bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced antitumor effect and lower viral reactivation with high doses of ex vivo expanded NK cells administered after haploidentical transplantation.
Authors: Ciurea Stefan O. , Saliba Rima , Soebbing Doris , Rondon Gabriela , Cao Kai , Ahmed Sairah , Olson Amanda Leigh , Bashir Qaiser , Kaur Indreshpal , Shpall Elizabeth J. , Lee Dean Anthony , Champlin Richard E. 
Published: July 2019

74 Background: NK cells have potent antitumor and antiviral effects. We hypothesized that multiple infusions of high doses of mb-IL21 ex vivo expanded NK cells administered peri-transplant will enhance graft-versus-leukemia effect and decrease viral reactivation. Methods: In the phase 1 dose escalation study patients received NK cells starting at 1x105 to 1x108/Kg/dose (N = 13). No dose limiting toxicities were observed. In the phase 2 study, 12 patients with myeloid malignancies received mbIL-21 ex vivo expanded NK cells at dose 1x108NK cells/kg with a K562 feeder cell system and with 41BB. NK cells were generated from peripheral blood mononuclear cells of the same donor and infused fresh on day -2, and cryopreserved on day +7 and +28. Conditioning regimen consisted of melphalan, fludarabine and TBI. All patients had bone marrow graft. Here we report updated results of all patients treated to date on this study. Results: Twenty-five patients (18 AML/MDS and 7 CML) were treated to date. The median age was 45 years, the median follow-up of survivors was 28 months. 16/18 AML/MDS patients had high-risk disease. No adverse effects occurred. Engraftment was achieved in all 24 evaluable patients after a median of 19 days. The cumulative incidence (CI) of grade 2 aGVHD was 38% at day 100. No chronic GVHD was observed. The CI of TRM was 21% at 2 years. The CI of relapse at 1 year was 8%. The 2-years PFS was 66%. Ten patients reactivated CMV. Immunologic reconstitution of T cell subsets showed a 5.7 fold higher number of NK cells on day 28 in patients who received highest NK cell doses vs. others. A matched-pair analysis done with an independent CIBMTR cohort of patients who received either MAC (N = 61) or RIC (N = 57), showed a significantly improvement in relapse rate and PFS in favor of patients treated on trial. Conclusions: Administration of higher doses of NK cells was associated with higher NK cell numbers early post-transplant, suggesting that a dose-dependent effect could be achieved. A low relapse rate and lower viral reactivation post-transplant continues to be seen, suggesting that NK cells exert both anti-tumor and antiviral effects in this setting. Clinical trial information: NCT01904136.
Managing immune-related adverse events (irAEs): A new educational resource for health care professionals (HCPs) and patients.
Authors: Wood Laura S. , Hoffner Brianna , Rubin Krista M. , Davies Marianne , Tushla Lisa A. , Guild Valerie , Guild Samantha R. 
Published: July 2019

75 Background: Immune checkpoint inhibitors (ICIs) have changed treatment options for many cancer patients. Educating HCPs, patients, and caregivers is crucial to early identification of irAEs, ensuring prompt intervention and improved outcomes. Resources for oncology HCPs are scattered, including published articles, websites, and pharmaceutical materials. These resources are restricted to information from the package insert and limited in the scope of guidance provided. Methods: Melanoma advance practice providers (APPs) collaborated with the AIM at Melanoma Foundation and Terranova Medica in 2016 to create the Melanoma Nurse Initiative, featuring educational information regarding immunotherapy and irAE management. Based on website success (>9200 professional interactions), learner survey data, and continued expansion of agents and indications, the need for a more expansive resource was identified. Results: AIM With Immunotherapy ( www.aimwithimmunotherapy.org/ ) launched in October 2018. Resources were developed by APPs with extensive experience with immunotherapy, education, and irAE management. Care Step Pathways provide comprehensive information on assessment, toxicity grading, and management. The HCP Toolkits include printable pages on drug information, side effect management, clinical pearls, and resources. Patient Action Plans, individualizable for each patient, include many detailed irAE information sheets. Videos for both HCPs and patients as well as a community Q/A panel provide additional multimedia, interactive resources. Learner surveys are planned to gauge how the content is used in the clinic setting and remaining unmet educational needs. Conclusions: Knowledge regarding immunotherapy, irAEs, and management of toxicities unique to immunotherapy is critical to maximizing clinical outcomes and quality of life for patients and their caregivers. AIM With Immunotherapy is a new website developed by expert oncology practitioners that provides comprehensive non-branded HCP resources and printable information to facilitate effective education of patients receiving immunotherapy.
Immune-related adverse event (irAE) education, self-efficacy, and potential irAE experiences in patients treated with immunotherapy for non-small cell lung cancer (NSCLC).
Authors: Mujumdar Urvi , Wang Huifen , Lawler Elizabeth , Lanzarini Victoria , Lowe Maria , Trunova Nataliya , Klein Alyssa B. , Emmas Cathy 
Published: July 2019

