bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic and immune landscape of metastatic melanoma (MM) treated with pembrolizumab (PEM).
Authors: Kanjanapan Yada , Lien Scott , Yang Cindy , Clouthier Derek L. , Elston Sawako , Jiang Haiyan , Butler Marcus O. , Hogg David , Ohashi Pamela S , Pugh Trevor John , Siu Lillian L. , Spreafico Anna 
Published: February 2018

184 Background: Predictive biomarkers for PEM in MM is an active area of research. Methods: INSPIRE (NCT02644369) is a biomarker-driven Princess Margaret Cancer Centre initiative to evaluate genomic and immunologic changes in tumor and blood of patient (pts) treated with PEM at 200 mg IV Q3W. Baseline (BL) and on treatment (post 2-3 doses of PEM) fresh tumor biopsies were collected for DNA/RNA sequencing, immune-profiling, and tumor PD-L1 expression by immunohistochemistry (QualTek), with longitudinal blood collection for immunophenotyping. Results: As of 9/2017, 11 MM pts (9 cutaneous, 1 choroidal, 1 mucosal) were enrolled. Median treatment duration was 6 months (0.75 – 14.25); 7 pts remain on study. 7/11 (64%) pts had partial response (PR), 3/11 (27%) progressive disease (PD) and 1 was not evaluable (NE) per RECIST 1.1. Based on data for 8 pts (6 PR, 2 PD), higher percentage (%) PD-1 (mean 70 vs 12%), TIGIT (82 vs 43%) and 4-1BB (23 vs 4%) positivity on CD8 T cells in tumor vs blood was seen (all p < 0.05). In BL blood, lower % TIGIT positive CD8 T cells was detected in pts with PR vs PD (38 vs 58%, p < 0.05). T cell profile of 4 pts with paired BL and post PEM samples is shown in Table 1. Mean tumor PD-L1 score was 24% (0 - 90%), with no correlation to PEM response. Genomic analysis on 8 pts (5 PR, 2 PD, 1 NE) found mean tumor mutation burden (TMB) of 538. B2M deletion was seen in 2/2 PD and 0/6 PR pts. Among pts with PRs, 4/6 (67%) had TAP1 and TAP2 amplification post PEM therapy. HLA-A and HLA-B amplifications were each found in 3/6 (50%) PR pts, with only 1 present at BL. TMB was not associated with response to PEM. Conclusions: In this exploratory analysis of MM pts treated with PEM, there was significantly discordant T cell phenotype in tumor vs blood at BL. Our findings suggest B2M deletion to be associated with PEM resistance. The observed development of HLA-A/B and TAP1/2 amplification in 50-67% pts with PR post PEM suggests potential predictive significance, although further validation is warranted. Clinical trial information: NCT02644369. [Table: see text]
Increasing physician recognition and management of immune-mediated adverse events (imAEs): Results of a structured learning platform.
Authors: Rasheed Zeshaan , Kim Caius , Vissers Eugene , Asnis-Alibozek Aviva G. , Antonia Scott Joseph 
Published: February 2018

211 Background: Immunotherapies have significantly improved cancer outcomes across multiple tumor types, while concurrently introducing new and unique toxicities, requiring timely recognition and intervention. To advance physician knowledge of imAEs, an educational online platform was developed for use by AstraZeneca clinical trial investigators (PIs). Herein, we report the impact of this educational strategy on PIs’ knowledge and confidence in recognizing and managing imAEs. Methods: The web-based learning platform included 8 structured and interactive modules (mode of action, colitis, pneumonitis, rash, hepatitis, endocrinopathy, neurotoxicity and nephritis), each containing 3 lessons reviewing background, pathophysiology and diagnosis of individual imAEs, management strategies and expert videos. Pre- and post-training questions to test knowledge (n = 5) and confidence (n = 2) were offered. The platform launched in May 2016 and remains active. PIs participating in durvalumab and/or tremelimumab clinical trials are eligible for participation. Results: As of Jan 19 2017, 2372 PIs have been invited to participate, 356 accessed the platform, and 294 completed ≥1 lesson (57% mode of action, 62% colitis, 42% pneumonitis, 20% rash, 24% hepatitis, 18% endocrinopathy, 19% neurotoxicity, 15% nephritis). Although an overall high proportion of correctly answered questions was identified at the pre-training stage (73% of 2935 total questions, n = 169 PIs), accuracy increased by a mean of 11% (range -3‒27%) at the post-training stage (84%). In each module, there was ≥1 question (range 1‒3) for which correct answers increased by ≥15% post- vs pre-training. Overall, after learning, confidence levels in recognition and management of imAEs increased by 28% (57 to 85%, p < 0.05; n = 35‒102 PIs) and 28% (51 to 79%, p < 0.05; n = 28‒101 PIs), respectively. Conclusions: The number of PIs completing ≥1 lesson indicates a desire for imAE training. This educational initiative enhanced knowledge, and among PIs with suboptimal confidence pre-training, 1 in 2 reported increased confidence in imAE recognition and management, which may improve patient care and maximize treatment potential.
