tbuckley/cabot-search huggingface dataset:
A phase I study to evaluate the safety and effectiveness of neoantigen-based personalized dendritic cell vaccine in patients with advanced solid tumors.
Authors: Jianhui WU, Daoning LIU, Liang Yan, Ang Lv, Xiuyun Tian, Xudong CHENG, Meng Fu, Hui Qiu, Bonan Liu, Qiao Liu, Chengpeng Li, Zhen Wang, Xiaopeng Wang, Chunyi Hao
Journal: Journal of Clinical Oncology (2021)

e14512 Background: Patients with solid tumor may get benefits from neoantigen-based cancer vaccines, which has showed some clinical efficacy data in clinical trials. This study was designed to evaluate the safety and efficacy of a neoantigen-based dendritic cell vaccine in patients with advanced solid tumors Methods: In this single arm study, patient-specific mutation-containing epitopes were detected from patient's tumor tissue. Tumor specimens were processed for whole transcriptome RNA sequencing, whole exome sequencing and HLA typing analysis. Total 10-20 immunogenic neoantigens for each patient were formulated and loaded into patient’s dendritic cells to manufacture the patient-specific anti-cancer vaccines. The patient was administered vaccine injections (Days 0, 14, 35, 56 and 98) into inguinal lymph nodes and intra-cutaneous. Peripheral blood was collected during the treatment (Days 14,15, 35, 36, 56, 57,77, 99 and 120) for safety evaluation and for assessment of the expansion of antigen-specific T cells in vivo. Patients were followed up until confirmed disease progression, withdrawal consent or adverse event intolerance. Results: Between 2019 and 2020, six patients received the neoantigen-based DC vaccine. The tumor types were laryngeal carcinoma, leiomyosarcoma, biliary tract carcinoma and hepatocellular carcinoma. All six enrolled patients had stage III or IV disease and had failed at least one line of systematic therapy at baseline. Preliminary data revealed that 6 pts (5 female and 1 male) with mean age of 44 (41-50) yrs. received ≥3 dose of DC vaccine. Doses ranged from 2×10 6 cells/ml to 10×10 6 cells/ml. All observed treatment related Adverse Events were Grade 1 or Grade 2. The most common (≥10%) drug-related adverse events were fatigue (15%), fever (15%), and elevated AST (20%). Five patients received at least one disease assessment post baseline visit. There were no tumor response. The patient with biliary tract carcinoma, laryngeal ca, leiomyosarcoma had SD status for 11 weeks, 30 weeks and 16 weeks respectively. Patients were assessed with the ELISPOT, which showed a CD8 + neoantigen-specific T-cells expansion was detected from each of the six patients’ peripheral blood after the fifth vaccine injection, which demonstrate the preliminary proof of concept for this personalized neoantigen-based dendritic cell vaccine. Conclusions: In this study, neoantigen-based dendritic cell vaccine has showed preliminary activity in advanced solid tumor patients with well-tolerated safety profile, which indicated the neoantigen-targeting DC vaccine has potential to be an effective treatment (with alteration of the immune cell milieu) in solid tumor patients.
Fucoidan-functionalized activated platelet-hitchhiking micelles simultaneously track tumor cells and remodel the immunosuppressive microenvironment for efficient metastatic cancer treatment
Authors: Rong Guo, Miao Deng, Xuan He, Mengmeng Li, Jiaxin Li, Penghui He, Houqin Liu, Man Li, Zhirong Zhang, Qin He
Journal: Acta Pharmaceutica Sinica B (2021)

Tumor metastasis is responsible for most mortality in cancer patients, and remains a challenge in clinical cancer treatment. Platelets can be recruited and activated by tumor cells, then adhere to circulating tumor cells (CTCs) and assist tumor cells extravasate in distant organs. Therefore, nanoparticles specially hitchhiking on activated platelets are considered to have excellent targeting ability for primary tumor, CTCs and metastasis in distant organs. However, the activated tumor-homing platelets will release transforming growth factor-β (TGF-β), which promotes tumor metastasis and forms immunosuppressive microenvironment. Therefore, a multitalent strategy is needed to balance the accurate tumor tracking and alleviate the immunosuppressive signals. In this study, a fucoidan-functionalized micelle (FD/DOX) was constructed, which could efficiently adhere to activated platelets through P-selectin. Compared with the micelle without P-selectin targeting effect, FD/DOX had increased distribution in both tumor tissue and metastasis niche, and exhibited excellent anti-tumor and anti-metastasis efficacy on 4T1 spontaneous metastasis model. In addition, due to the contribution of fucoidan, FD/DOX treatment was confirmed to inhibit the expression of TGF-β, thereby stimulating anti-tumor immune response and reversing the immunosuppressive microenvironment. The fucoidan-functionalized activated platelets-hitchhiking micelle was promising for the metastatic cancer treatment.
Expedited development and review pathways for novel oncology drugs.
Authors: Lisa Ambrosini Vadola, Ann Winter-Vann, Miriam Knoll, Robin Whitsell
Journal: Journal of Clinical Oncology (2021)

