bluuebunny/crossref_metadata_2025_split huggingface dataset:
An in vivo model to evaluate donor-dependent cytokine release in response to single-agent or combination immune-oncology therapies.
Authors: Draheim Kyle , Jiao Jing , Yang Jiwon , Cai Danying , Cheng Mingshan , Keck James G. 
Published: May 2020

3114 Background: Although immune-oncology therapies such as checkpoint inhibitor, bi-specific antibody and CAR-T cell therapies are successfully used for cancer therapy, they can have very severe adverse effects such as cytokine release syndrome (CRS). The animal models and in vitro human PBMC assays presently in use do not reliably predict CRS in patients. Currently, the only widely accepted predictors of CRS are cancer burden and therapeutic dose. Despite this, most pre-clinical assays that evaluate CRS do not incorporate cancer cells and the safety of drug combinations has not been widely explored. A predictive assay that identifies patient/cancer/therapy combinations at risk for developing CRS upfront in addition to treatment efficacy would improve the safety of immune-oncology drug development. Methods: We have developed sensitive in vivo humanized mouse models for quantitating CRS that are rapid, reproducible and able to show variation among PBMC donors. The NSG mouse and its derivatives are engrafted with cancer cells and human PBMCs. Mice are then dosed with checkpoint inhibitors or bi-specific antibodies as a single therapy or in combination. Cytokine release is evaluated 2-6 hours post dosing. This assay can be modified to also evaluate efficacy by using luciferase labeled cancer cells and monitoring tumor burden using the Xenogen IVIS imaging system. Results: For all therapy groups, each cytokine tested (including human IFN-γ, IL-2, IL-6, IL-10 and TNF) was upregulated 2-6 hours after drug treatment, but different PBMC donors had various cytokines release levels. Cytokine release levels correlated with a dose response, PBMC engraftment levels and tumor burden. We can demonstrate additive and synergistic cytokine release in the combination treated groups and compare efficacy versus single agents. Our in vivo method was able to determine CRS missed in the in vitro testing method. Conclusions: We have developed a rapid, sensitive and reproducible novel in vivo PBMC humanized mouse model that can differentiate human PBMC donors based on individual safety response to single agent and combination therapeutics of immune checkpoint inhibitors and bispecific T-cell-engaging antibodies. Additionally, this assay can utilize luciferase labelled cell lines to measure treatment efficacy. Using this assay, we can potentially evaluate both cytokine release and efficacy of current immune-oncology therapies as single agents and in combination. This assay has immediate utility in current and future drug development.
Investigating the tumor immune infiltrate for populations that predict immune-related adverse events (irAEs) in patients receiving PD-1 inhibitors.
Authors: Blum Steven Michael , Smith Neal , Sade-Feldman Moshe , Frederick Dennie T. , Jenkins Russell William , Cohen Justine Vanessa , Lawrence Donald P. , Mooradian Meghan , Freedman Christine , Fadden Riley , Rubin Krista M. , Richey Sarah , Flaherty Keith , Wargo Jennifer Ann , Hacohen Nir , Sullivan Ryan J. , Boland Genevieve Marie , Villani Alexandra C 
Published: May 2020

3116 Background: The mechanistic relationship between clinical benefit and immune-related adverse events (irAEs) in response to immune checkpoint inhibitors (ICIs) remains unclear, with several clinical studies reporting that irAEs are biomarkers of responses. Single-cell RNA sequencing (scRNAseq) analysis of tumors from patients with advanced melanoma before and after treatment with ICIs have identified immune cells that correlate with response to ICIs. We sought to evaluate if these populations were also associated with irAEs. Methods: A published scRNAseq data set generated with the Smart-Seq2 protocol (Sade-Feldman M, et al. Cell 2018.) was re-analyzed, stratified by two definitions of irAEs: (1) toxicity requiring systemic immunosuppression (prednisone > 10mg/day) or (2) systemic immunosuppression and/or endocrinopathy. Unbiased single-cell analysis was performed, followed by sub-clustering of T cell populations. The percentage of cells in each cluster was determined on a per sample basis. Results: 13,184 immune cells from 39 samples collected from 25 patients were re-analyzed. 27 samples were from patients who did not respond to ICIs, while 12 samples came from responding patients. 21 samples came from patients who required immunosuppression, 5 samples from patients with isolated thyroiditis, and 13 samples from patients who met neither irAE criteria. Unsupervised scRNAseq analyses focused on ICI efficacy re-capitulated published associations between response and populations that included B-cells (p < 0.01) and TCF7 expressing T-cells (p < 0.01). While these cell populations were not associated with either definition of toxicity, we observed a non-Treg CD4 expressing T cell population (0.8-10.5% cells/sample) that positively correlated with either definition of toxicity (p < 0.05) but not efficacy. Conclusions: In a patient cohort with advanced melanoma, tumor-infiltrating immune cell populations associated with response to ICI therapy were not associated with irAEs. This suggests that biomarkers of ICI response may not function as biomarkers of irAEs, and ongoing analysis will seek to validate this result. Understanding the differences between ICI response and irAEs may identify new therapeutic targets for maximizing efficacy while mitigating toxicity.