T cell responses to tumor associated antigens in multiple myeloma patients treated with MV-NIS, an oncolytic measles virus.
Authors: Packiriswamy Nandakumar , Upreti Deepak , Zhou Yumei , Dispenzieri Angela , Peng Kah Whye , Russell Stephen J. 
Published: February 2018

218 Background: Evidence from mouse studies shows that Oncolytic viral mode of tumor cell killing can boost the cytotoxic T lymphocyte response against tumor associated antigens (TAA), leading to ‘bystander’ killing of uninfected tumor cells. Methods: To investigate whether oncolytic virotherapy can boost immune responses to tumor antigens in human subjects we studied T cell responses to 10 different TAA reported to have high expression in patients with multiple myeloma (n = 10) before and after intravenous administration of an oncolytic measles virus (MV-NIS). Baseline and 6 week post-therapy PBMC samples were stimulated with peptides specific to each of the selected TAA and their responses to this antigenic stimulation were measured using IFNγ ELISPOT. Results: Despite their prior exposure to multiple immunosuppressive treatment regimens, some of the tested patients had higher T cell responses to some of the TAA even prior to MV-NIS. Baseline T cell responses against MAGEc1 were present in 50% of the patients, and against hTERT and NYESO-1 in 30% of the patients. Furthermore, MV-NIS treatment significantly boosted T cell responses against NYESO-1, MAGEc1, MAGEA1 and MUC1 in 40% of the patients. Interestingly, in one outlier patient who achieved a stringent and durable complete disease remission after MV-NIS therapy, strong baseline T cell responses were present against 8 of the 10 tested TAA but did not change significantly after virotherapy. Based on the T cell responses to the TAA, three distinct phenotypes can be identified. Phenotype 1 was characterized by positive T cell responses to TAA prior and post therapy, Phenotype 2 was characterized by positive T cell responses to TAA only post therapy and phenotype 3 was characterized by negative T cell responses to TAA prior and post therapy. Conclusions: Our data suggests oncolytic measles virotherapy boosted the cytotoxic T lymphocyte response against tumor associated antigens in some of the patients. Identifying patient’s phenotype based on responsiveness to the TAA could be useful marker for identifying the immune responsive state in multiple myeloma patients and identify patients who can be most responsive to oncolytic measles virotherapy. Clinical trial information: NCT00450814.
Synergy of optimized administration sequence and timing of active DC immunotherapy with a PD1 checkpoint inhibitor in a mouse model of renal cell carcinoma.
Authors: Zubkova Olga A. , Agapova Larissa S. , Ovsepyan Armen A. , Ivanova Vilena , Zeynalova Elmira , Lykov Maxim V. , Eremeev Artem V. , Karpov Andrey P. , Ruchko Sergey V. , Nicolette Charles A. , Shuster Alexander M. 
