combination with tremelimumab, durvalumab monotherapy, and tremelimumab monotherapy in patients with advanced gastric cancer.
Authors: Ronan Joseph Kelly, Jeeyun Lee, Yung-Jue Bang, Khaldoun Almhanna, Mariela A. Blum Murphy, Daniel V.T. Catenacci, Hyun Cheol Chung, Zev A. Wainberg, Michael Gibson, Keun Wook Lee, Johanna C. Bendell, Crystal S. Denlinger, Philip Z. Brohawn, Peng He, Jennifer McDevitt, Judson Englert, Geoffrey Yuyat Ku
Journal: Journal of Clinical Oncology (2018)

4031 Background: The combination of durvalumab (D; anti–PD-L1) and tremelimumab (T; anti–CTLA-4) has the potential to amplify T-cell responses against tumors through immune checkpoint blockade, resulting in antitumor activity. Methods: This is an ongoing Phase Ib/II study in patients (pts) with metastatic or recurrent gastric or gastroesophageal junction carcinoma. An initial safety run-in was conducted in 6 pts who received D 20 mg/kg and T 1 mg/kg IV Q4W for 4 cycles followed by D 10 mg/kg Q2W for ≤12 mo. For Phase II expansion, all pts were immunotherapy naive and had progressed after systemic platinum- or fluoropyrimidine-based chemotherapy. Second-line (2L) pts were randomized 2:2:1 to D+T, D 10 mg/kg Q2W up to 12 mo, or T 10 mg/kg Q4W for 7 doses then Q12W for 2 doses. Third-line (3L) pts received D+T. Tumor cell PD-L1 expression was assessed by IHC (Ventana SP263). Results: As of Sept 13, 2017, 58 pts received D+T (35% PD-L1 > 1%), 24 pts received D (38% PD-L1 > 1%), and 12 pts received T (50% PD-L1 > 1%); median duration of follow-up was 9.2, 3.5, and 9.2 mo, respectively. Drug-related grade 3/4 adverse events (AEs) occurred in 17 pts (29%) who received D+T; most frequent was colitis (5%). Six (50%) and 4 (17%) pts had grade 3/4 AEs related to T or D alone, respectively. Ten pts (17%) who received D+T discontinued due to drug-related AEs; most frequent was colitis (5%). One pt (4%) with D and 4 pts (33%) with T discontinued due to drug-related AEs. There were no drug-related deaths. In the T cohort, 1 pt (8%) had a confirmed PR; progression-free survival (PFS) and overall survival (OS) rates are not presented due to small sample size. Clinical activity in the other cohorts is shown below. Conclusions: D+T has a manageable safety profile in 2L and 3L advanced gastric cancer, with encouraging OS versus D monotherapy. Clinical trial information: NCT02340975. 2L D+T n = 27 3L D+T n = 25 2L D n = 24 Confirmed + unconfirmed ORR, n (%) 95% CI 3 (11.1) 2.4‒30.2 3 (12.0) 3.0‒36.3 2 (8.3) 1.5‒36.4 DCR—8 wk, n (%) 95% CI 12 (44.4) 25.5–64.7 11 (44.0) 24.4–65.1 3 (12.5) 2.7–32.4 Median PFS (95% CI), mo 1.8 (1.6–3.3) 1.8 (1.6–3.5) 1.6 (1.0–1.8) Median OS (95% CI), mo 9.2 (4.2–12.8) 10.6 (4.8–17.0) 3.2 (1.7–4.4)
REMINET: A European, multicentre, PHASE II/III randomized double-blind, placebo-controlled study evaluating lanreotide as maintenance therapy after first-line treatment in patients with non-resectable duodeno-pancreatic neuroendocrine tumours.
Authors: Come Lepage, Laetitia Dahan, Jean-Louis Legoux, Karine Le Malicot, Rosine Guimbaud, David Tougeron, Guillaume Cadiot, Frédéric Di Fiore, Denis Michel Smith, Karine Bouhier Leporrier, Olivia Hentic, Astrid Lièvre, Roger Faroux, Nadia Bouarioua, Marianne E. Pavel, Ivan Borbath, Juan W. Valle, A Rinke, Michel Ducreux, Thomas Walter
Journal: Journal of Clinical Oncology (2016)

