bluuebunny/crossref_metadata_2025_split huggingface dataset:
MGMT gene polymorphisms in patients with severe hematological toxicity treated with temozolomide for adult diffuse gliomas: Results from a tertiary-care comprehensive cancer center.
Authors: Moitra Prithwijit , Chatterjee Abhishek , Kota Priti Khatri , Kowtal Pradnya , Dasgupta Archya , Sastri Jayant , Sahay Ayushi , Shridhar Epari , Patil Vijay Maruti , Moiyadi Aliasgar , Sarin Rajiv , Gupta Tejpal 
Published: June 2021

e14032 Background: Polymorphisms in MGMT gene have been implicated in temozolomide (TMZ)-induced hematological toxicity in patients with adult diffuse gliomas. We aimed to investigate the association of three single nucleotide polymorphisms (SNPs) in the MGMT gene viz. L84F, I143V/K178R with severe hematological toxicity in patients of adult diffuse glioma treated with TMZ at an academic neuro-oncology unit of a tertiary-care comprehensive cancer centre from India. Methods: Thirty-three patients of adult diffuse glioma treated with multi-modality adjuvant therapy including TMZ who developed CTCAE V5.0 grade 2-4 hematological toxicity were included after written informed consent. Genomic DNA was extracted from peripheral blood mononuclear cells for SNP analysis. Correlation of MGMT SNP with patient demographics and hematological toxicity was assessed using the Chi-square and Fisher’s exact test. Results: Twenty-four patients (72.7%) developed grade 3-4 hematological toxicity with TMZ with a distinct female predilection. The variant T allele of L84F was expressed in 28.7% of the total 66 analyzed alleles which was markedly higher than previously reported in the general population of South Asian ancestry. The variant G allele of I43V/K178R was expressed in 9.3% (6/64) of 64 analyzed alleles. Persistent myelosuppression lasting beyond 2 months after cessation of TMZ correlated with I143V/K178R hetero/homozygous compared to wild type allele (p = 0.03). However, no significant correlation could be seen between any of the tested MGMT SNPs and grade of hematological toxicity. Conclusions: There is a higher prevalence of the L84F polymorphism in Indian patients with severe hematological toxicity than previously reported in the literature. The variant G allele of I143V/K178R is associated with prolonged and persistent myelosuppression induced by TMZ. A larger case-control is being planned to further elucidate the causal relationship between MGMT gene polymorphisms and TMZ-induced severe hematological toxicity.
Association of inoperable glioblastoma with a heterogeneous functional and survival outcome.
Authors: Harlay Vincent , Loundou Anderson , Boucard Celine , Petrirena Gregorio , Barrie Maryline , Campello Chantal , Autran Didier , Padovani Laetitia , Figarella Dominique , Boissonneau Sebastien , Dufour Henry , Baumstarck Karine , Tabouret Emeline , Chinot Olivier L. 
Published: June 2021

e14036 Background: “Biopsy only” GBM patients is an understudied group of patients associated to a poor outcome, which has been reported to represent 21% of histologically confirmed GBM in the US National Cancer Data Base. Pattern of care included radiotherapy-temozolomide (RT-TMZ) standard regimen completed in 15% of patients, any other form of oncologic treatment in 60%, and supportive care alone in 25% of patients (Kole, Cancer 2016). Our objective was to explore heterogeneity of inoperable GBM patients group, both for patients characteristics, pattern of care planned and completed, functional and survival outcome. Methods: Patients with inoperable GBM included in a prospective regional glioma cohort initiated in 2014 were retrospectively reviewed for patients characteristics, MRI finding, treatment allocation and delivery. Functional independency analyzed as a cumulative time of KPS≥70, PFS and OS were analyzed. Results: Of 535 patients referred to our center, 449 patients were included at initial surgery, of which 158 patients (35%) underwent biopsy only. 18 patients were excluded for missing data leaving 139 patients for the present analysis. 54 (39%) were referred to RT-TMZ (50 patients completed concomitant treatment), 68 (49%) considered unfitted for RT received chemotherapy upfront (CT-UF) (of which 3 were subsequently referred to RT), 17 (12%) referred to palliative care only (PC). Groups differed at baseline for age (mean 60, 68, 69y for RT-TMZ, CT-UF, PC respectively); for KPS (70, 60, 50 for RT-TMZ, CT-UF, PC respectively); for mean tumor surface (793, 1420, 1412 cm2 for RT-TMZ, CT-UF, PC); for tumor extension (bilateral in 6.4% and 29.3% for RT-CT and CT-UF respectively); for steroid intake (45, 60, 100 mg daily respectively). Median OS was 14 months (95% CI, 9.65-18.71), 8 months (95% CI, 4.62-7.67), 2 months (95% CI, 0.67-3.33) for RT-TMZ, CT-UF, PC respectively. Of importance, mean duration of functional independence was of 8.3 months, 2.1 months, and 0.1 month for RT-TMZ, CT-UF, and PC respectively; 33/139 (24%) of the patients experienced functional independency for more than 40% of their life time. Conclusions: Inoperable GBM constitute a large and heterogeneous population in which more than 1/3 of the patients are amenable to standard of care, with survival outcome similar to the one of patients who underwent surgery. Patients considered unfit for RT-CT at diagnosis fail to be referred subsequently to RT after CT and exhibit a poor survival outcome that deserve new effective treatments. Cumulative duration of functional independence is limited and should be considered as part of treatment evaluation.