Published: February 2018

31 Background: AGS-003 is an immunotherapy consisting of autologous dendritic cells electroporated with amplified total tumor RNA plus synthetic CD40L RNA and is currently being tested in combination with standard of care to extend survival of newly diagnosed metastatic renal cell carcinoma (RCC) patients in the Phase 3 ADAPT clinical trial. We set out to establish a model system based on the Renca mouse model to more thoroughly study the AGS-003 mechanism of action and identify optimal combination therapies, including with a PD1 checkpoint inhibitor (aPD1 CPI). Methods: Mouse DC precursors were processed in a similar manner to how human monocytes are processed to manufacture AGS-003. Mature DCs were injected s.c. to treat BALB/c mice in an orthotopic syngeneic RCC model. This model system was utilized to test the efficacy and mechanism of action of the AGS-003-like homologous mouse DCs in combination with a murine monoclonal antibody PD1 CPI (anti-mPD1). Results: Murine DCs with similar properties to AGS-003 in combination with anti-mPD1 and sunitinib, resulted in recruitment and migration of lymphocytes into the tumor microenvironment and an increase in peripheral blood CD8+CD28+CD45RA- memory T cells in vivo. Multiple combination dosing strategies were tested and only one dosing regimen (DCs administered prophylactically followed by aPD1 mAb administered therapeutically) showed a substantial synergistic effect (67 days median OS) while all other DC/aPD1 dosing combinations did not exceed the efficacy of DC monotherapy treatment (44.5-48 days median OS). Control animals treated with PBS had a median OS of 29 days. Conclusions: These data demonstrate the importance of the administration sequence for active immunotherapy and aPD1 CPI combination therapy. Our data suggest that the cellular immune response must be initiated and established prior to administration of the aPD1 CPI/sunitinib combination therapy in order to observe synergy in this RCC mouse model. This model may be useful to explore additional combination therapies and effective treatment regimens with other therapeutic agents to guide future clinical development.
Safety and feasibility of immuno-cryotherapy.
Authors: Raja Junaid , Ghodadra Anish , Gettinger Scott N. , Kluger Harriet M. , Sznol Mario , Schalper Kurt Alex , "Kevin" Kim Hyun S. 
Published: February 2018

34 Background: To investigate the safety and feasibility of image guided immuno-cryotherapy in patients with immune checkpoint inhibitor failure. Methods: Consecutive patients with primary or acquired failure to immune checkpoint inhibitor therapy were studied following treatment with concomitant image-guided cryotherapy and immune checkpoint inhibition. In addition to demographic features, type of malignancy, size of targeted metastatic lesion, number of cycles of cryotherapy, systemic immunotherapy, and adverse events in a 90 day post procedural window were extracted. The primary end point was safety and adverse events stratified by the common terminology for adverse events (CTCAE) criteria. As a secondary endpoint, efficacy of the cryotherapy was assessed by iRECIST. Results: Ten patients underwent combined image-guided cryotherapy and checkpoint immunotherapy between 2015 and 2017. Five patients received CTLA 4 blockade with cryotherapy, and 8 patients received PD1 axis blockade and cryotherapy. Six patients had metastatic non-small cell lung cancer and 4 had metastatic melanoma. Immunoprofiling demonstrated one patient each with a mutation in NRAS (G12C), NRAS (Q61R), KRAS (G12C), and ALK; and 2 with aBRAF V600E mutation. Cryotherapy was performed in immunotherapy failure sites, including liver (5) and adrenal glands (3), lymph node and muscle. The median size of targeted lesions was 4.5 cm (standard deviation 3.7cm). There were no grade 3 or higher adverse event, though 6 patients had grade 1 and 2 adverse effects in the periprocedural period which included fatigue, local pain, and poor appetite, isolated cases of diarrhea, colitis, pneumothorax, and procedural site hematoma. Regarding therapeutic response: 5 patients demonstrated partial response, 1 stable response, and 1 progression of disease. Two patients died in the followup period from non-treatment induced causes and 1 is awaiting follow-up. Disease control rate was 85.7%. Conclusions: Immuno-cryotherapy with immune checkpoint therapy in patients with immune checkpoint inhibitor resistance is safe and feasible in metastatic NSCLC and melanoma. There were no grade 3 or above adverse events.
