tbuckley/cabot-search huggingface dataset:
A cell-based platform to potentiate oncolytic virus: Potential approach for cancer therapies.
Authors: Duong Nguyen, Alberto Gomez, Ashley Alamillo, Forrest Neuharth, Ivelina Minev, Thomas Herrmann, Barbara Haertl, Laura Edith Schneider, Boris Minev, Dobrin Draganov, Antonio F. Santidrian
Journal: Journal of Clinical Oncology (2020)

21 Background: Oncolytic virotherapy has been pursued by multiple companies and institutions with few candidates reaching the clinic and demonstrating limited efficacy. The therapeutic potential of oncolytic viruses can be severely restricted by innate and adaptive immune barriers. To overcome this obstacle, we load and protect tumor selective CAL1 oncolytic vaccinia virus into adipose-derived stem cells (AD-MSC) to generate a new therapeutic agent called SNV1(SuperNova1). Methods: SNV1s were generated by incubating AD-MSC with CAL1 virus. SNV1 was analyzed for its ability to kill cancer cell lines and protect virus in the presence of active neutralizing antibodies and complement. In animals, SNV1 was intratumorally injected in various xenograft and syngeneic models. Viral biodistribution was also evaluated by PCR. Immune infiltration were analyzed using flow cytometry. Results: Compared to the naked virus, SNV1 showed improved protection against the humoral barriers and efficient eradication of various human cancer cell lines in vitro. Intratumoral SNV1 treatment showed statistically significant and potentiated tumor growth inhibition compared to control or CAL1 naked virus treatment in all tested models (prostate, breast, melanoma, colon, and prostate cancers). Importantly, local administration of SNV1 induced systemic therapeutic effects. Five days after SNV1 administration, tumor infiltrating lymphocytes (TILs) from both treated and untreated tumors showed increased CD4 and CD8 T-cell populations. As well as decreased frequency of Tregs, and improved effector to Treg ratios, which was associated with inhibition of tumor growth at the treated tumor site and also at distant untreated sites. Ongoing and persistent virus infection could be detected in the treated tumor as late as 15 days after administration. Conclusions: This study demonstrates the ability of our cell-based platform to protect and potentiate oncolytic vaccinia virus by circumventing the innate and adaptive immune barriers, resulting in enhanced oncolytic virotherapy. These findings provide fundamental rationale for the development of cell-based platforms to maximize the therapeutic potential of various oncolytic viruses.
Adolescent obesity and midlife cancer risk: a population-based cohort study of 2·3 million adolescents in Israel
Authors: Ariel Furer, Arnon Afek, Adir Sommer, Lital Keinan-Boker, Estela Derazne, Zohar Levi, Dorit Tzur, Shmuel Tiosano, Avi Shina, Yuval Glick, Jeremy D Kark, Amir Tirosh, Gilad Twig
Journal: The Lancet Diabetes & Endocrinology (2020)
Prognosis of patients developing immune-related adverse events with immune checkpoint inhibitors in melanoma influenced by the ability to resume therapy.
Authors: Jung Min Song, Tapas Ranjan Behera, Kathryn Demski, Ann Yurco, Pradnya Dinkar Patil, Pauline Funchain
Journal: Journal of Clinical Oncology (2020)