e13578 Background: Following approval of the Food and Drug Administration (FDA) Safety and Innovation Act in 2012, the FDA launched a 3-year plan to promote innovation, increase stakeholder involvement, secure the drug supply chain, and fund these endeavors by collecting user fees. The FDA created its fourth expedited pathway, Breakthrough Therapy Designation (BTD) to focus on the development and approval of therapies to treat serious and life-threatening conditions that lack adequate therapies. Our 2017 study (ASCO abstract #e18270) identified a trend of increased use of these approaches with oncology drugs, particularly the BTD, which was a nascent pathway at the time. We aimed to reexamine FDA pathway and approval trends in oncology interventions. Methods: We analyzed publicly available data on novel drug approvals by the FDA’s Center for Drug Evaluation and Research (CDER) from 2012-2020 and the 4 expedited pathways (BTD, Accelerated Approval, Fast Track Designation [FTD], and Priority Review). Results: Between 2012 and 2020, CDER approved 380 new chemical entities, including 101 oncology drugs. Due to data limitations, 3 novel oncology biologics (approved by the Center for Biologics Evaluation and Research) and 4 diagnostics were excluded from the analyses. Oncology drugs comprised a mean 27% (range 14-34%) of all approvals from 2012-2020, including 25% from 2012–2016 and 28% from 2017-2020. Of all approved oncology drugs from 2012-2020, 94% (range 82-100%) utilized at least one expedited pathway. Oncology approvals were more likely than non-oncology approvals to have used one or more expedited pathways. Use of these pathways for oncology approvals increased from 2012-2016 to 2017-2020: ≥2 (65% vs 78%) and ≥3 (35% vs 50%) pathways. BTD usage for oncology drugs increased from 35% in 2012-2016 to 57% in 2017-2020, though for 2012-2016, the time interval between awarding the (new) designation and the remainder of development activities must be considered. Presumably because BTD grants additional benefits over FTD, generally the use of FTD for oncology drugs has declined over time. The use of Priority Review and Accelerated Approval has remained the same. Despite the pandemic, for oncology and non-oncology drugs alike, approvals using pathways remained consistent between 2019 and 2020. Conclusions: Efficient FDA review plays an important role in oncology drug development. Since its inception in 2012, BTD has been adopted and expeditiously used, comprising more than half of all novel oncology drug approvals from 2017-2020. Our data show a gradual increase in approvals of drugs granted BTD, which, given the duration of drug development, likely reflects the time between the acceptance of the BTD request and remainder of the pre-submission development activities. As BTD was expressly developed to increase stakeholder interaction and prioritize innovation, the speed-to-adoption and use of this pathway among oncology interventions is promising.
The anti-cancer effect of statins in obese esophageal cancer patients undergoing esophagectomy.
Authors: Eihab N Abdelfatah, Moshim Kukar, Sarbajit Mukherjee, Adrienne Groman, Saikrishna S. Yendamuri
Journal: Journal of Clinical Oncology (2021)