VCAN accumulation and proteolysis as predictors of T lymphocyte-excluded and permissive tumor microenvironments.
Authors: Emmerich Philip , Matkowskyj Kristina A. , McGregor Stephanie , Kraus Sean , Bischel Kristen , Qyli Tonela , Buehler Darya , Pasch Cheri , Babiarz Christopher , Depke Mitchell , Clipson Linda , Wisinski Kari Braun , Burkard Mark E. , Baschnagel Andrew , Uboha Nataliya Volodymyrivna , Asimakopoulos Fotis , Deming Dustin A. 
Published: May 2020

3127 Background: Immune checkpoint inhibitors (ICIs) represent a major advance for treating solid tumors. However, only a minority of patients (pts) benefit from these therapies and markers that predict response have been elusive. Versican (VCAN) is an immunosuppressive proteoglycan in the tumor microenvironment (TME), which releases an immunostimulatory N-terminal fragment versikine (Vkine) when cleaved by ADAMTS proteases. We have demonstrated in colorectal cancers (CRC) that a low VCAN/high Vkine (VCAN proteolytic predominant [VPP]) phenotype correlates with increased tumor-infiltrating CD8+ T lymphocytes (TILs). Here we examine the accumulation of VCAN as a marker of immune exclusion and its proteolysis as a marker of an immune-permissive TME. Methods: Immunohistochemistry for VCAN, Vkine and CD8+ was performed on samples from 1662 pts across breast (BC), CRC, endometrial cancer, pancreatic adenocarcinoma (PDAC), esophageal cancers and neuroendocrine tumors (NETs), across stages of disease (I-IV) and with diverse prior treatments. Stromal intensities of VCAN and Vkine staining quantified in collaboration with blinded surgical pathologists using a 0-3+ scale. 0/1+ were considered “low” for both VCAN and Vkine, whereas 2/3+ were considered “high”. The number of CD8+ TILs were counted using 400x magnification, the equivalent of a high power field (hpf). Results: Across the entire cohort VCAN phenotypes were diverse (VCAN high/Vkine low, 21%; VCAN high/Vkine high, 23%; VCAN low/Vkine low, 29%; VCAN low/Vkine high (VPP), 27%). Consistent with VCAN accumulation as a marker of T cell exclusion, VCAN low cancers had increased TILs compared to VCAN high (4.8 vs 18.3 TILs/hpf, p < 0.001). Low VCAN was identified in 85% esophageal, 79% NET (including small cell lung cancer [SCLC]) 72% endometrial, 47% MSI-H CRCs, 28% triple-negative BC and only 22% MSS CRC, 18% PDAC, 17% ER+ BCs. The VPP subgroup had the highest TILs per hpf across tumors. VPP was identified in 47% of esophageal, 45% endometrial, 41% NETs (including SCLC), 24% MSI-H CRCs, and only 9% MSS CRC, 7% ER+ BCs, 3% triple-negative BCs, and 0% of PDAC (n = 131 PDAC pts). Conclusions: VCAN accumulation correlates with T lymphocyte exclusion, while VCAN proteolysis predicts an immune permissive phenotype. VCAN accumulation and proteolysis are now incorporated into ICI clinical trials as a potential marker of response. Future studies will clarify the role of these biomarkers in predicting benefits of immuno-oncology treatment strategies.