61 Background: Immune checkpoint inhibitors (ICPis) have improved survival in melanoma patients, however their use is associated with 5-60% patients experiencing severe immune related adverse events (irAEs). Severe irAEs may affect survival benefit imparted by ICPis. Objective: We aimed to analyze disease outcomes with resumption of immunotherapy as compared to non-resumption of immunotherapy in patients with severe irAEs (Grade 3/4 in CTCAE v5.0). Methods: Patients with melanoma being treated with ICPis who developed severe irAEs were discussed in an institutional irAE tumor board (TB). We analyzed all patients discussed in TB from September 2017 to September 2019 for cancer outcome of withholding versus resuming immunotherapy in the face of severe irAEs. Results: Out of 26 total patients with melanoma discussed in TB, 23 had severe irAE. Colitis was the most common irAE 9/23 (39.1%) followed by 2/23 (8.7%) of pneumonitis and hepatitis each. ICPi was resumed in 8 patients (resume group) (median age 53, range 42-67) and withheld in 15 patients (non-resume group) (median age 57, range 42-91). In the resume group all 8 patients (100%) are alive, of which 2/8 (25%) had disease progression (median follow up 106.5wk, range 35wk-131wk); whereas, in the non-resume group 9/15 (60%) progressed, of which 6/15 (40%) died (median follow up 91wk, range 3wk-197wk). Conclusions: Our data suggest that the ability to resume ICPi after an episode of severe irAE is associated with better prognosis in terms of disease progression and survival. Immunotherapy being the mainstay of the management in metastatic melanoma, inability to resume therapy is associated with worse prognosis. Timely management of irAEs should be prioritized in order to resume treatment.
Neoadjuvant gemcitabine and nab-paclitaxel followed by concurrent capecitabine/radiation in borderline resectable (BR) pancreatic cancer: A single-institution experience.
Authors: Niraj K. Gupta, Kirpal Singh, Murad Aburajab, Vinay Mathavan, Mazen Al-Satie, Timothy Glass, Christopher A. Leagre, Michael Rowe, Thomas Tigges, Robert H. Liebross, Chad Davis, Sweta Tandra, Vas Tumati, Jianmin Tian, Brandon Martinez, Joshua Dowell, Kristen Kay Schmidt, Vincent Flanders
Journal: Journal of Clinical Oncology (2020)

718 Background: Neo-adjuvant therapy is becoming a preferred approach in the management of BR pancreatic cancer patients. There is no consensus on an ideal treatment regimen. We report our experience with a combination of nab-Paclitaxel/Gemcitabine followed by concurrent Capecitabine and radiation treatments in BR pancreatic cancer patients. Methods: A prospectively maintained database of patients with BR pancreatic cancer undergoing neo-adjuvant treatments at our cancer center between 01/2013- 11/2017 was reviewed. Patients were treated with Gemcitabine(1gm/m2) and nab-paclitaxel (125mg/m2) given on D1-8-15 every 28 days. Pts. were re-assessed after two cycles and the responding pts received two additional cycles. Pts. who continued to respond after four cycles were treated with capecitabine (825mg/m2) and radiation treatments(50.4Gy). Results: A total of 32 patients with PS 0/1 were treated. Median age was 59 yrs (42-76), 19 Males and 13 females. After 2 cycles of Gem/nab-paclitaxel, none of the pts. had progressive disease. Thirty patients (93%) were able to complete all four cycles of Gem/nab-paclitaxel. Twenty nine (90%) received capecitabine and radiation treatments. Imaging to assess response was done 4 weeks after completing radiation and the results were were; 2 CR, 11 PR, 14 SD, 2 PD. Surgery was performed 6-8 weeks after completing radiation. Twenty six (81%) underwent planned resection, 2 had PD, 3 declined surgery and 1 had significant decline in PS. Twenty two out of Twenty six patients undergoing surgery had a R0 resection (80%). Grade-III/IV toxicities with the neo-adjuvant treatments were seen in 41% and 7 % of the pts., respectively. No thirty day post-op mortality, pancreatic leaks or re-operations were observed. The median PFS among all patients was 11.7 months, 2 yr OS 49% and median OS was 27.6 months, compared to 23.4 months, 65% and median OS not reached, in patients who underwent surgical resection. Conclusions: Nab-Paclitaxel and Gemcitabine followed by Capecitabine and radiation is an effective neo-adjuvant treatment strategy with acceptable toxicity-profile for patients with BR pancreatic cancer.
Phase II study of the combination of abemaciclib and pembrolizumab in locally advanced unresectable or metastatic gastroesophageal adenocarcinoma: Big Ten Cancer Research Consortium BTCRC-GI18-149.
Authors: Nataliya Volodymyrivna Uboha, Jens C. Eickhoff, Chandrikha Chandrasekharan, Shadia Ibrahim Jalal, Al Bowen Benson, Dustin A. Deming, Stephen Lindemann, Howard S. Hochster
Journal: Journal of Clinical Oncology (2020)

