bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study to evaluate the T-cell engager AMV564 alone and in combination with pembrolizumab in subjects with advanced solid tumors.
Authors: Starodub Alexander , Piha-Paul Sarina Anne , Karim Raghad , Ruegg Curtis , Smith Victoria , Chun Patrick Youngwhan 
Published: May 2020

3101 Background: Overcoming the immune-suppressive tumor environment induced by myeloid-derived suppressor cells (MDSC) is a major challenge in immune therapy. CD33 signaling in immature myeloid cells promotes expansion of MDSC and production of immune-suppressive factors. AMV564 is a bivalent, bispecific T-cell engager that binds CD3 and CD33. Preferential binding of AMV564 to areas of high CD33 density enables selective targeting of MDSC. Ex vivo data (Cheng 2017; Blood;130:51) and an ongoing clinical trial in acute myeloid leukemia (NCT03144245) demonstrate the ability of AMV564 to deplete MDSC while sparing monocytes and neutrophils. Methods: In this 3+3 dose escalation study, patients with advanced solid tumors receive AMV564 once daily via subcutaneous (SC) injection for 2 out of 3 wks per cycle, alone or in combination with pembrolizumab (200 mg every 3 wks). Key objectives are to evaluate AMV564 safety, identify a maximum tolerated or recommended phase 2 dose, and evaluate PK, immunophenotype of myeloid and T cell compartments, and preliminary efficacy. Results: Eleven patients have been enrolled: 8 monotherapy (3 at 15 mcg/d, 5 at 50 mcg/d) and 3 combination (5 mcg/d). Tumor types include ovarian (n = 2), small bowel, gastroesophageal junction, endometrial, rectal, penile, urothelial, squamous cell carcinoma (skin), appendiceal, and non-small cell lung. AMV564 was associated with grade (G) 1-2 injection site reactions and G1-2 fevers, which were manageable with acetaminophen and diphenhydramine, as well as G2 weight gain and G3 anemia. No dose-liming toxicity has been observed in any cohort. Three monotherapy patients (15 mcg/d) were evaluable for efficacy with ≥1 on-treatment scan; 2 had SD and 1 PD per RECIST 1.1 criteria. T cell activation, as shown by redistribution from the periphery (margination), was apparent in the first week of dosing for most patients. Compensatory myelopoiesis led to initial expansion of MDSC which were then depleted by AMV564. Increased cytotoxic T cell activation and T-helper (Th) 1 response was evidenced by increased T-bet positive CD4 and CD8 cells and controlled or decreased regulatory T cells. In some patients, effector memory CD8 cell populations (Tem and Temra) were expanded. Conclusions: AMV564 is safe and tolerable when administered SC at doses of 15 mcg/d alone and 5 mcg/d in combination with pembrolizumab. AMV564 depleted MDSC populations and altered T cell profiles consistent with activation of cytotoxic T cells and a Th1 response. Clinical trial information: NCT04128423 .
An increase in serum choline levels to predict progression-free survival (PFS) in patients (pts) with advanced cancers receiving pembrolizumab.
Authors: Watson Geoffrey Alan , Zhang Wenjiang , Liu Zhihui (Amy) , Spreafico Anna , Hansen Aaron Richard , Bedard Philippe L. , Lheureux Stephanie , Abdul Razak Albiruni Ryan , Cescon David W. , Butler Marcus O. , Xu Wei , Mak Tak , Siu Lillian L. , Chen Eric Xueyu 
Published: May 2020

3102 Background: Recent work from our laboratory demonstrated that T cell-derived acetylcholine induces vasodilation and increases T cell migration to infected tissues in response to viral infection (Cox et al. Science 2019). Choline acetyltransferase catalyzes the production of acetylcholine from choline and acetyl-CoA, however acetylcholine is challenging to quantify due to its extremely short half-life while choline is stable. This study is the first reported attempt to correlate serum choline levels in patients (pts) with advanced solid tumors receiving pembrolizumab with treatment outcomes. Methods: Blood samples were collected pre-treatment in 106 pts treated with pembrolizumab 200 mg IV Q3W in the investigator-initiated INSPIRE study (NCT02644369). Of these, 81 pts had on-treatment blood samples collected at week 7 (pre-cycle 3). Serum choline was analyzed with an HPLC-tandem mass spectrometry assay. PD-L1 staining was performed in baseline