Endoplasmic reticulum stress induced Lox-1+ CD15+ polymorphonuclear myeloid-derived suppressor cells in hepatocellular carcinoma and associated with poor prognsis.
Authors: Li Xing , Wu Xiang-yuan , Jiang Nan , Xing Yan-Fang , Chen Jie , Lin Qu 
Published: February 2018

38 Background: A recent study indicated that Lectin-type oxidized LDL receptor-1 (LOX-1) was a distinct surface marker for human polymorphonuclears myeloid-derived suppressor cells (PMN-MDSC). The present study was aimed to investigate the existence LOX-1 PMN-MDSC in hepatocellular carcinoma (HCC) patients, the latent mechanism and their association with clinical parameters. Methods: 30 HCC patients and 30 health control were included. LOX-1+CD15+ PMN-MDSCs were investigated. Results: LOX-1+CD15+ PMN-MDSC were significantly elevated in both WB and PBMC of HCC patients compared with healthy control. LOX-1+CD15+ PMN-MDSC were more abundant in PBMC than WB. Addition of PMN-MDSCs resulted in significantly reduced proliferation and IFN-γ production of T cells with a dosage dependent manner. LOX-1-CD15+ PMNs present no suppressive function. The suppression on T cell proliferation and IFN-γ production was reversed by ROS inhibitor and Arginase inhibitor. ROS level of LOX-1+CD15+ PMN by DCFDA were higher in LOX-1+CD15+ PMN-MDSCs than LOX-1-CD15+ PMNs, as well as the mRNA levels of the NADPH oxidase NOX2. Meanwhile, the expression of arginase I and activity of arginase were also significantly raised in LOX-1+CD15+ PMN-MDSCs. LOX-1+CD15+ PMN-MDSCs displayed significantly higher expression of spliced X-box–binding protein 1 (sXBP1), ATF3 and CCAAT/enhancer binding protein (CHOP) were higher. For HCC patients, LOX-1+CD15+ PMN-MDSCs in WB were positively related to Cancer of the Liver Italian Program (CLIP) score. Conclusions: LOX-1+CD15+ PMN-MDSC were elevated in HCC patients and suppressed T cell proliferation through ROS/Arg I pathway with ER stress as a potential feature. LOX-1+CD15+ PMN-MDSC presented positive association with the prognosis of HCC patients.
Targeting intracellular oncoproteins with single domain antibody for cell therapy of esophageal cancer.
Authors: Gao Bin , Lv Lihui , Xia Zhenkun , Gu Mingzhu , Liu Ying , Guo Zhixia , Liang Meng , Yuan Yunchang ,   ASCO_MAR
Published: February 2018

56 Background: Intracellular oncoproteins such as NY-ESO-1 and WT1 are widely distributed in different cancers and ranked as number 1 and 10 prioritized cancer antigen by international experts. It is difficult to target these antigens due to the intracellular nature by conventional antibodies. Methods: Here we reported the development of antibodies to target intracellular antigens, the same way as TCR does, recognizing MHC complex with peptides derived from intracellular oncoproteins. Phage display libraries were screened out against HLA-A2 assembled with different peptides from both WT1 and NY-ESO-1. Antibodies were tested to bind to corresponding HLA-A2/peptides complex on ELISA and FACS and finally the ability to bind to paraffin samples derived from malignancy cancer patients were confirmed. Results: We have identified several antibodies that specifically recognize the corresponding HLA-A2/peptide. Particularly, 2F4 and 1H1 could bind to RMFPNAPYL of WT1 HLA-A2 monomer on ELASA assay, by contrast the antibody did not bind to 5 other non-related HLA-A2 monomers. Furthermore, on FACS assay, both antibodies bound to WT1 peptide loaded T2 cells that express empty HLA-A2 complex on the surface. 2F4 could be routinely expressed as Fc fusion protein and maintained TCR-like feature and could recognize tumor cell lines expressing both HLA-A2 and WT1 antigen on FACS analysis. Both antibodies bind to HLA-A2/ WT1 with the affinity ranging between 10-8 and 10-9 M by Biacore analysis. Finally, paraffin sections from esophageal cancer patients were stained with antibody specific to HLA-A2/RMF and about 30% of samples shown strong reactions and The antibody to HLA-A2/SLL ( NY-ESO-1) shown a similar results although weaker stains due to the lower affinity of the antibody. Conclusions: Intracellular oncoproteins could be targeted by antibodies recognizing HLA associated with the onco-peptide processed. These antibodies have potential applications on CAR-T cell therapy or the development of bi-specific therapeutics for a number of malignancy tumors.