Biosimilar trastuzumab active post marketing surveillance real world 2020 data update: Results from a patient support program for patients under treatment with the first biosimilar trastuzumab approved in Brazil.
Authors: Silva Allisson Monteiro da , Watanabe Thais Tiemi Wepeck Oliveira , Honda Eimy , Yamaguchi Juliana 
Published: June 2021

e14504 Background: In 2017, biosimilar trastuzumab (Zedora) became the first biosimilar trastuzumab approved in Brazil. In May 2018 an active postmarketing surveillance program was instituted. Data from this program was presented in ASCO in 2019 and 2020. Now, with an extended follow up (May 2018 to December 2020) and more patients included, we present updated data from the surveillance program. Methods: This is a prospective observational study to evaluate data from the patient support program. Patients who received prescription for biosimilar trastuzumab were invited to participate. After agreement of informed consent, they were followed by periodical phone calls after each infusion and up to 3 months after the end of treatment. Treatment related data and adverse events (AEs) were collected. Results: A total of 74 reports containing 656 adverse events (AEs) were received from the active postmarketing surveillance program between May 2018 and December 2020. Of the 74 reports, 73 are female patients with HER2+ breast cancer (BC) and 1 is a male patient with gastric adenocarcinoma. The patients mean age was 52 years (31 to 79 years). Regarding to AEs severity and expectedness, 588 (89.63%) were non-serious AE (413 expected / 175 unexpected) and 68 (10.37%) were serious AE (51 expected / 17 unexpected). Considering all serious unexpected AEs (17), 13 were assessed as not related to trastuzumab therapy and 4 were assessed as related to therapy. For the 175 non-serious unexpected AEs, 56 were assessed as not related to therapy and 119 were assessed as related to therapy. The three most frequently reported AEs according to SOC (System Organ Classification) were general disorders and administration site conditions 111 (16.92%), gastrointestinal disorders 98 (14.93%) and nervous system disorders 88 (13.41%). The five most commonly reported adverse events (MedDRA PT - Preferred term) were diarrhea 27 (4.11%), fatigue 24 (3.66%), nausea 22 (3.35%), weight decreased 18 (2.74%) and infusion related reaction 17 (2.59%). Further monitoring is continued. Conclusions: Nature of AEs noted in patients with breast cancer and gastric cancer treated with biosimilar trastuzumab (Zedora) were consistent with the known safety profile of Trastuzumab. The risk benefit remains consistent with the reference safety information and no new safety signals were detected.[Table: see text]
The correlation between tumor microenvironment and the clonality of the T-cell repertoire in lung cancer and colorectal cancer.