76 Background: Immunotherapy presents new challenges for effective patient engagement to ensure that irAEs are reported and treated appropriately. This study directly assesses how NSCLC patients in an online community perceived their irAE education and experience of potential irAEs. Methods: PatientsLikeMe is an online community for patients to track and share their experiences with the goal of improving health outcomes across all conditions. For this study, US residents ≥ 18, with self-reported immunotherapy treatment for NSCLC were invited to a baseline survey at enrollment and follow-up survey after 3 months (Dec 2017-Aug 2018). Quantitative and qualitative analyses were performed. Results: Respondents (N = 72) were female (69%), white (94%), and mean age of 64.3 (SD 9.3). Current immunotherapy use was reported by 60 (83%) patients and prior use by 12. Most (66 [92%]) reported that a healthcare provider (HCP) shared information about irAEs before they started treatment and 47 (71%) sought additional information. 43 (60%) reported experiencing a potential irAE while on treatment, 34 (79%) of whom indicated reporting this to a HCP. Free-text responses revealed a need for more clarity on side effects and severity, and that lapses in patient-provider communication sometimes occurred. The 3-month follow-up survey was completed by 39/72 patients; 28 (72%) remained on immunotherapy, and 8 (21%) had stopped since baseline. Of the 20 patients (51%) who reported experiencing a potential irAE in the past 3 months, 15 had also reported this at baseline, and 13 reported this to a HCP. Free-text responses revealed that many patients opted to wait until the next scheduled appointment to report irAEs or they self-managed minor side effects. Conclusions: Patients reported satisfaction with information received and responded appropriately to potential irAEs, but also suggested a need to improve information and communication with care teams. As patients become more accustomed to their treatment, there may be changes in reporting of irAEs. As this data is from a self-selected convenience sample of patients, results may be limited in generalizability.
Prognostic and predictive factors associated with ipilimumab related adverse events: A retrospective analysis of 11 NCI sponsored ipilimumab phase I clinical trials.
Authors: Chauhan Aman , Kabir Tanvir , Wu Jianrong , Wei Jing , Kunos Charles 
Published: July 2019