TPS4148 Background: Patients (pts) with metastatic or locally advanced, non-resectable, Well-Differentiated Duodeno-Pancreatic (WDDP) NETs are treated following European guidelines. Pts with more aggressive disease, i.e. progressive and/or symptomatic metastases, significant hepatic invasion ( > 30-50%), and/or bone metastases, combination chemotherapy is considered; otherwise biotherapy (everolimus or sunitinib) is an option. The recommendations are to stop chemotherapy once disease control is obtained. The concept of maintenance therapy is well established in several cancer types. In this study we will evaluate the role of a somatostatin analogue (LAN) as maintenance in patients with stable/responding disease after 1L therapy (which may have been interrupted for tolerability issues) until progression. Somatostatin analogues are well tolerated and have demonstrated anti-proliferative effect making them ideal candidates for maintenance therapy. Methods: REMINET is an academic randomized, double-blind, placebo-controlled, phase II/III study. A total of 222 adults patients pts with a metastatic (synchronous or metachronous) or locally advanced, non-resectable, grade 1 or 2 WDDP NETs (WHO 2010 classification; Ki-67 ≤ 20%) and documented stable disease or objective response after 1L therapy at least 4 weeks prior to randomization, will be enrolled and randomly assigned in a 1:1 ratio to receive 120 mg LAN or placebo, every 28 days, until disease progression or unacceptable toxicity. Stratification factors: Centre, Grade 1 vs. 2, 1L treatment (chemotherapy vs. biotherapy). The primary endpoint of the phase III part is Progression-Free Survival (PFS) assessed by the investigators (RECIST v1.1). The aim of the phase II part is to demonstrate a 6-months PFS > 45% in LAN arm. Main secondary endpoints are PFS according to central review, overall survival, safety and quality of life. Frozen blood samples (-80°C) will be BioBanked for ancillary studies. The study is currently open in Europe. Status: A total of 13 patients are already randomized. Clinical trial information: NCT02288377.
Adequacy of surgical staging to predict survival in early stage ovarian cancer.
Authors: Rachel Hope Occhiogrosso, Margaret Steinhoff, Christina Raker, Phinnara Has, Paul DiSilvestro
Journal: Journal of Clinical Oncology (2016)

e17037 Background: Treatment of early stage ovarian cancers (EOCs) is oophorectomy with “complete” surgical staging (bilateral lymphadenectomy, peritoneal/pelvic washings, and omental sampling), but recent research has revealed variable adherence with these standards despite the fact that up to 30% of EOC cases have occult metastases. Inadequate staging has significant treatment implications given that more aggressive treatment is indicated for those with high-risk EOCs and more conservative management should be considered for those with true lower-risk EOCs. Methods: A retrospective IRB-approved review of women diagnosed with early-stage ovarian cancers at Women and Infants’ Hospital from 1995-2009 was performed. 608 cases were identified of which 369 met inclusion criteria. All available records were reviewed and coded for patient characteristics, surgical and staging information, and outcome and recurrence. Data was analyzed with STATA. Results: Staging was considered complete in 222 patients (60.3%), partial in 98 (26.6%), absent in 43 (11.7%) and unknown in 5. Adequacy of staging was significantly associated with 10-year recurrence-free survival (RFS), with 80.4%, 67.9% and 67% respectively for completely, partially and unstaged patients (p = 0.03). Additionally, adequacy of staging was significantly associated with overall (all-cause) survival (OS) (p = 0.04), with a 10-year OS rate of 76.0% among fully staged patients as opposed to 62.8% of partially staged women. When stratified into “high risk” (stages IC, II, and all grade III cancers) versus “low risk” cases, significance persisted in the low risk population for 10-year RFS and OS (p = 0.009 and p = 0.01, respectively). Similarly, younger age ( < 48 years) was the only significant factor associated with completion of staging (p = 0.02). Conclusions: Adherence to surgical staging guidelines for presumed early stage ovarian cancer yields a statistically significant improvement in 10-year recurrence-free survival as well as overall survival. Notably, older patients were significantly less likely to be fully staged. Adequacy of surgical staging has significant implications for post-surgical treatment recommendations in women with early stage ovarian cancer.
Early proliferation of PD-1+ CD8 T cells in peripheral blood as predictive of response to PD-1 inhibition for patients with advanced NSCLC.
Authors: Rathi Narayana Pillai, Alice O. Kamphorst, Shu Yang, Taofeek Kunle Owonikoko, Gabriel Sica, Tahseen Nasti, Rama Akondy, Andreas Wieland, Hong Wu, Nikita Patel, Ke Yu, Lydia Koenig, Madhusmita Behera, Megan McCausland, Fadlo Raja Khuri, Rafi Ahmed, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2017)