tumor tissues using 22C3 antibody and scored using modified proportion score. Tumor mutational burden (TMB) was calculated based on number of nonsynonymous mutations detected using whole exome sequencing. Multivariable Cox models were used to assess the impact of choline on PFS and OS, while adjusting for cohort, PD-L1 expression and TMB. Results: This pan-cancer group of 106 pts (median age 55, 62% females) comprised of 5 cohorts: squamous cell carcinoma of the head and neck = 19 pts, triple negative breast cancer = 22, high grade serous ovarian cancer = 21, melanoma = 19, mixed solid tumors = 32. With a median follow-up of 11 months, the median PFS = 1.9 months and median OS = 13.9 months for the entire cohort. In univariable analysis adjusted by cohort, baseline serum choline levels in 106 pts did not correlate with PFS or OS. However, an increase in serum choline level at week 7 compared to pre-treatment (D choline) in 81 pts was significantly associated with a better PFS (aHR 0.49, 95% CI 0.28-0.85, p = 0.01), and a trend towards a better OS (aHR 0.57, 95% CI 0.32-1.03, p = 0.064). In multivariable analysis, D choline remains significantly associated with an improved PFS (p = 0.0087) after adjustment for cohort, PD-L1 and TMB. Conclusions: This is the first exploratory report of serum choline levels in pan-cancer pts receiving pembrolizumab. The association between improved PFS and D choline suggests a possible role for the cholingeric system in the regulation of antitumor immunity. Further nonclinical and clinical studies are required to validate this finding.
A phase I, dose-escalation study of ADG106, a fully human anti-CD137 agonistic antibody, in subjects with advanced solid tumors or relapsed/refractory non-Hodgkin lymphoma.
Authors: Zhang Li , Zhao Hongyun , Ma Yuxiang , Zheng Xin , Jiang Ji , Zhang Yang , Hong Shaodong , Liu Guizhong , She Xiaohong , Ni Qingjiang , Zhu Lvyu , Zhu Yi , Du Fangyong Felix , Luo Peter 
Published: May 2020

3105 Background: ADG106 is a fully human agonistic anti-CD137 monoclonal IgG4 antibody, targeting a unique epitope of CD137 with novel mechanism of actions for CD137 agonism, CD137 ligand antagonism and potent cross-linking via FcgRIIb. This phase 1 study was conducted to assess its safety, tolerability, pharmacokinetic (PK) profile, immunogenicity and preliminary efficacy. Methods: Eligible patients with age 18 to 75, ECOG ≤1, measurable lesion received intravenous infusion of ADG106 every 3 weeks for a maximum of 24 months. Accelerated titration was applied in 0.1mg/kg dose level and traditional Fibonacci 3+3 method was applied in 0.5, 1.5, 3.0, 5.0 and 10.0 mg/kg dose levels. A dose-expansion cohort will be started for dose levels that have been proved tolerable and with evidence of clinical or biological activity. Results: Data cutoff at Jan 17 2020, 15 patients [5 adenoid cystic carcinoma (ACC), 5 non-small cell lung cancer (NSCLC), 3 nasopharyngeal carcinoma, 1 malignant pleural mesothelioma and 1 follicular lymphoma] were enrolled and received treatment: 0.1mg/kg (n = 1), 0.5mg/kg (n = 3), 1.5mg/kg (n = 5), 3mg/kg (n = 3), and 5mg/kg (n = 3). Of these 15 patients, 6 with ongoing treatment, 9 discontinued (8 progression disease, 1 lack of clinical benefit). Medium treatment duration was 2 cycles (range 2-8). No dose limiting toxicities were observed. Seven (47%) patients experienced treatment-related AEs (TRAEs): rash (13%), pruritus (13%), nausea (7%), pyrexia (7%), hemoptysis (7%), mouth ulceration (7%), vomiting (7%), chest discomfort (7%), LDH increased (7%). All TRAEs were grade 1, no grade ≥3 occurred. One serious adverse event (anemia, not related) was observed. Pharmacokinetic analysis of ADG106 showed a half-life ranging from 5~10 days, with dose-dependent increase of systemic exposure. Treatment induced anti-drug antibodies were developed in 3 (20%) patients. No objective response was observed among the 14 evaluated patients. Disease control rate was 57% (8 stable disease), tumor shrinkage was observed in 3 (21%) patients (2 ACC, 1 NSCLC). Conclusions: ADG106 is safe and tolerable at doses up to 5 mg/kg in solid tumors and non-Hodgkin lymphoma. The dose expansion cohorts have started at selected doses. Clinical trial information: NCT03802955 .