86 Background: We review factors affecting ipilimumab (ipi) associated toxicity in various NCI sponsored phase I clinical trials. Methods: NCI database for NCI sponsored phase I clinical trials evaluating ipilimumab was queried for adverse effects, radiological response data, lymphocyte counts, LDH, albumin, ECOG performance status, duration of treatment and diagnosis. Only treatment related AEs were analyzed. Events repeating across consecutive cycles were treated as a single event. Duration of treatment was calculated starting from cycle 1 day 1 of the treatment. IRB approval from NCI was obtained prior to the study. Results: Data from 373 patients from 11 phase I ipilimumab clinical trials were available for analysis. Median age of the study cohort was 55 years. 68%(n = 235) were males. Number of grade 3 and 4 AEs were associated with better radiological response. Mean grade 3 and 4 AEs in CR+PR cohort was 1.167 vs 0.645 in non-responder cohort (p = 0.001). No significant differences in low or high grade AEs were noticed in study cohorts differentiated based on ECOG PS (0 vs 1/2). ECOG PS 3/4 were not included in clinical trials. Pretreatment lymphocyte count, LDH or albumin was not predictive of increased ipilimumab associated toxicity. Ipilumumab associated grade 3 and 4 toxicity was directly associated with the number of concurrently used study agents. Mean grade 3 and 4 AEs were as follows in following cohorts: ipi alone; 0.631 vs ipi+ 1 drug; 0.877 vs ipi+ 2 drugs; 1.408 (p < 0.0136). Number of low grade (grade 1 and 2) toxicity was associated with duration of treatment. r = 0.456 (p < 0.0001). Number of high grade (grade 3 and 4) toxicity was not associated with duration of treatment with ipilimumab. r = 0.032 (p = 0.546). Conclusions: Ipilimumab associated grade 3 and 4 toxicity predicts response to therapy and is associated with higher CR/PR. ECOG PS, pretreatment lymphocyte count, LDH and albumin levels are not associated with ipilimumab toxicity. Lastly, addition of antitumor agents to ipilimumab has potential to cause a significant increase in serious AE’s.
T-cell lymphoma secondary to checkpoint inhibitor (CPI) used for other malignancies.
Authors: Anand Kartik , Ensor Joe , Pandita Shruti , Pingali Sai Ravi , Pant Shubham , Yee Cassian , Duvic Madeleine , Pandita Tej , Torres-Cabala Carlos A. , Miranda Roberto N. , Zu Youli , Iyer Swaminathan Padmanabhan 
Published: July 2019

88 Background: Wartewig et al. (Nature 2017) proved in a preclinical mouse model that anti-PD1 therapy could cause T-cell lymphoma. T-cell lymphoma as an adverse event of CPIs has never been reported. A 75-year-old male with h/o urothelial carcinoma presented with lung metastasis of adenocarcinoma of unknown primary that showed PDL1 staining 5% of cells. Patient was treated with carboplatin & paclitaxel. For progressive disease, the patient received Pembrolizumab. After 4 cycles of CPI he developed lymphocytosis and lymphadenopathy and diagnosed with peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), with bone marrow (BM) involvement. Patient died before receiving any treatment for lymphoma. We hypothesized that CPI caused clonal expansion of T cells. Methods: We performed T-cell receptor (TCR) sequencing by Immunoseq assay in biopsy specimens. We queried FDA Adverse Events Reporting System (FAERS) and VigiBase databases for T-cell lymphoma/leukemia, PTCL, NOS, Mycosis Fungoides, Anaplastic Large & Cutaneous T-cell Lymphoma as an adverse event (AE) secondary to nivolumab, pembrolizumab or ipilimumab. Results: Through TCR sequencing we identified single clonal expansion before PD1 therapy in lung (0.008%) to 11% in bone marrow and 40% in lymph node (post treatment samples). Additional targeted exome sequencing of the lymphoma revealed a TET2 mutation. We conclude that anti-PD1 caused clonal expansion of the T cells harboring TET2 mutation leading to T-cell lymphoma. Findings of FARES and VigiBase review are shown in the Table. Conclusions: T-cell lymphoma is a rare complication of CPIs, with high mortality (20%). Long term follow up of patients receiving CPIs is needed. [Table: see text]
Psychosocial distress and access to resources: Preliminary findings from Immunotherapy & Me.
Authors: Mulcahy Maxwell , House Linda S. , Power Nicholas James , Olson Julie , McManus Shauna , Jones Tameka N. , Schwartzberg Lee S. 
Published: July 2019