ESR1 mutations provide novel targets for breast cancer immunotherapy.
Authors: Goldberg Jonathan , Qiao Na , Gross Brett , Meric-Bernstam Funda , Guerriero Jennifer , Chen Ken , Philips Anne V. , Peoples George Earl , Alatrash Gheath , Mittendorf Elizabeth A. 
Published: May 2020

3135 Background: Estrogen receptor (ER)-positive breast cancer is not considered immunogenic. Standard treatment is endocrine therapy to include aromatase inhibitors (AI). However, constitutively activating mutations in estrogen receptor alpha ( ESR1) emerge with treatment making tumors resistant to AI therapy. While these mutations represent a pathway of resistance, they also represent potential neoepitopes that can be targeted with immunotherapy. Here we characterize the role of ESR1 mutations as novel targets for breast cancer immunotherapy. Methods: Immunogenic epitopes derived from mutated ESR1 (i.e. D538G, Y537S and E380Q) were identified in silico using the Immune Epitope Database and by determining overlapping peptides. In vitro T2 binding assays were used to measure the affinities of these peptides to HLA class-I, specifically HLA-A*0201. Dissociation assays were employed to characterize the stability of the peptide-HLA complex. Peptide-HLA-A*0201 tetramer staining was used to determine the expansion potential of peptide-specific cytotoxic T lymphocytes (CTL) from peripheral blood of healthy females. Cytotoxicity assays were used to determine the ability of peptide-specific CTLs to lyse cells presenting mutated ESR1-derived peptides. Results: We identified 22 nonameric and decameric peptides derived from the most common ESR1 mutations; 10/22 demonstrated high affinity (i.e. IC50 < 500nM) binding to HLA-A*0201. The 3 highest predicted peptides demonstrated low IC50 values (13 nM, 19.5 nM and 56.6 nM), indicating very tight binding to HLA-*0201. In vitro assays confirmed high affinity binding for 10 of the 22 in silico-predicted peptides with an average fold change of 1.52 compared to non-pulsed T2 cells, and a median dissociation half-life of 6.45 hours. Tetramer staining of peptide specific CTLs from normal donor peripheral blood mononuclear cells showed relatively high expansion frequencies, with the highest three frequencies noted for D538G (1.04%), Y537S (0.49%) and V392I (0.27%). Using 4-hour in vitro cytotoxicity assays, in comparison with non-pulsed T2 cells, there was significantly higher lysis of peptide pulsed T2 cells that were cocultured with matching peptide-specific CTL: D538G (67.1 % vs 36.9%, P < 0.001), Y537S (59.5% vs 37.5%, P < 0.01), and E380Q (36.3% vs 7.8%, P < 0.001). Conclusions: These data confirm the immunogenicity of epitopes derived from the most common ESR1 mutations. Further investigation of these peptides as part of novel immunotherapies, to include vaccine strategies is warranted.
Personalized viral-based prime/boost immunotherapy targeting patient-specific or shared neoantigens: Immunogenicity, safety, and efficacy results from two ongoing phase I studies.
Authors: Drake Charles G. , Johnson Melissa Lynne , Spira Alexander I. , Manji Gulam Abbas , Carbone David Paul , Henick Brian S. , Ingham Matthew , Liao Chih-Yi , Roychowdhury Sameek , Kyi Chrisann , Basciano Paul Andrew , Bournazou Eirini , Abhyankar Jesse , Bezawada Ashish , Kounavouth Sonia , Schenk Desiree , Ferguson Andrew R. , Rousseau Raphael F. , Catenacci Daniel V.T. 