Authors: Cao Hua , Duan Jingxian , Jiang Shunda , Mu Tianhao , Xu Ruilian 
Published: June 2021

e14524 Background: The tumor microenvironment has been shown to affect the responsiveness of immunotherapy. Effective anti-tumor immune response requires the activation and expansion of specific antigen-reactive T cell clones. It was reported that increased T cell clonality was associated with improved response to immunotherapy. However, what type of tumor microenvironment facilitates T cell clonal expansion remained controversial. The study aims to investigate the correlation between tumor microenvironment and the clonality of the T cell repertoire in lung cancer and colorectal cancer. Methods: 4 lung cancer patients and 4 colorectal cancer patients were enrolled in this study. Tumor tissues and peripheral blood samples were collected for RNA sequencing and T cell receptor CDR3 sequencing. The infiltration levels of 28 immune cells were estimated based on the mRNA expression of the genetic markers. The T cell clonality was defined as 1-Peilou’s evenness. Data were presented as mean± S.E.M. Results: The mean T cell clone counts in the blood samples of the 8 patients were 25676±4782 (ranging from 10259 to 45016), and the mean clonality of the TCR repertoires was 0.20±0.02 (ranging from 0.11 to 0.27). The clonality of T cells in colorectal cancer patients was similar to that of the lung cancer patients (0.22±0.02 versus 0.18±0.03, p = 0.31), showing comparable potentials of antigenic responses. The tumor infiltration of regulatory T cells, type 17 T helper cells, CD56bright natural killer cells, and natural killer cells varied greatly among patients, the coefficient of variation of those cells were 54.61%, 54.61%, 54.43%, and 55.62% respectively. In contrast, the coefficient of variation of monocytes was 23.34%, displaying a relatively even distribution among patients. The Pearson’s correlation coefficient was calculated to show the correlation between T cell clonality and the infiltration level of all 28 types of immune cells. Notably, only the infiltration of type 17 T helper cells significantly associated with T cell clonality, the positive correlation gave an R square value of 0.68 (r = 0.82, 95% confidence interval of 0.04-0.98, p = 0.04). The infiltration levels of CD4+ T cells, CD8+ T cells, regulatory T cells, type 1 and type 2 T cells, and gamma delta T cells were not affected by T cell clonal expansion. The expression of B cells, dendritic cells, macrophages, natural killer cells, and monocytes did not correlate with T cell clonal expansion. However, the abundance of neutrophils appears to positively correlate with T cell clonality (p = 0.09). Conclusions: The clonal expansion was significantly associated with the infiltration of type 17 T helper cells but not other subtypes of T cells, showing that the type 17 T helper cells are crucial to the antigenic responses in lung cancer and colorectal cancer. A neutrophil enriched tumor microenvironment may facilitate T cell clonal expansion.
Unaltered IL-2 encapsulated in acoustically active lipid microspheres for systemic but targeted microdose delivery to tumor microenvironment.
Authors: Larsen Clayton , Keltner Llew , Redmond William L , Li Rhodemann 
Published: June 2021

e14535 Background: In order to take local advantage of exogenous interleukin-2 (IL-2) on effector T-cells within the tumor microenvironment while simultaneously avoiding systemic Treg immunosuppressive effects, microdoses of recombinant human IL-2 (rhIL-2) were encapsulated in gas-filled lipid microspheres (eIL-2), then activated with ultrasound. This novel therapeutic agent (eIL-2) was selectively delivered to the tumor via sonoporation and its anti-tumor effects were determined alone and in combination with PD-1 blockade. Methods: In an MC38 colon cancer model, jugular button catheters (Instech) were surgically implanted in a total of 56 animals (8 animals per arm) prior to tumor inoculation to facilitate repeatable IV injection of both anti-PD-1 (RMP1-14; BioXCell) and microspheres. Imagent perflexane lipid microspheres were incubated with rhIL-2 and the high concentration infranatant was separated, discarded, and replaced with sterile saline to resuspend microspheres to formulate eIL-2 on-site. Tumor-bearing mice were dosed on Days 1, 4, 8, and 12. Ultrasound (US) settings used were 2.2 MHz frequency, and 0.339 mechanical index (MI) during insonation. Once every 10 seconds a microbubble destruct pulse of 1.304 MI lasting 1,100 milliseconds was applied. Total insonation time was 5 minutes using a commercial ultrasound scanner (Mindray TE7) operating within diagnostically safe exposure limits. Study groups included Group 1: no treatment; Group 2: aPD-1, 3 mg/kg; Group 3: aPD-1, 3 mg/kg, Imagent + US; Group 4: Free rhIL-2, 10,000 IU (0.61μg)/animal; Group 5: eIL-2, approximately 0.2 μg encapsulated/animal; Group 6: Free rhIL-2, 10,000 IU (0.61μg)/animal, aPD-1, 3 mg/kg; Group 7: eIL-2, approximately 0.1 μg encapsulated/animal, aPD-1, 3 mg/kg. Results: The anti-PD-1 dose of 3 mg/kg demonstrated an expected tumor growth inhibition over control of -38.2% on Day 6, -35.6% on Day 8 and -30.3% on Day 12. Adding eIL-2 + ultrasound external stimuli approximately doubled the tumor inhibition effect of RMP1-14 to -68.1% on Day 6, -69.2% on Day 8 and -62.0% on Day 12. We also analyzed cytokine levels in the peripheral blood (Day 12) using a multiplex ELISA and observed elevated levels of pro-inflammatory cytokines including IFN-g, IL-12, and IL-1a, which likely serve to enhance anti-tumor immunity. IL-15 was also increased following treatment, which supports effector T cell survival. Conclusions: Using a novel form of recombinant human interleukin-2 encapsulated within a gas-filled lipid microsphere, we demonstrated that ultrasound-activated local delivery via sonoporation plus systemic PD-1 blockade led to improved tumor control and increased expression of pro-inflammatory cytokines. This novel approach enhances the efficacy of checkpoint blockade for the treatment of solid tumors. Further experiments are underway to interrogate mechanisms of action.