Hepatotoxicity in advanced cancer patients receiving immune-based cancer treatment.
Authors: Alshawa Anas , Fujii Takeo , Abu Sbeih Hamzah , Blechacz Boris , Bilen Mehmet Asim , Hess Kenneth R. , Suarez-Almazor Maria E. , Hong David S. , Tsimberidou Apostolia Maria , Gong Jing , Stephen Bettzy , Subbiah Vivek , Piha-Paul Sarina Anne , Fu Siqing , Mendoza Tito R. , Thirumurthi Selvi , Meric-Bernstam Funda , Naing Aung , Miller Ethan 
Published: February 2018

67 Background: Immune-based cancer treatment (IBCT) is increasingly used to treat a variety of cancers. Despite the promising results, adverse events such as dermatitis, colitis, and hepatitis remain a concern. Hepatitis is usually mild but may be severe, requiring modification or cessation of treatment. Here, we describe several cases of immune-mediated hepatitis. Methods: We identified patients enrolled in clinical trials using IBCT through the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, between January 2010 and July 2015. Charts were reviewed for mention of “autoimmune hepatitis”, “hepatitis” or abnormal transaminases, all of which were attributed to IBCT by the treating physician. Hepatotoxicity was graded based on CTCAE v4.0. Results: We identified 12 cases of immune-related hepatotoxicity out of 290 patients. Three patients (1.03%) had grade 3 elevation of transaminases, designated as “autoimmune hepatitis.” Each required systemic steroids and transaminases returned to baseline within a month. IBCT was temporarily held in 2 cases and was permanently discontinued in the third due to grade 4 myositis rather than hepatitis. One patient (0.3%) had grade 2, and eight patients (2.8%) had grade 1 transaminases elevations that were possibly attributable to immunotherapy, but which resolved spontaneously without alteration in treatment. Other significant reported immune-related toxicities ≥ grade 3 were: dermatitis (n = 4), enterocolitis (n = 3), myasthenia gravis (n = 2), myositis (n = 2), pneumonitis, pleuritis, and pancreatitis (n = 1 each). Conclusions: 1.03% of patients experienced grade 3 elevation of transaminases that were attributable to immune therapy. Hepatic adverse events related to immunotherapy in our study were manageable. Further studies are needed to develop biomarkers to identify patients at risk to develop such toxicities. [Table: see text]
mRNA-nanoparticles to enhance and track dendritic cell migration.