TPS461 Background: Metastatic gastroesophageal adenocarcinoma (GEA) has poor prognosis. Overall survival (OS) remains around 12 months (mo) with current therapies. Pembrolizumab is approved for advanced GEA that has progressed on at least 2 prior lines of systemic therapy. However, the majority of patients progress on this treatment, and less than 15% of patients experience objective response (OR). This study will evaluate efficacy of pembrolizumab in combination with cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, abemaciclib, in patients with advanced GEA. Preclinical studies have demonstrated that CDK4/6 inhibitors can increase anti-tumor immunity and can synergize with immune checkpoint inhibitors. Based on these data, we hypothesize that abemaciclib will augment response to pembrolizumab in GEA. Methods: This is a multi-institutional, single arm, open label, phase II study of abemaciclib in combination with pembrolizumab in patients with advanced GEA who have progressed or were intolerant to at least 2 prior lines of therapy. Patients previously treated with immune checkpoint inhibitors or with microsattelite unstable tumors will be excluded. Treatments will be given on a 21 day cycle until disease progression or intolerable toxicities. Pembrolizumab, 200 mg intravenously, will be given on day 1, and abemaciclib, 150 mg, will be taken orally twice a day on days 1-21. Primary endpoint is progression free survival (PFS). Secondary endpoints include PFS rate at 6 mo, disease control rate, OS and OR rate. Correlative endpoints will examine relationship between PDL1 status, genomic signature and treatment response. Saliva samples will be collected for microbiome analysis. Archival tumor tissue and blood samples will be banked for future studies. A total of 31 evaluable subjects will be enrolled to detect an anticipated increase in the median PFS from 2 months (null hypothesis) to 4 months with 80% power at the one-sided 0.05 significance level. The trial is open to enrollment. Clinical trial information: NCT03997448.
Cost-effectiveness analysis of pressurized intraperitoneal aerosol chemotherapy (PIPAC C/D) in patients with gastric cancer and peritoneal metastasis.
Authors: Mehdi Javanbakht, Mohsen Yaghoubi, Atefeh Mashayekhi, Philipp Horvath, Alfred Koenigsrainer, Marc A. Reymond
Journal: Journal of Clinical Oncology (2020)

387 Background: The efficacy of systemic chemotherapy is still highly unsatisfactory for patients with gastric cancer and peritoneal metastases (PM). The aim of this study was to assess the costs effectiveness of pressurized intraperitoneal aerosol chemotherapy with low-dose cisplatin and doxorubicin (PIPAC C/D) for advanced gastric cancer. Methods: We developed a state transition Markov Model to estimate the costs and effectiveness of the use of PIPAC C/D versus palliative chemotherapy. Intervention was assessed in two different levels including upfront therapy (PIPAC C/D plus XELOX chemotherapy versus first-line chemotherapy alone) and second line therapy (PIPAC C/D only versus second-line chemotherapy (ramucirumab monotherapy)). Data from multiple sources such as published literature and UK-based databases were used to inform the economic model. Deterministic and probabilistic sensitivity analyses were conducted to explore the impact of key parameter variation on the results. Results: For the upfront therapy the estimated total costs in the intervention and comparator arms were £33,587(SD: £2,394) and £17,477 (£927) respectively. PIPAC C/D plus XELOX led to an increase of 0.56 in QALYs. Estimated incremental cost per quality adjusted life years (QALYs) was £28,879. Result from probabilistic sensitivity analysis showed that PIPAC C/D plus XELOX is cost effective in more than 50% of Monte Carlo simulations at £30,000 threshold. For the second-line therapy, the total costs for PIPAC C/D was £15,985 (£1,391) and for the second-line palliative chemotherapy was £36,319 (£3,673). PIPAC C/D led to an increase of 0.21 in QALYs and £20,222 reduction in costs, meaning the intervention is dominant strategy in the second line therapy as it is less costly and more effective. Conclusions: The cost effectiveness results for the upfront therapy indicate that PIPAC C/D plus chemotherapy intervention is more costly and more effective and a cost effective intervention. PIPAC C/D only intervention has the potential to reduce costs and improve clinical outcomes for patients with advanced gastric cancer with peritoneal metastasis and therefore a dominant strategy.
The impact of precision medicine on real-world clinical care: A single institution retrospective study.
Authors: Rajvi Patel, Ryann Quinn, Xinhua Zhu
Journal: Journal of Clinical Oncology (2020)