91 Background: Immunotherapy & Me ( IO & Me) is an innovative program of supportive resources developed by Cancer Support Community to investigate and support the unique needs of immunotherapy patients. Here, we describe psychosocial distress and confidence accessing resources among a sample of program participants. Methods: IO & Me is recruiting at 4 community clinics and 1 academic center. Eligible patients must be on an anti-cancer immunotherapy. At enrollment, participants consent, provide demographic/clinical history, and report level of confidence accessing cancer treatment information and resources related to treatment decision making (TDM) and managing symptoms/side effects (SEs). Distress is reported with CancerSupportSource (CSS), a tool where patients rate level of concern on 15 items. Once enrolled, participants can access educational resources (print materials, SE tracker, eLearning courses) and a toll-free helpline staffed by licensed mental health professionals (Cancer Support Helpline). Follow-up surveys are available every 30 days for 6 months. We present data from 68 participants at enrollment and 22 at first follow-up. Results: Participants were 87% White; 69% male; mean age = 65 years (SD = 13). 43% had lung cancer; 22% melanoma; 9% kidney cancer. At baseline, the frequency who felt very or extremely confident accessing resources related to: TDM = 68%; managing SEs = 60%; treatment information = 75%. For distress, top concerns were: fatigue (35% of participants); health insurance/money worries (34%); exercise/physical activity (32%). After 30 days, the frequency who felt confident accessing resources for: TDM = 100%; managing SEs = 91%; treatment information = 100%. Top concerns were: changes/disruptions in work, school, or home life (14%); feeling irritable (9%); sleep problems (9%). Conclusions: Preliminary results show greater variability in distress and confidence accessing resources at baseline than 1-month into the program, at which time few endorse cancer-related concerns and most feel confident accessing resources. These findings highlight the utility of providing patients with educational/support resources and the value of customizable programs like IO & Me. Clinical trial information: NCT03347058.
A germline microRNA-based biomarker signature of immune-associated toxicity to anti-PD1/PDL1 therapy.
Authors: Weidhaas Joanne B. , Scheffler Aaron Wolfe , Salzman David , Kalbasi Anusha , Wilenius Kirk , Rietdorf Emily , Heilig Mara , Pitka Mattias , Desler Caroline , Ruan Dan , Ribas Antoni , Drakaki Alexandra , Scholz Mark C. , Telesca Donatello 
Published: July 2019

96 Background: Treatment with anti-PD1/anti-PDL1 agents is associated with toxicity termed immune related adverse events (iRAEs). While the prevalence of Grade 2 and higher iRAEs is approximately 25-30%, biomarkers have not been previously identified. We tested the hypothesis that functional, germ-line mutations would predict iRAEs. Methods: Four classifiers were trained on a set of 61 melanoma patients evaluated for toxicity and response. Subjects were classified as experiencing high toxicity (≥ Grade 2) vs low toxicity (< Grade 2). Performance of the classifiers was tested on a validation set of 89 cancer patients with a variety of cancer types, with the most common being GU and NSCLC. Classifiers were built for each treatment of marker data including classification trees, LASSO-regularized logistic regression, boosted trees (BT), and random forests. The final performance measures, accuracy, specificity, sensitivity, negative predictive value, positive predictive value, area under the curve (AUC), and F1 score, were reported on the categorical treatment of the training data using leave-one-out cross validation on the validation data. We also evaluated the association between our most significant toxicity biomarker and response to anti-PD1/PDL1 therapy. Results: Within the melanoma training sample, we found a biomarker signature where toxicity is predicted with 79.0% accuracy (F1 = .714, AUC = .827) using BT. The same biomarker panel also accurately predicted toxicity in the validation cohort with 85.6% accuracy (F1 = .760, AUC = .883). Of the most predictive biomarkers, three were in microRNA binding sites in RAC1, CD274, and KRAS, two in immune related genes IL2RA and FCGR2A, and one in the DNA repair gene ATM. Our most significant biomarker in RAC1 did not predict response to anti-PD1/PDL1 treatment (p=0.91). Conclusions: We have identified a germ-line biomarker signature which predicts Grade 2 or higher iRAEs for patients treated with anti-PD1/anti-PDL1 therapy, regardless of cancer type, and does not predict an increased likelihood of response to these therapies. These findings are an important step in defining how to better safely personalize immune therapy, whose use is growing rapidly.
Phase I/II dose escalation and expansion study of FLX475 alone and in combination with pembrolizumab in advanced cancer.
Authors: Ho William , Nasrah Nicole , Johnson Dan 
Published: July 2019