e16012 Background: In addition to lowering lipid levels and treating atherosclerotic disease, statins have demonstrated anti-inflammatory and anti-tumor activity in various cancer types. We evaluate this effect in esophageal cancer patients undergoing esophagectomy. Methods: All patients undergoing esophagectomy for esophageal cancer at Roswell Park Comprehensive Cancer Center between March 2007 and December 2015 were included. The association between pre-surgery statin use with overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) was analyzed using Cox proportional hazards regression, with age, sex, American Society of Anesthesia (ASA) score, neoadjuvant therapy, surgical technique, tumor stage, histology, and grade considered in multivariable analyses. Survival analyses were independently performed for body mass index (BMI)-based patient subgroups. Results: 212 patients met inclusion criteria for this study. Median follow up period was 36 months. Estimated five-year RFS for the patient cohort overall was 55.7% and estimated five-year DSS was 53.9%. Estimated five-year OS was 45.4%. There was no significant association between statin use and outcomes of esophagectomy patients overall. However, in subgroup analysis analyzing patients by BMI category, there was a significant association between statin use and outcomes in patients with BMI ≥ 30 (n = 95 patients). Multivariate analysis in obese patients demonstrated an association of statins with improved OS (HR 0.52, p = 0.049), DSS (HR 0.46, p = 0.034) and RFS (HR 0.43, p = 0.036). The other variables significantly associated with outcome measures were stage ≥ 2 (OS HR 2.36, p = 0.010; RFS HR 2.50, p = 0.018; DSS HR 2.51, p = 0.011) and ASA score ≥ 3 (RFS HR 2.26, p = 0.037; DSS HR 2.33, p = 0.019). Conclusions: Statin use is associated with improved RFS, DSS and OS of obese patients undergoing esophagectomy for esophageal cancer. This novel finding suggests an interaction between the pathophysiologic state of obesity and the pleiotropic effects of statins. BMI could be explored as a potential biomarker for adjunctive statin use in future trials.[Table: see text]
Comprehensive molecular characterization of Chinese patients with intrahepatic and extrahepatic cholangiocarcinoma.
Authors: Bin Yi, Lianke Liu, Dejian Gu, Rongrong Chen, Xuefeng Xia, Xiaoqing Jiang
Journal: Journal of Clinical Oncology (2021)

e16128 Background: Cholangiocarcinoma (CCA) is a heterogeneous disease arising from a complex interaction between host-specific genetic background and multiple risk factors. Globally, CCA incidence rates exhibit geographical variation, with much higher incidence in parts of the Eastern world compared to the West. Therefore, understanding the molecular characteristics of Chinese CCA patients is helpful for individualized treatment of patients. Methods: We reviewed 397 Chinese cholangiocarcinoma patients, including 125 extrahepatic and 272 intrahepatic, with paired tumor-normal samples sequenced by a 1021 gene panel. Tumor mutational burden(TMB) was defined as the number of somatic non-synonymous mutations per megabase of the panel region. Results: The genomic profiling was analyzed and indicated that TP53 and KRAS were the most frequently mutated gene, which were detected in 47% and 27% samples. The common targets gene of FGFR2 and IDH1 were detected in 6% and 4% patients in our cohort. Meanwhile, the prevalence of gene mutated was compared between intrahepatic and extrahepatic cholangiocarcinoma. The TP53 mutation was more frequently prevalence in intrahepatic cholangiocarcinoma (51% vs 36%, p = 0.0048); and the FGFR2 fusion more detected in extrahepatic cholangiocarcinoma (4% vs 10%, p = 0.0214). The TMB was also analyzed in our study and ranged from 1 to 194 (median:5). No difference was found between intrahepatic and extrahepatic cholangiocarcinoma in TMB. Besides, the TP53 mutations showed significant association with higher TMB (p &lt; 0.0001), both intrahepatic and extrahepatic cholangiocarcinoma; and KRAS mutations showed significant association with higher TMB (p = 0.029) in intrahepatic cholangiocarcinoma. Interesting, KRAS mutations was also association with TMB in extrahepatic cholangiocarcinoma; The KRAS-mutated &amp; TP53-wildtype(wt) patients showed higher TMB than double-wt patients (5.5 vs 4, p = 0.048) and the only TP53-mutated patients showed higher TMB than double-mutated patients (8 vs 6, p = 0.047). Conclusions: In conclusion, the genomic profiling and molecular characterization were difference between intrahepatic and extrahepatic cholangiocarcinoma, which may helpful in clinical diagnosis and treatment.
Updated report of a phase II randomized trial of transoral surgical resection followed by low-dose or standard postoperative therapy in resectable p16+ locally advanced oropharynx cancer: A trial of the ECOG-ACRIN cancer research group (E3311).
Authors: Robert L. Ferris, Yael Flamand, Gregory S. Weinstein, Shuli Li, Harry Quon, Ranee Mehra, Joaquin J. Garcia, Jolie Ringash, Jan S. Lewin, Umamaheswar Duvvuri, Bert W. O'Malley, Enver Ozer, Giovana R. Thomas, Wayne Koch, Michael Elliot Kupferman, Richard Bryan Bell, Nabil F. Saba, Miriam Lango, Lynne I. Wagner, Barbara Burtness
Journal: Journal of Clinical Oncology (2021)