806 Background: In Oncology, precision medicine (PM) utilizes next generation sequencing (NGS) to analyze actionable mutations (AMs) in tumors. It is commonly done for patients (pts) with advanced cancer resistant to standard treatment. FoundationOne-CDx (F1CDx) is the only FDA approved test that utilizes NGS for genomic profiling of tumors. It is necessary to report the real-world data and its impact on clinical care. Our aim was to identify pts at our institution with AMs on F1CDx testing who received non-FDA approved targeted treatments (TT) and assess objective response rate (ORR), progression free survival (PFS), and overall survival (OS). Methods: Retrospective study of pts at our institution from 2012 and 2018 that received non-FDA approved TT based on F1CDx testing. Descriptive statistics were used to describe the demographic and clinical characteristics. ORR based on interval scans at 3 (ORR1), 6 (ORR2), and 12 (ORR3) months (mos) were estimated using standard methods for proportions. Kaplan-Meier method was used to estimate PFS and OS. Results: Of 1000 pts, 652 had tumors harboring AMs, however, only 38 pts met study criteria of receiving non-FDA approved TT with sufficient follow up time. Median age was 57.7 years and 92% of pts received at least one prior line of therapy. Majority of the pts (58%) had gastrointestinal tumors. PDL-1, microsatellite instability, and tumor mutational burden constituted 50% of AMs and 45% of pts received TT with immunotherapy. 14/38 pts had ORR1, 12/13 pts had ORR2, and 6/7 pts had ORR3. PFS was estimated to be 2.73 mos (95% CI: 2.33 to 5.39) and OS was 9.93 mos (95% CI: 4.47 to 33.68). Conclusions: The majority of pts had progression within 3 mos of initiating TT indicating a PM approach with non-FDA approved TT may not be an effective strategy. However, a minority of pts (4 with colorectal and 1 with pancreatic cancer), derived significant benefit in achieving sustained partial response and one pt with complete response at 3 years. Although genomic profiling of tumors may be a step in the right direction, we need better and more cost effective strategies to identify pts who will truly benefit from a PM approach. More PM trials are needed to establish the standard of care to guide real-world practice.
Real-world data on treatment patterns of advanced CRC in third-line and beyond.
Authors: William A. Flood, Vlad Kozlovsky, Neil Margolis, Sandeep K. Reddy
Journal: Journal of Clinical Oncology (2020)

56 Background: NCCN guidelines state “regorafenib (Stivarga) [REG], and Trifluridine+Tipiracil (Lonsurf) [LON] are treatment options for patients who have progressed through all available regimens”. Available clinical trial data has not established whether recycling of prior regimens (oxaliplatin/irinotecan/5FU) with exchange of biologics (bevacizumab, ziv-aflibercept, cetuximab, panitumumab) is superior to changing class of therapy with oral well tolerated agents such as REG and LON. Methods: Data from a pre-authorization platform used by multiple commercial insurance companies in the US (Eviti) was analyzed. 6325 treatment plans of advanced CRC patients were evaluated. Analysis for request for use of REG and LON was limited to third-line and later of therapy in patients with a diagnosis of advanced CRC patients. Results: Of 394 treatment plans beyond second-line of therapy, REG was preferred over LON (239 v 155). Excluding growth factors, anti-emetics, and leucovorin, REG and LON were the 9th and 13th most frequently requested drugs in this clinical setting. Irinotecan was the most commonly requested drug in this setting at &gt;10x the frequency of REG. Ramucirumab was requested more often than REG, and Pembrolizumab, Nivolumab, and Ziv-aflibercept were more requested than LON. HEOR models that included expected supportive care drugs and medication complication management fees estimated the cost of REG at $62,515 per patient versus LON at $26,596 with similar duration of therapy. Conclusions: Therapeutic preferences exist in third-line and later treatment of advanced CRC patients which cannot be fully explained by clinical trial outcome differences, HEOR cost differences, or NCCN guideline preferences. Recycling of chemotherapy and biologics in the late line setting is common and occurs more frequently than switching to a drug regimen with an alternative mechanism of action.
Phase I study of a new concept cancer vaccine composed artificial intelligence (AI)-designed shared-antigen peptides plus combined synergistically activating antigen-specific CTL reaction (CYT001) in patients with advanced hepatocellular carcinoma (CRESCENT 1).
Authors: Sadahisa Ogasawara, Hiroaki Kanzaki, Keisuke Koroki, Kengo Kanayama, Susumu Maruta, Kazufumi Kobayashi, Souichiro Kiyono, Masato Nakamura, Naoya Kanogawa, Takayuki Kondo, Eiichiro Suzuki, Yoshihiko Ooka, Shingo Nakamoto, Akinobu Tawada, Tetsuhiro Chiba, Makoto Arai, Hiroyuki Nakada, Nobuko Yamaguchi, Hideki Hanaoka, Naoya Kato
Journal: Journal of Clinical Oncology (2020)