e20648 Background: Anti PD-1 and PDL-1 antibodies are now established immune targeted therapies for a subset of patients with advanced non-small cell lung cancer (NSCLC). There is a need for predictive biomarkers to better guide patient selection. We profiled peripheral blood samples from patients receiving PD-1 pathway targeted antibodies for lymphocyte subsets and correlated temporal changes with clinical response. Methods: NSCLC patients treated at our institution with PD-1 or PDL-1 inhibitors (nivolumab, pembrolizumab, and atezolizumab) consented to an IRB-approved biomarker profiling protocol. We collected baseline peripheral blood samples before first treatment and subsequently prior to each new treatment cycle until progression of disease or for a maximum of six cycles. Peripheral blood mononuclear cells (PBMCs) were isolated and analyzed by flow cytometry for kinetics of proliferation of PD1+CD8+ T cells. Clinical response to anti PD-1 therapy was classified according to Response Evaluation Criteria in Solid Tumors (RECIST1.1) criteria and correlated with T cell proliferation kinetics. Results: We enrolled 27 patients with baseline characteristics: median age 66, male 70%, smokers 85%, adenocarcinoma 70%; 10 (37%) patients achieved partial response (PR), 7 (26%) had stable disease (SD) and 10 (10%) had disease progression (PD) as best response. There was a &gt; 1.5-fold increase in Ki67+CD8+ T cells expressing PD-1 within 4 weeks of treatment initiation in 80% of patients with PR compared with 30% in patients with SD and 30% in those with PD. Conclusions: Early proliferation of PD1+CD8+ T cells in peripheral blood is a potential pharmacodynamic biomarker of anti PD-1 immunotherapy that could serve as a tool to identify the NSCLC patient subset most likely to respond to PD-1 and PDL-1 inhibitors.
Chemotherapy outcomes for unresectable and metastatic biliary tract cancers (BTC): Role of fluoropyrimidine (FP) chemotherapy—A retrospective analysis.
Authors: Mona Lisa Alattar, Pavel Levin, Muhammad S Beg, Udit Verma, Yull Edwin Arriaga, Samira K. Syed, Sirisha Karri
Journal: Journal of Clinical Oncology (2016)

e15623 Background: Unresectable and metastatic BTC portend very poor overall survival (OS), with historical OS less than 1.5 years. Gemcitabine (G) and cisplatin (C) combination has become the standard of care. We examined the use of GC in our patient population and also compared the effectiveness of FP-based combination therapies. Methods: We retrospectively reviewed the data for patients (pts) obtained from tumor registry, treated for BTC at UT Southwestern Medical Center and Parkland Hospital, Dallas, Texas between May 2007 and December 2015.Pts diagnosed with unresectable or metastatic BTC who received at least one cycle of chemotherapy were included. Results: Of 136 pts, 49 pts were evaluable. Median age was 57 years (range 25-74) with the majority having metastatic disease at diagnosis (94%). 54% of pts had intrahepatic cholangiocarcinoma, 28% had a gallbladder primary with the remaining extrahepatic cholangiocarcinoma, hilar and ampullary (8.7%, 4.3% and 4.3%, respectively). The most common first line chemotherapy was GC (36/49, 71%) with tumor control rate (CR+PR+SD) of 60%, median event-free survival (EFS) of 4.3 months (mos). Other first-line regimens included G alone (10%), G combinations or FP-based regimens ( < 10%). Of the 49 pts, 26 (53%) received second line chemotherapy. 21 (80%) pts received FP-based regimens. FP regimens included irinotecan (FOLFIRI or XELIRI) with or without EGFR Ab (13/26, 50%) with tumor control rate of 54% (3PR+4SD) and median EFS of 2.9 mos. 6/26 pts received FP with oxaliplatin with or without EGFR Ab and 3 these pts had SD. Conclusions: This is one of the largest retrospective reviews of outcomes in pts with metastatic/unresectable BTC. FP-based regimens particularly FOLFIRI with or without EGFR Ab demonstrated good disease control even in second line setting and needs to be further investigated in a prospective randomized trial.
Notice of Retractions: “First Foods Most: After 18-Hour Fast, People Drawn to Starches First and Vegetables Last,” “Fattening Fasting: Hungry Grocery Shoppers Buy More Calories, Not More Food,” and “Watch What You Eat: Action-Related Television Content Increases Food Intake” by Brian Wansink
Authors: Howard Bauchner
Journal: JAMA Internal Medicine (2018)