Authors: Grippin Adam , Sayour Elias , Wummer Brandon , Monsalve Adam , Wildes Tyler , Dyson Kyle , Mitchell Duane Anthony 
Published: February 2018

72 Background: Despite aggressive clinical interventions, glioblastoma (GBM) remains almost universally fatal. In a pilot, randomized, and blinded clinical trial, we recently demonstrated that administration of RNA-loaded dendritic cell (DC) vaccines was associated with significantly improved progression-free and overall survival in patients with GBM (Mitchell et al, Nature 2015). Furthermore, clinical outcomes correlated with migration of Indium-111-labeled DCs to vaccine-site draining lymph nodes (LNs) measured by SPECT/CT imaging. While these studies demonstrated that DC migration may be an important clinical biomarker for response to DC vaccination, the complexity and regulatory requirements associated with nuclear labeling to track DC migration limits widespread application of this technique. We have therefore developed RNA-loaded magnetic nanoparticles (RNA-NPs) to enhance DC migration to LNs and track that migration with a widely available imaging modality (i.e. MRI). Methods: Cationic liposomes were loaded with iron oxide nanoparticles with or without cholesterol modification. The resulting nanoparticles were complexed with RNA and used to transfect DCs ex vivo. RNA-NP-loaded DsRed+ DCs were then injected intradermally into mice and tracked noninvasively with T2-weighted 11T MRI before excision and quantification with flow cytometry. Results: In vitro experiments demonstrate that iron oxide loading does not reduce RNA-NP-mediated transfection of DCs. Additionally, replacement of cationic lipids with cholesterol increased RNA-NP transfection of the DC2.4 cell line and enhanced the T cell stimulatory capacity of treated bone marrow-derived dendritic cells (BMDCs). Compared to electroporation, RNA-NPs enhanced DC migration to lymph nodes and reduced T2 MRI intensity in DC-bearing lymph nodes. Conclusions: This data suggests that iron oxide-loaded RNA-NPs enable noninvasive cell tracking with MRI and enhance DC migration to lymph nodes. We have further shown that inclusion of cholesterol in RNA-NPs augments the stimulatory capacity of transfected DCs. Future work will consider effects of RNA-NPs on antitumor immune responses and the utility of MRI-detected DC migration as a biomarker of vaccine efficacy.
Immunologic efficacy of E39 & E39' vaccination in a phase I/IIa trial in ovarian and endometrial cancer patients.
Authors: Brown Tommy A , Peace Kaitlin M. , Myers John W , Vreeland Timothy J , Hale Diane F , Jackson Doreen O , Greene Julia M , Berry John S , Clifton Guy T , Herbert Garth S , Peoples George Earl 
Published: February 2018

75 Background: The treatment options for cancer are ever-evolving & now include vaccines targeting tumor-specific immunogenic peptides to induce tumor cytolysis. Folate binding protein (FBP) is a tumor-associated antigen (TAA) highly expressed in most endometrial & ovarian cancers (Ca), shielded from the normal immune system. The most promising FBP peptides are E39 & an attenuated form, E39' (aka J65). In our most recent phase I/IIa trial we evaluated an E39+GM-CSF inoculation series at 3 doses (VG) vs controls (CG) as well as booster vaccination with E39 or E39' after the initial inoculation series. Here we present the immunologic data from this phase I/IIa trial. Methods: Patients (pts) with ovarian or endometrial Ca who were disease-free after standard of care therapy but at risk for recurrence were enrolled. HLA-A2+ pts were vaccinated in a 3+3 dose escalation of 100mcg, 500mcg, & 1000mcg. The remaining pts received 1000mcg inoculations. Vaccine was given every 3-4 weeks for a total of 6 inoculums. Pts were then offered to participate in booster vaccination with 9 pts randomized to receive E39 & 9 pts E39'. FBP expression level was measured on the resected disease. Overall immunologic response & by subgroups was measured by delayed type hypersensitivity (DTH) & ELISPOT in the VG. Results: A total of 29 pts were vaccinated. Mean DTH prior to the initial dose of E39 was 5.74mm & after final dose was 10.33mm (p = 0.018). Mean overall ELISPOT change over time through 18 months was +69.1 when compared to baseline (p = 0.675). At 18 months, mean ELISPOT increased by 97.1 in 1000mcg vs -57.0 in < 1000mcg dosed pts (p = 0.047) & by +255.33 in pts with > average initial DTH vs -0.75 in < average initial DTH (p = 0.004) when compared to baseline. Immunological analyses were not significantly different between FBP hi/lo expression or E39 vs E39’ booster (p > 0.05). Conclusions: E39 demonstrated significant overall immunogenicity on in vivo testing as measured by DTH. Ex vivo analysis (ELISPOT) suggests that E39 is more immunogenically efficacious in pts with > average initial DTH & those who are optimally dosed (1000mcg). FBP expression level & E39 vs E39’ use in booster inoculations did not significantly impact in vivo or ex vivo immunogenicity. Clinical trial information: NCT01580696.