Updated safety and efficacy of MSB2311 (an anti-programmed death-ligand 1 antibody) in Chinese patients with advanced solid tumors and hematological malignancies from a phase 1 study.
Authors: Shen Lin , Gong Jifang , Zhang Jian , Ji Dongmei , Zhong Haijun , Yuan Ying , Yang Lei , Zhang Qingyuan , Li Yufeng , Wang Mengde , Qi Chuan , Xia Zhenzhong , Lu Lingmin , Huang John , Sun Ling , Xu Li , Shi Michael , Hu Xichun 
Published: June 2021

e14547 Background: MSB2311 is a novel humanized PD-L1 antibody with a unique pH-dependent antigen binding property that enables intra-tumor recycling and potentiates tumor penetration. Methods: Patients with metastatic solid tumors or selected lymphoma progressed on or after standard treatments were enrolled in this phase I study. In dose escalation part, MSB2311 was given at dose levels of 3, 10, and 20 mg/kg intravenously every 3 weeks. At the dose expansion part, patients with enriched biomarker expression, including EBV+, PD-L1+ (TPS≥50%), MSI-High or TMB-High (≥10muts/Mb), were dosed at 20mg/kg Q3W or 10mg/kg Q2W. Primary objectives are to evaluate the safety and tolerability and to identify MTD and RP2D. Secondary objectives include the assessment of pharmacokinetic parameter, immunogenicity, and preliminary anti-cancer activity per RECIST1.1. Results: As of data cutoff by Aug 31, 2020, 33 Chinese patients had been treated, including 27 heavily pre-treated solid tumor patients and 6 lymphoma patients. No dose limiting toxicity was reported and MTD has not been reached. The most common AEs (>20%) included: anemia, hypothyroidism, aspartate aminotransferase elevated, proteinuria, weight loss. 13 patients (39.4%) experienced grade 3 AEs, and 6 patients (18.2%) experienced SAEs. No treatment related grade 4 or 5 event was reported. Of the 17 efficacy evaluable solid tumor patients with biomarker selection, 6 achieved confirmed partial response with 35% ORR: 2/8 (25%) at 10 mg/kg Q2W and 4/9 (44%) at 20 mg/kg Q3W. Additionally, one patient achieved sustained iPR via iRECIST. 4 out of 7 responding patients (including one iPR) achieved tumor shrinkage of more than 50%, 3 of them got durable response (≥24 weeks).1 out of 6 lymphoma patients achieved PR. Conclusions: MSB2311 demonstrated a manageable safety profile and promising preliminary antitumor activity in patients with advanced solid tumors and selected lymphomas. Clinical trial information: NCT04272944.
Development and characterization of a HCMV multiantigen therapeutic vaccine for GBM using the UNITE platform.