that included Brian Wansink, PhD, as author.At that time, Cornell University
18-FLT-PET/CT as an imaging biomarker in patients with ASS1-deficient thoracic cancers treated with ADI-PEG20, pemetrexed and cisplatin.
Authors: Peter Wojciech Szlosarek, Teresa Szyszko, Simon Pacey, James F. Spicer, Melissa Phillips, Jeremy P. C. Steele, Adalberto Barba, Monica Diaz, Amanda Johnston, Bor-Wen Wu, John S. Bomalaski, Gary J. R. Cook
Journal: Journal of Clinical Oncology (2016)

11567 Background: Loss of argininosuccinate synthetase 1 (ASS1) sensitizes malignant pleural mesothelioma (MPM) and lung carcinoma (NSCLC) cells to apoptosis following arginine (L-Arg) deprivation. We showed that the L-Arg depletor pegylated arginine deiminase (ADI-PEG20, ADI) enhances the cytotoxic effect of pemetrexed (PEM) in ASS1-negative tumor cells involving suppression of pyrimidine synthesis and the salvage pathway. The latter was linked to inhibition of thymidine kinase 1 with reduced uptake of 18-FLT on PET imaging in vivo. In the phase I dose-escalation TRAP study (NCT02029690) we showed that ADI added to first-line PEM and cisplatin (CIS) chemotherapy (ADIPEMCIS) doubled the partial response (PR) rate in patients (pts) with ASS1-deficient MPM and NSCLC (Mol Cancer Ther 2015;14:B23). Here, we explored the role of 18-FLT-PET as a novel biomarker for assessing disease response to ADIPEMCIS. Methods: 18-FLT-PET was undertaken to assess tumor proliferation at baseline (scan 1), 24 hours post first dose of ADI and prior to PEMCIS on day 3 (scan 2), post first cycle ADIPEMCIS on day 15 (scan 3) and at end of ADIPEMCIS (scan 4) in 20 pts (10 pts each with MPM and NSCLC) since March 2015. Treatment response was measured using EORTC PET response criteria (PR, stable disease or SD, progressive disease or PD). A majority of pts have accrued to the PET imaging and updated results will be correlated with the RECIST responses. Results: Comparing with the baseline PET imaging in n = 11 pts: 2/9 (22%), 6/9 (67%), 1/9 (11%) had a PR/SD/PD on scan 1; 4/11 (36%), 6/11 (55%), 1/11 (9%) had a PR/SD/PD on scan 3; and 5/8 (63%), 3/8 (37%) had a PR/SD on scan 4. RECIST revealed PR = 5/9 (56%), SD = 3/9 (33%), and PD = 1/9 (11%) at end of treatment in the same group. Conclusions: 18-FLT-PET provides early evidence of response to L-Arg deprivation in pts with ASS1-deficient thoracic tumors. Furthermore, the rate of metabolic PRs is maintained and increases with more completed cycles of ADIPEMCIS. Our 18-FLT-PET studies confirm that L-Arg depletion impacts tumor proliferation as seen in the preclinical studies and warrants further investigation as a novel antimetabolite strategy with antifolate drugs for cancer therapy. Clinical trial information: NCT02029690.