The prevalence of HLA LOH across 10 cancer types in Chinese patients.
Authors: Huang Jian'An , Hu Jie , Fu Xiaorui , Zhang Xiuqing , Tong Fan , Du Xinhua , Luo Ziwen , Yi Yuting , Guan Yan-Fang , Xia Xuefeng 
Published: May 2020

3124 Background: Recognition of tumor neoantigen is the key to generating immune response. The expression and integrity of human leukocyte antigen (HLA) are the prerequisites for neoantigen presentation, and loss of heterozygosity in HLA (HLA LOH) may facilitate immune evasion. However, the incidence of HLA LOH in Chinese cancer patients is unknown. Methods: In this study, 45 samples sequenced with both 1021-gene panel and whole-exome sequencing(WES) were used to evaluate the consistency of HLA LOH in the two testing strategies. The prevalence of HLA LOH analysis was performed in 1546 advanced patients across 10 diverse cancer types and 114 early-stage lung cancer patients who had undergone tumor profiling using 1021-gene panel. Exon 2, exon 3 and bilateral introns of HLA-A/B/C genes were well covered in 1021-gene panel. HLA LOH were analysis using LOHHLA algorithm (McGranahan, et al. 2017). Results: In the HLA LOH analysis of 45 samples, the consistency of 1021-gene panel and WES was 95.6% (43/45). Among the 1660 samples, 1.3% (21) were detected as HLA homozygous at all of the three site. HLA LOH was found in 45.1%(697/1546) of all the advanced patients, range from 24.1% to 59.7%. In colorectal cancer, the HLA LOH ratio of MSS samples was significantly higher than that of MSI-H samples (46.2%, 61/132 vs 16.7%, 3/18 p =0.0214). For NSCLC, the proportion of HLALOH in early-stage (I-IIIa) lung adenocarcinoma and lung squamous cell carcinoma was 25.7% (18/70) and 65.9% (29/44), respectively, consistent with the report. However, advanced (IIIa-IV) lung adenocarcinoma and lung squamous cell carcinoma were 49.4%(168/340) and 58.7%(179/305), respectively. The reason for the difference between early-stage lung adenocarcinoma and advanced lung adenocarcinoma needs further study. In 43.8% of cases (326/744), LOH occurred simultaneously in HLA-A, B and C,suggesting that the Class I locus was often lost together. Conclusions: We can use multi-gene panel for HLA LOH analysis, provided that the relevant regions are well captured. The prevalenceof HLA LOHpresent differences among cancer types.Understanding these distributions may provide more information for immunotherapy research. [Table: see text]
Personalized neoantigen/cancer testis antigen nanovaccine (PVAC) in combination with PD-1 monoclonal antibody and/or antiangiogenic treatment in patients with metastatic solid tumors.
Authors: Wei Jia , Liu Qin , Sha Huizi , Qian Hanqing , Shao Jie , Zhu Lijing , Wang Lifeng , Li Rutian , Liu Baorui 
Published: May 2020

3134 Background: T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated to drive anti-tumor responses. Nanotechnology has been reported to enhance immune responses of vaccines. Moreover, immunizing patients against such neoantigens, in combination with checkpoint inhibitor (CPI) and/or antiangiogenic drugs may elicit greater anti-tumor responses. Methods: Patient-specific mutation-containing neoantigens were selected on the basis of tumour-specific mutations whole-exome sequencing (WES) and RNA sequencing. Cancer testis antigens were obtained according to immunohistochemical staining and HLA-binding affinity prediction. Personalized neoantigen/cancer testis antigen nanovaccine (PVAC) is an amphiphiles nanovaccine loaded with personalized vaccine encoding multiple neoantigens designed to induce neoantigen specific T cells responses. Patients will receive PVAC in combination with PD-1 monoclonal antibody and/or antiangiogenic drugs. Primary end points include safety and tolerability. Results: 13 microsatellite stability (MSS) patients, which had relapsed from standard treatments, are enrolled in this study. 5 patients (1 gastric cancer, 1 liver cancer, 1 cervical carcinoma, 1 soft tissue sarcoma, 1 renal carcinoma) received PVAC in combination with PD-1 mAb, and another 8 patients (3 gastric cancer, 2 colon cancer, 1 NSCLC, 1 renal carcinoma) received PVAC in combination with PD-1 mAb and antiangiogenic therapy. No DLTs were reported. Five patients developed grade 1 and one patients developed grade 2 subcutaneous indurations in the injection sites, which collected with nanovaccine. One patient had grade 2 rash caused by antiangiogenic drug. No drug related SAEs have been observed. There are 1 CR, 6 PR, 4 SD and 2 PD. Neoantigen specific T cell responses have been detected by IFN-γ ELISpot from PBMCs. Conclusions: PVAC is safe and well tolerated. Clinical responses have been observed in combination with PD-1 mAb and antiangiogenic drugs and neoantigen-specific T cell response have been observed after vaccination. Clinical trial information: ChiCTR1900022986 .