TPS24 Background: Regulatory T cells (Treg) can dampen anti-tumor immune responses in the tumor microenvironment (TME). The predominant chemokine receptor on human Treg is CCR4, the receptor for the chemokines CCL17 and CCL22, which are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff) in the setting of an inflammatory anti-tumor response. Preclinical studies with orally-available CCR4 antagonists have demonstrated potent inhibition of Treg migration into tumors, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding PK properties. A robust PD assay measuring receptor occupancy on circulating Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors via CCR4 signaling. These human PK, PD, and safety data have enabled a streamlined design of a Phase 1/2 study of FLX475 in cancer patients both as monotherapy and in combination with checkpoint inhibitor. Methods: This clinical trial is a Phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and preliminary anti-tumor activity of FLX475 as monotherapy and in combination with pembrolizumab. The study is being conducted in 2 parts, a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). In Part 1 (Phase 1) of the study, at least 3 to 6 eligible subjects will be enrolled in sequential cohorts treated with successively higher doses of FLX475 as monotherapy or in combination with pembrolizumab (Part 1b). In Part 2 (Phase 2) of the study, expansion cohorts of both checkpoint-naïve and checkpoint-experienced patients with tumor types predicted to be enriched for Treg and/or CCR4 ligand expression (i.e. “charged tumors”) -- including both EBV+ and HPV+ tumors and NSCLC, HNSCC, and TNBC -- will be enrolled using a Simon 2-stage design. As of November 6, 2018, Cohort 1 has been completed without DLT. Clinical trial information: NCT03674567.
A phase Ib trial of cabozantinib in combination with durvalumab (MEDI4736) in previously treated patients with advanced gastroesophageal cancer and other gastrointestinal (GI) malignancies (CAMILLA).
Authors: Saeed Anwaar , Koestler Devin , Williamson Stephen K. , Baranda Joaquina Celebre , Sun Weijing , Al-Rajabi Raed Moh'd Taiseer , Kasi Anup , Al-Kasspooles Mazin Francis , Subramaniam Dharmalingam , Anant Shrikant 
Published: July 2019

TPS56 Background: GI malignancies including Gastric (GC), esophageal (EAC), colon (CRC), and hepatocellular carcinoma (HCC) remain a significant health problem in the US & globally. The current standard upfront therapy has < 12 month median survival. Hypoxia mimetic agents such as VEGFR targeted therapy down regulate the angiogenesis pathway and sensitize tumors to chemotherapy. Cabozantinib targets multiple tyrosine kinases, including VEGFR, MET, and AXL, and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with PD-1 or PD-L1 inhibitors. We believe that modulating the tumor microenvironment with small molecule inhibitors like cabozantinib will have synergistic effect when combined with checkpoint based immunotherapy like durvaluamb in patients with chemo refractory GC, EAC, CRC and HCC. Methods: The study is funded by research grants from both Exelixis and AstraZeneca. A phase 1 dose escalation is followed by an open-label single arm expansion. Dose escalation will be conducted using a 3+3 design. Starting dose for cabozantinib is 20mg daily. Single agent durvalumab MTD has been used, given that a regimen with full dose durvalumab may be better accepted as a backbone for comparison in future studies. MTD of cabozantinib in combination with standard dose durvalumab will be defined as the highest safely tolerated dose where 0/6 or 1/6 patients experience a DLT and ≥ 2 patients have experienced a DLT at the next higher dose level. Primary objective is to determine the Recommended Phase 2 Dose (RP2D). Secondary objectives include safety, ORR, PFS and OS. Eligible patients received > 1 line of therapy, no prior checkpoint inhibitors, have measurable disease, & ECOG PS 0-1. Phase 1 dose escalation will enroll 9-18 patients and the expansion phase will enroll 12-21 patients. Correlative studies include assessment of tumor microenvironment, angiogenesis & immune molecular markers. The dose escalation phase is currently enrolling. Clinical trial information: NCT03539822.