Published: May 2020

3137 Background: Neoantigens are key targets of a tumor-specific immune response and CD8 T cells targeting neoantigens drive clinical benefit in patients (pts) treated with checkpoint inhibitors. Methods: Two Phase I studies are being conducted to assess the safety, immunogenicity, and early clinical activity of a viral-based neoantigen-targeting prime/boost immunotherapy aimed at maximizing the CD8 T cell response. Both studies use a chimpanzee adenovirus prime followed by increasing doses of repeat boosts with a self-amplifying mRNA in combination with IV nivolumab +/- SC ipilimumab. In the first study, GO-004, patient-specific neoantigens are predicted using Gritstone's EDGE model and incorporated into both prime/boost vectors. In GO-005, shared neoantigens derived from common driver mutations (including several from KRAS) are encoded in off-the-shelf prime/boost vectors. Results: To date, 12 pts have been treated: 6 pts with GEA, NSCLC, or MSS-CRC (GO-004) and 6 pts with NSCLC, MSS-CRC, or PDA (GO-005) with all pts receiving IV nivolumab and 5 pts also receiving SC ipilimumab. Nine pts continue to receive study treatment. No DLTs have been observed. Treatment-related AEs are reversible and include Grade 1/2 fever (7/12), injection site reactions (4/12), fatigue (3/12), diarrhea (2/12), hypotension (2/12), pruritus (2/12), skin reactions (2/12), anorexia (1/12), dyspnea (1/12), hyponatremia (1/12), infusion-related reactions (1/12), myalgia (1/12), and asymptomatic Grade 3 CK elevation (1/12). At the time of analysis, 8 of 12 pts with ≥ 1 radiographic assessment have a best response of stable disease (SD) (3) and progressive disease (PD) (4), and one pt with no evaluable disease at baseline continues on study > 8 months. In GO-005, 1 pt with SD has a 20% reduction in tumor dimensions that correlates with a decrease in ctDNA. In 4 pts in GO-004 analyzed to date, all pts showed substantial neoantigen-specific CD8 T cell responses to multiple neoantigens after priming which increase further in 2 of 3 pts analyzed after subsequent boosts. In GO-005, 1 of 3 pts showed a robust KRAS G12C-specific CD8 T cell response. Induced T cells express IFNg and granzyme B, consistent with an effector response. Conclusions: Taken together, these early data support the tolerability of a viral-based prime/boost immunotherapy, demonstrate marked immunogenicity, and are consistent with potential clinical activity. Additional pts and data at higher dose levels will be presented. Clinical trial information: NCT03639714, NCT03953235 .
Phase I study of 9-ing-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, as a single agent and combined with chemotherapy, in patients with refractory tumors.
Authors: Carneiro Benedito A. , Cavalcante Ludimila , Bastos Bruno R. , Powell Steven Francis , Ma Wen Wee , Sahebjam Solmaz , Harvey Donald , De Souza Andre Luiz , Dhawan Mallika Sachdev , Safran Howard , Giles Francis J. , Munster Pamela N. 