Safety and tolerability of intratumorally administered OH2, an oncolytic herpes simplex virus 2, in patients with advanced solid tumors: A phase I dose escalation clinical study.
Authors: Huang Jing , Zhang Bo , Tang Jialin , Chang Qing , Zhang Rui , Geng Chengyun , Wu Dawei , Qi Ling , Gu Xiangyong , Liu Binlei 
Published: May 2020

3139 Background: There have been limited reports concerning treatment outcomes of oncolytic viruses in solid tumors other than melanoma. OH2 is a genetically engineered oncolytic herpes simplex virus type 2 designed to selectively amplify in tumor cells and express GM-CSF to enhance tumor-specific immune responses. Methods: We conducted an open-label, single-center, phase 1 study. Eligible pts were 18-75 years of age; had histologically confirmed advanced solid tumor; had progressed after standard systemic treatments. Pts were required to have tumor(s) deemed safe to inject, with a longest diameter of at least 0.5cm. Other eligibility criteria included measurable lesion as per RECIST v1.1; ECOGPS score of 0-1 and adequate organ functions. A 3+3 dose-escalation strategy was used in the study and 3 dose levels (106, 107 and 108 CCID50/mL) of OH2 were assessed. OH2 was administered intratumorally every 3 weeks for the first cycle and every 2 weeks.Treatment may continue afterwards in ptswith potential clinical benefit at the discretion of the investigators. The primary objective was the safety and tolerability of OH2 injection as defined by the dose limiting toxicities (DLTs) within the first 3 weeks of therapy, and the maximum tolerated dose (MTD). Secondary objectives included efficacy and immunogenicity of OH2. Results: 11 pts were enrolled between April 17, 2019 and November 4, 2019. The median follow-up duration was 8.36 months (95%CI: 5.64-11.08). OH2 was well-tolerated as no DLTs were reported and no MTD reached. Before the end of the DLT assessment period,1 pt withdrew consent, and 1 pt died of arrhythmia unrelated to OH2, with negative OH2 DNA copies in serum, urine and saliva samples. Most treatment-related adverse events (TRAEs) observed were of grade 1-2, except that 1 pt in the 108 CCID50/mL group developed grade 3 fever. The most common TRAEs were fever (n =5) and blood bilirubin level increase (n = 4). There were no grade 4 or 5 TRAEs. One pt(rectal cancer) had PR and 2 (appendix cancer and ovarian cancer) had SD as per RECIST v1.1. One patient (esophageal cancer) achieved iPR as per iRECIST criteria. The duration of follow-up for the 2 responders were 9.70 months and 8.36 months, respectively, and both had ongoing responses. Notably, regression of a non-injected lesion was observed in 1 patient. Conclusions: OH2 had a favorable safety profile with no DLTs and MTD. The dose expansion study in selected tumor types is currently underway. Clinical trial information: NCT03866525 .
Analysis of mutation detection of POLD1/pole in pan-cancer.