Authors: Adhikari Amit , Macauley Juliete , Johnson Yoshimi , Connolly Mike , Coleman Tim , Heiland Teri 
Published: June 2021

e14565 Background: Glioblastoma (GBM) is an aggressive form of brain cancer with a median survival of 15 months which has remained unchanged despite technological advances in the standard of care. GBM cells specifically express human cytomegalovirus (HCMV) proteins providing a unique opportunity for targeted therapy. Methods: We utilized our UNITE (UNiversal Intracellular Targeted Expression) platform to develop a multi-antigen DNA vaccine (ITI-1001) that codes for the HCMV proteins- pp65, gB and IE-1. The UNITE platform involves lysosomal targeting technology, fusing lysosome-associated protein 1 (LAMP1) with target antigens resulting in increased antigen presentation by MHC-I and II. ELISpot, flow cytometry and ELISA techniques were used to evaluate the vaccine immunogenicity and a syngeneic, orthotopic GBM mouse model that expresses HCMV proteins was used for efficacy studies. The tumor microenvironment studies were done using flow cytometry and MSD assay. Results: ITI-1001 vaccination showed a robust antigen-specific CD4 and CD8 T cell response in addition to a strong humoral response. Using GBM mouse model, therapeutic treatment of ITI-1001 vaccine resulted in ̃56% survival with subsequent long-term immunity. Investigating the tumor microenvironment showed significant CD4 T cell infiltration as well as enhanced Th1 and CD8 T cell activation. Regulatory T cells were also upregulated upon ITI-1001 vaccination and would be an attractive target to further improve this therapy. In addition, tumor burden negatively correlated with number of activated CD4 T cells (CD4 IFNγ+) reiterating the importance of CD4 activation in ITI-1001 efficacy and potentially identifying treatment responders and non-responders. Further characterization of these two groups showed high infiltration of CD3+, CD4+ and CD8+ T cells in responders compared with non- responders along with higher CD8 T cell activation. Conclusions: Thus, we show that vaccination with HCMV antigens using the ITI-1001-UNITE platform generates strong cellular and humoral immune responses, triggering significant anti-tumor activity that leads to enhanced survival in mice with GBM.
Safety of immune checkpoint inhibitors in patients with preexisting autoimmune disorders.
Authors: Kumar Rohit , Chan Abigail Sy , Bandikatla Sudeepthi , Mudra Sarah , Ranjan Smita , Ngo Phuong 
Published: June 2021

e14568 Background: In recent years, immune checkpoint inhibitors (ICIs) have been approved for a growing number of cancer types. Approximately 10-30% of cancer patients have a concomitant diagnosis of autoimmune disorders (AID). Activation of the immune system with ICIs poses a potential risk of AID worsening. The majority of the ICI clinical trials excluded these patients from the study. There is a paucity of data regarding the benefits and risks of ICIs in cancer patients with AIDs. The primary objectives of this study were to determine the incidence of immunotherapy related AID worsening and all immunotherapy related adverse events (irAEs). Secondary outcomes were time to AID worsening and survival difference. Methods: All adult patients (age ≥18 years) with solid malignancy who received ICIs between Jan 2016 to June 2019 were identified using the University of Louisville pharmacy database. Medical records were reviewed to include all the patients with preexisting AIDs. Descriptive statistics were used to determine the incidence of AID worsening and all irAEs. Baseline characteristics were compared between cancer patients with versus without AID worsening using Pearson chi2 and Student’s t-test, where appropriate. Multivariate Cox regression analysis was used to compared survival between the 2 groups. Results: A total of 40 patients with AIDs were identified during the study period. The cancer types were melanoma (57.5%), lung (15%), breast (5%), and others (22.5%). AIDs were rheumatological (52.5%), gastroenterological (12.5%), neurological (12.5%), dermatological (20%) and hematological (2.5%). The incidence of all irAEs was 60% (grade ≥3 in 20%) and AID worsening was 40% (grade ≥3 in 15%). Baseline characteristics of the 2 comparison groups are shown in table. The median time from ICI initiation to AID worsening was 94.5 (range 21-431) days. In multivariate Cox regression analysis, adjusted for demographics, cancer type, and stage, survival was similar for patients who had AID worsening versus those who did not (HR 0.30 (95%CI 0.06-1.40, p=0.128). Conclusions: In our single-institution study, cancer patients with preexisting AID do have an increased risk of irAEs with high-grade toxicities in 20% compared to historically reported 5% in the general cancer population; about 15% of patients reported grade ≥3 worsening of their AIDs. However, though the risk of irAEs is numerically higher in patients with AID, it may be acceptable to the patients if the potential benefits of ICIs outweigh the risks. Baseline demographics and clinical characteristics.[Table: see text]