6010 Background: Definitive or postoperative chemoradiation (CRT) is highly curative for human papillomavirus-associated (HPV+) oropharynx cancer (OPC) but induces significant toxicity. As a potential deintensification strategy, we studied primary transoral surgery (TOS) and, in intermediate pathologic risk patients, reduced dose postoperative RT (PORT). Methods: E3311 is a phase II trial with randomization to reduced- or standard-dose PORT for resected stage III-IVa (AJCC7) intermediate pathologic risk HPV+ OPC, stratified by smoking history. Primary endpoints have been reported; we now present updated 3-year PFS and patient-reported outcomes (PRO), including head and neck-cancer specific quality of life (FACT-H&amp;N) and swallowing perception and performance (MDADI). Results: Of 519 enrolled patients, 495 underwent TOS. The primary oncologic endpoint was 2-year PFS for 50 Gy (Arm B) or 60Gy (Arm C). Among 360 eligible and treated patients (ETP), Arm A (observation, N = 38) enrolled 11%, Arms B (N = 100) or C (N = 109) randomized 58%, and Arm D (66Gy + weekly cisplatin, N = 113) enrolled 31%. With 35.1 months median follow-up, 3-year PFS Kaplan-Meier estimate is 96.9% (90% CI [91.9%, 100%]) for Arm A; 94.9% (90% CI [91.3%, 98.6%]) for Arm B; 93.5% (90% CI [89.4%, 97.9%]) for Arm C; and 90.7% (90% CI [86.2%, 95.4%]) for Arm D. Recurrences and death without recurrence were 4 and 1 in Arm B, and 5 and one in Arm C. Smokers ( &gt; 10 pack-years) did not have worse 3-year PFS in Arms B or C. Treatment arm distribution and outcome for ineligible patients who started adjuvant therapy mirrored the 360 ETP. A comparison combining arms B/C versus arm D in the proportion of patients stable/improved in FACT-H&amp;N total score, from baseline to 6 months post-treatment as a pre-specified endpoint, was 56% vs. 38% (p value = 0.011, one-sided Fisher’s exact test); however, underlying differences in treatment and risk may be confounding. An exploratory comparison between Arms B and C revealed improvement in FACT H&amp;N (63% in Arm B vs. 49% in Arm C had a stable/improved score, p-value = 0.056). Conclusions: Primary TOS and reduced PORT retained outstanding oncologic outcome at 35 months follow up, with favorable QOL and functional outcomes, in intermediate risk HPV+ OPC. Clinical trial information: NCT 01898494.
Case series on the safety of mRNA COVID19 vaccines in cancer patients undergoing treatment.
Authors: Faysal Haroun, Malak Alharbi, Alison Hong
Journal: Journal of Clinical Oncology (2021)