Published: May 2020

3507 Background: Overexpression of GSK-3β, a serine/threonine kinase, is associated with advanced stage malignancies, aggressive tumor growth, and chemotherapy resistance. 9-ING-41 is a GSK-3β inhibitor with significant broad spectrum pre-clinical antitumor activity, including chemotherapy-resistant models. This first-in-human study (NCT03678883) is evaluating the safety, pharmacokinetics (PK), and efficacy of 9-ING-41 monotherapy and in combination with chemotherapy in patients (pts) with refractory malignancies. Methods: 9-ING-41 is given intravenously (IV) twice-weekly as a single-agent (21-day cycle) or combined with gemcitabine, gemcitabine/nab-paclitaxel, carboplatin, carboplatin/paclitaxel, doxorubicin, lomustine or irinotecan in patients previously treated with the same chemotherapy. Results: As of Jan 2020, 101 pts were enrolled. Tumor types: 25 pancreatic (PDAC), 14 colorectal (CRC), 10 non-small cell lung cancer (NSCLC), 8 GBM and other gliomas, 7 melanoma, 5 appendiceal, 4 breast (BC), 30 others. Seven single agent dose levels (DL) completed (1, 2, 3.3, 5, 7, 9.3, 12.4 mg/kg) without any 9-ING-41-attributable SAEs. 9-ING-41 attributable AEs include: transient visual change (color perception; n = 29), starting at DL 3 (3.3mg/kg), all G1/2; infusion reactions (n = 14), all G1/2, starting at DL 5 (7mg/kg). 9-ING-41’s mean terminal half-life is 12-20 hrs. Cmax and AUC0-72, are dose proportional with no accumulation. One BRAFV600K-mutated melanoma with > 20 brain metastases, post checkpoint/BRAF/MEK failure has an ongoing CR starting at cycle 2 and sustained after 9 months on treatment. 32 (31%) pts had SD as best response (6 PDAC, 6 CRC, 3 appendiceal, 2 BC, 2 salivary gland, 2 melanoma, 1 Merkel cell, 2 GBM/glioma, 1 RCC, 1 HCC, 1 NSCLC, 1 esophageal, 1 parotid gland, 1 nasopharyngeal, 1 peritoneal, 1 T cell-ALL). 8 pts remained on study treatment > 5 months (1 melanoma, 3 PDAC, 1 appendiceal, 1 GBM, 1 peritoneal, 1 salivary gland) with median treatment duration of 198 days (range 163-261). 32 pts continue to receive 9-ING-41. Conclusions: 9-ING-41 has dose-proportional PK, is well tolerated with significant antitumor activity as monotherapy and in combination with chemotherapy in pts with refractory tumors. 1 ongoing CR was observed in a refractory BRAF-mutated melanoma. A biologically active dose has been reached, although MTD has not been determined. Enrollment is ongoing. Clinical trial information: NCT03678883 .
Utility of circulating tumor DNA (ctDNA) versus tumor tissue clinical sequencing for enrolling patients (pts) with advanced non-colorectal (non-CRC) gastrointestinal (GI) cancer to matched clinical trials: SCRUM-Japan GI-SCREEN and GOZILA combined analysis.
Authors: Ohba Akihiro , Nakamura Yoshiaki , Taniguchi Hiroya , Ikeda Masafumi , Bando Hideaki , Mizuno Nobumasa , Kato Ken , Morizane Chigusa , Nishina Tomohiro , Ueno Makoto , Furuse Junji , Hara Hiroki , Denda Tadamichi , Kawakami Hisato , Esaki Taito , Moriwaki Toshikazu , Yasui Hisateru , Komatsu Yoshito , Yoshino Takayuki , Ohtsu Atsushi 
Published: May 2020

3516 Background: We recently reported that clinical assessment of genomic biomarkers using ctDNA had advantages over tumor tissue-based sequencing for enrollment into matched clinical trials across a wide range of GI cancers. Herein we investigated the utility of ctDNA in non-CRC cancers in a SCRUM-Japan GI-SCREEN and GOZILA combined analysis. Methods: In GI-SCREEN, tumor tissue samples of pts with non-CRC were analyzed by a next generation sequencing (NGS)-based assay, Oncomine Comprehensive Assay, since Feb 2015. In GOZILA, plasma samples of non-CRC pts were analyzed by an NGS-based ctDNA assay, Guardant360, since Feb 2018. Results: As of Apr 2019, 2,952 pts in GI-SCREEN and 633 pts in GOZILA were enrolled. Baseline characteristics between the groups were well matched except that GOZILA included more pancreatic (P < 0.0001) and liver cancers (P = 0.016) but fewer gastric cancers (P < 0.0001) and GIST (P = 0.020) than GI-SCREEN. The success rates of the tests were 86.6% in GI-SCREEN and 87.3% in GOZILA (P = 0.649). Median turnaround time (TAT) was 37 days in GI-SCREEN and 12 days in GOZILA (P < 0.0001). The proportion of cases with actionable alterations detected (tissue vs blood; 29.8% vs 46.8%, P < 0.0001) and enrolled into matched clinical trials (4.8% vs 6.5%, P = 0.286) for each group by cancer type are shown in the Table. Pts with upper GI cancers, especially those in GOZILA, were more often enrolled into matched trials; trial enrollment for those with hepatobiliary and pancreatic (HBP) or other cancers was similar regardless of testing method. Median time from GI-SCREEN or GOZILA enrollment to clinical trial enrollment was 5.0 and 1.0 months (mo), respectively (P < 0.0001). Objective response rates (ORR) and progression-free survival (PFS) were not significantly different (tissue vs. blood; ORR: 14.6 vs. 26.3%, P = 0.30: median PFS: 3.3 vs. 2.6 mo, P = 0.71). Conclusions: Clinical sequencing of ctDNA, with its shorter TAT, contributed to rapid enrollment of non-CRC pts into matched clinical trials compared to those tested by tumor tissue sequencing, particularly for those with upper GI cancer, without compromising efficacy. Clinical trial information: UMIN000029315 . [Table: see text]
A phase Ib study of simmitecan (LP) single-agent and in combination with 5-fluorouracil/leucovorin (5-FU/LV) or thalidomide (T) in patients with advanced solid tumor.