TPS595 Background: CYT001 (CYTLIMIC Inc.) is a novel cancer vaccine involving artificial intelligence (AI)-designed shared-antigen peptides and optimal combined adjuvants that boost the cancer-immunity cycle. The two multi-HLA reactive peptides heat shock protein 70 (HSP70) and glypican 3 (GPC3) were screened by an AI-based prediction system according to the proteome, mRNA, and histopathology data fromhuman samples. These immunogenic peptides were confirmed to show cross-reactivity to HLA-A 24:02, 02:01, and 02:06. Poly-ICLC (Oncovir Inc.) binds to Toll-like receptor 3 (TLR3) and melanoma differentiation antigen 5 (MDA5) on antigen-presenting cells (APCs)and activates APCs. LAG-3Ig (Immutep Inc.) binds to the major histocompatibility complex (MHC) class II molecules of APCs and activates APCs. Both poly-ICLC and LAG-3Ig synergistically activate antigen-specific CTL reactions as effective combination adjuvants. The present study aims to evaluate the safety and tolerability of CYT001 (mixture of HSP70 peptide [2.0 mg], GPC3 peptide [2.0 mg], poly-ICLC [1.0 mg], and LAG-3Ig [1.4 mg]) in patients with advanced hepatocellular carcinoma (HCC). Methods: This is a single-center, phase 1, open-label, single-arm, investigator-initiated clinical trial of CYT001 for advanced HCC patients with no eligible standard systemic therapy, Child–Pugh A liver disease, and HLA-A 24:02, 02:01, or 02:06. Enrolled patients will receive CYT001 as a subcutaneous injection on days 1, 8, 15, and 21 in the 1st and 2nd cycles, days 1 and 15 in the 3rd and 4th cycles, and day 1 in the 5th cycle or later of 28-day cycles. The primary endpoint is dose-limiting toxicity, and the secondary endpoints are safety and the response rate. The transition of the CTL reactions of both the HSP70 and GPC3 peptides will be evaluated using blood samples of the subjects. Exploratory analyses include investigation of candidate biomarkers for treatment efficacy using liver tumor biopsy samples (baseline and after the 1st cycle) and blood samples (baseline and every days of administration). Clinical trial information: jRCT2031190072.
Association between financial links to indoor tanning industry and conclusions of published studies on indoor tanning: systematic review
Authors: Lola Adekunle, Rebecca Chen, Lily Morrison, Meghan Halley, Victor Eng, Yogi Hendlin, Mackenzie R Wehner, Mary-Margaret Chren, Eleni Linos
Journal: BMJ (2020)

Abstract Objective To assess whether an association exists between financial links to the indoor tanning industry and conclusions of indoor tanning literature. Design Systematic review. Data sources PubMed, Embase, and Web of Science, up to 15 February 2019. Study selection criteria Articles discussing indoor tanning and health were eligible for inclusion, with no article type restrictions (original research, systematic reviews, review articles, case reports, editorials, commentaries, and letters were all eligible). Basic science studies, articles describing only indoor tanning prevalence, non-English articles, and articles without full text available were excluded. Results 691 articles were included in analysis, including empiric articles (eg, original articles or systematic reviews) (357/691; 51.7%) and non-empiric articles letters (eg, commentaries, letters, or editorials) (334/691; 48.3%). Overall, 7.2% (50/691) of articles had financial links to the indoor tanning industry; 10.7% (74/691) articles favored indoor tanning, 3.9% (27/691) were neutral, and 85.4% (590/691) were critical of indoor tanning. Among the articles without industry funding, 4.4% (27/620) favored indoor tanning, 3.5% (22/620) were neutral, and 92.1% (571/620) were critical of indoor tanning. Among the articles with financial links to the indoor tanning industry, 78% (39/50) favored indoor tanning, 10% (5/50) were neutral, and 12% (6/50) were critical of indoor tanning. Support from the indoor tanning industry was significantly associated with favoring indoor tanning (risk ratio 14.3, 95% confidence interval 10.0 to 20.4). Conclusions Although most articles in the indoor tanning literature are independent of industry funding, articles with financial links to the indoor tanning industry are more likely to favor indoor tanning. Public health practitioners and researchers need to be aware of and account for industry funding when interpreting the evidence related to indoor tanning. Systematic review registration PROSPERO CRD42019123617.