e14562 Background: Millions of vaccines have been administered since Emergency Use Authorization has been granted for two mRNA COVID-19 vaccines (mCV). The Center for Disease Control (CDC) and Prevention recommends that immunocompromised individuals with no contraindications to vaccines may receive an mCV. The CDC suggests that patients receiving cancer therapies should be consulted about the unknown vaccine safety profile and effectiveness. The American Society of Clinical Oncology recognizes that vaccine may reduce the risk of infection for individuals with cancer. Vaccine trials have not actively enrolled immunocompromised or patients on active cancer therapy; therefore, the potential side effects and efficacy of the mRNA vaccines in these individuals are unexplored. Per state guidelines, many patients with cancer undergoing treatment qualify for vaccination however current vaccine uptake in that population is unknown. Data in this specific high-risk population is needed to increase confidence in the vaccine. We explored adverse events (AE) to the mCV in a small cohort of patients undergoing cancer therapy. Methods: Our case series evaluated patients' tolerance to the voluntary but recommended 2 doses of the mCV while on chemotherapy (CX), checkpoint inhibitors (CPI) or tyrosine kinase inhibitors (TKI) at the George Washington University (GWU) Cancer Center in Washington DC. Patient chart review and phone interviews were conducted. Patients had independently signed up for the mCV at the GWU Hospital or through the DC Health Department. Patients were asked if they had experienced any of the commonly reported side effects listed by the CDC or others new symptoms receiving the vaccine. Results: 12 patients had voluntarily received the mCV, all patients were above the age of 65 with a mean age of 72 (66-85). ECOG performance status was 2 or above in 4 patients. 6 patients were receiving single agent CPI, 1 patient was on combination CX and CPI. 2 patients were on oral TKI for EGFR mutated lung cancer. 3 other patients were on combination CX with rituximab, ramucirumab or radiation. In the 2 patients on daily TKI, treatment was not interrupted for the mCV. In the 10 other patients, all but one patient received the mCV at least one week after the last therapy. Both mCV were tolerated without any life-threatening AE or hospitalization. Pain and swelling at the vaccine site were the most common local AE and reported in 7 patients. 6 patients reported systemic AE most commonly myalgia and headaches. Conclusions: This exploratory analysis in 12 patients with cancer undergoing treatment did not uncover any additional SE signals. Larger studies are needed to evaluate AE and efficacy and to guide recommendations for COVID19 vaccination in this patient population.
Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer
Authors: Katelyn T. Byrne, Courtney B. Betts, Rosemarie Mick, Shamilene Sivagnanam, David L. Bajor, Daniel A. Laheru, E. Gabriela Chiorean, Mark H. O'Hara, Shannon M. Liudahl, Craig Newcomb, Cécile Alanio, Ana P. Ferreira, Byung S. Park, Takuya Ohtani, Austin P. Huffman, Sara A. Väyrynen, Andressa Dias Costa, Judith C. Kaiser, Andreanne M. Lacroix, Colleen Redlinger, Martin Stern, Jonathan A. Nowak, E. John Wherry, Martin A. Cheever, Brian M. Wolpin, Emma E. Furth, Elizabeth M. Jaffee, Lisa M. Coussens, Robert H. Vonderheide
Journal: Clinical Cancer Research (2021)

CD40 activation is a novel clinical opportunity for cancer immunotherapy. Despite numerous active clinical trials with agonistic CD40 monoclonal antibodies (mAb), biological effects and treatment-related modulation of the tumor microenvironment (TME) remain poorly understood.
Analysis of disseminated tumor cells (DTCs) in primary breast cancer patients with various molecular subtypes.
Authors: Ivonne Nel, Laura Weydandt, Annekathrin Höhn, Bahriye Aktas
Journal: Journal of Clinical Oncology (2021)

e13000 Background: Despite successful treatment of the primary tumor, recurrence occurs in about 30% of breast cancer patients. One reason might be hematogenous spread during early disease stages. Disseminated breast cancer cells (DTCs) preferentially migrate into the bone marrow (BM) at early stages of the disease. Due to low proliferation, DTCs are persistent against systemic chemotherapy and might cause metastatic relapse at a later stage. Methods: BM aspirates were collected from the anterior iliac crest of patients with primary mamma carcinoma during surgery. After density gradient centrifugation cell suspensions were transferred onto glass slides and subjected to immunocytochemical staining against pan-cytokeratin. DTCs were visualized in pink using alkaline phosphatase and short counterstaining with hematoxylin which colored the nuclei light blue. DTCs were semi-automatically detected and enumerated using the Aperio Versa microscope based scanning system with a rare events algorithm that was trained to identify DTC candidates according to color, shape, intensity and size. As a positive control with each run, we used reference slides with a mix of bone marrow cells and a defined number of HCT116 cells. Results: Between February 2019 and December 2020 BM aspirates from 158 primary breast cancer patients were collected. Per patient about 4 million BM cells were analyzed. DTC detection revealed a positivity rate of 29% (46 patients). Molecular subtype analysis of DTC positive patients showed that 37% of the primary tumors (17 patients) were luminal A and 37% (17 patients) luminal B. In 9% of the cases (4 patients), tumors were HER2 enriched and 15% (8 patients) were triple negative. DTC count indicated that the majority of luminal B patients had 11-20 DTCs whereas luminal A patients tended to have lower DTC quantities varying between 1 and 10 DTCs. Conclusions: DTCs may serve as independent prognostic markers. Follow-Up data might reveal whether DTC quantification and molecular subtypes at primary diagnosis can be used to stratify patients at elevated risk for recurrence.