Authors: Gong Jifang , Deng Ting , Li Jie , Lu Ming , Li Jian , Ba Yi , Yu Qiuqiong , Shen Lin 
Published: May 2020

3523 Background: Simmitecan (LP), a novel 9-substituted lipophilic camptothecin derivative, is a potent inhibitor of topoisomerase I with anti-tumor activity single agent or in combination with other anti-tumor agents, i.e. thalidomide or anti-PD-1 antibody in xenograft models. In this phase Ib study (NCT02870036), we evaluate the safety and anti-tumor effects of LP as monotherapy or in combination therapies in patients (pts) with advanced solid tumors. Methods: This open-label, multi-cohort phase Ib study was conducted at 3 academic centers in China. Eligible pts had advanced cancer without standard treatment options. Prior irinotecan treated failure pts was eligible. In the single agent study, enrolled pts was allocated to received intravenous(iv) 50, 80, or 120 mg/m2 of LP Q2W to determine the safety of LP. After single agent study finished, enrolled pts allocated in LP+5-FU/LV cohorts received 50, 65, or 80 mg/m2 of LP then LV 400 mg/m2 and 5-FU bolus at 400 mg/m2 followed by 5-FU continuous iv of 2400 mg/m2 Q2W; pts in LP+T cohorts received LP 65 mg/m2 Q2W + thalidomide 50mg QD or thalidomide 100mg QD, or LP 80 mg/m2 Q2W + thalidomide 50mg QD. Treatment repeated in 28-day cycles until disease progression or unacceptable toxicity. Results: Between October 2016 to February 2019, 41 pts, median age of 55.1 (range 29-69) years, were enrolled, 13 in LP monotherapy, 10 in LP + 5-FU/LV and 18 in LP + T. Over all, no dose limited toxicity (DLT) occurred. The most common (≥20%) grade 3/4 AE among three regimens was neutropenia (44%, 70% and 89% respectively in LP, LP+5FU/LV and LP+T),and treatment related SAEs were similar, i.e. anemia and febrile neutropenia (11.1% each) in LP, diarrhea (10%) in LP+5-FU/LV, febrile neutropenia (5.6%) in LP+T. Majority of enrolled pts (24/41, 59%) had progressed on prior irinotecan, nevertheless, partial response (PR) was observed in 1 colorectal cancer pt treated with LP 80 mg/m2 + thalidomide 50mg. Disease control rate (DCR, SD≥12 weeks or CR or PR) were 60%, 80% and 61% and median progress free survival were 2.71, 4.17 and 2.76 months respectively in LP, LP + 5-FU/LV and LP+T cohorts. Conclusions: This study showed the safety profiles are manageable, either LP monotherapy or combination therapies, no DLT or safety concern was elicited in combination compared to single agent, and the LP + 5-FU/LV regimen showed higher DCR. A phase II study in pts with metastatic NEC is on-going to explore safety and efficacy of LP + 5-FU/LV regimen combined with toripalimab, an anti-PD-1 antibody. Clinical trial information: 02870036 .