Authors: Yang Gao , Huang Jian'An , Zu Yukun , Zhang Yan , Dai Pingping , Han Yaqian , Geng Guojun , Zhu Xiaolei , Chang Ruimin , Huan Jiaojiao , Chen Chen , Guan Yan-Fang , Yang Ling , Yi Xin , Xia Xuefeng 
Published: May 2020

3142 Background: Previous studies proved that mutation of POLD1 and POLE elevates base-substitution mutations and lead to the elevation of tumor mutation burden (TMB). Other signature needs to explore to identify driver mutations in these two genes. Methods: Using gene-panel target-capture next generation sequencing, we analyzed the TMB and POLD1/POLE mutation in 17383 tumor tissue or plasma ctDNA samples from different patients. Results: Tumor mutation burdens were calculated of all the 17383 samples. According to the present research and our panel, we use 10 and 100 Mut/Mb to define hypermutation and ultra-hypermutation. Samples with hypermutation possessed 18.8% (n = 3268) and ultra-hypermutation possessed 0.3% (n = 58). In unselected, hypermutation and ultra-hypermutation group, POLD1 or/and POLE mutations were identified in 3.5% (n = 625), 56.1% (n = 32) and 87.9%(n = 372) samples. There were 0.5% (n = 81), 17.0% (n = 73) and 87.7%(n = 51) identified more than one mutation. These results showed that POLD1 or/and POLE mutations were enriched in samples with high TMB. We screened every known POLE and POLD1 driver mutations. There were 22 ultra-hypermutation samples identified these mutations, including A456P(3), P286R(10), V411L(6), M444K(1), S459F(1) in POLE and R1016H(1) in POLD1. Interestingly, all of them were identified in microsatellite stable (MSS) samples, which suggest that driver mutation may enriched in MSS samples. These already known driver mutation was not detect in 24 high-level microsatellite instability (MSI-H) and ultra-hypermutation samples. We further analyzed 10 POLD1/POLE mutations in other 5 MSS and ultra-hypermutation samples. POLE L424V was a pathogenic germline mutation but not defined as a driver mutation clearly before. POLE P286C had not been biochemically characterized but had different residue with P286R in the same position. Others had not been biochemically characterized (R232H, A234T, V945M, S1064I, Y467H in POLD1, D462N and R749Q, E1956D in POLE). These mutations were potential driver mutations and further research need to be support. Conclusions: We found that not only POLD1 or/and POLE mutations were enriched in samples with high TMB, but also driver mutations were enriched in microsatellite stable tumors. Further researches need to continue to identify more driver mutations of POLD1 and POLE.
CX-2029, a PROBODY drug conjugate targeting CD71 (transferrin receptor): Results from a first-in-human study (PROCLAIM-CX-2029) in patients (Pts) with advanced cancer.
Authors: Johnson Melissa Lynne , El-Khoueiry Anthony B. , Hafez Navid , Lakhani Nehal J. , Mamdani Hirva , Rodon Ahnert Jordi , Sanborn Rachel E. , Ho Thang , Li Rachel , Waldes Jana , Spira Alexander I. 
Published: May 2020

3502 Background: CX-2029 is a PROBODY drug conjugate (PDC) of MMAE, a potent microtubule inhibitor, directed against CD71 (transferrin receptor 1). In addition to being an abundant tumor antigen, CD71 is highly expressed on normal cells, precluding targeting by a traditional antibody drug conjugate (ADC). PDCs are masked ADCs, unmasked predominantly by tumor-associated proteases, thereby restricting target engagement to tumors. Both a CD71 PDC and ADC displayed broad activity in multiple xenograft tumor models; in toxicology studies, the PDC was tolerable at doses consistent with efficacy in non-clinical tumor models while the ADC was not. Methods: In a phase 1/2 first-in-human study of PDC CX-2029 in advanced solid tumors (N CT03543813 ), pts with ECOG 0–1 and ≥1 prior systemic therapy were enrolled into escalating dose cohorts of the PDC CX-2029 given IV every 21 days. Endpoints included evaluation of MTD, safety, antitumor activity, and potential biomarkers; plasma and tissue samples were collected for PK/PD analyses. Preliminary results are reported. Results: As of 30 November 2019, 34 pts were enrolled (median age 59 y; 59% male; 71% ECOG 1; median [range] of 3 [1–16] prior therapies). Pts received a median of 3 (1–12) CX-2029 doses. Starting dose for escalation was 0.1 mg/kg. Following a single CX-2029 dose, median molar ratio of masked CX-2029 to total CX-2029 for AUCtau was 0.938 (0.864–0.942); the ratio of free MMAE to total CX-2029 was <0.03. Infusion-related reactions were the most common treatment-related AE (TRAE) of any grade (88%; primarily low grade and with first infusion), followed by anemia (56%), fatigue and nausea (24% each), neutropenia (21%), and leukopenia (12%). Grade 3+ TRAEs in ≥10% pts were anemia (35%) and neutropenia (18%). In 32 response-evaluable pts, 1 pt had a confirmed partial response (squamous NSCLC); 9 had stable disease including 1 pt with ocular melanoma treated for 36 weeks. Conclusions: The observed safety profile for CX-2029 effectively reduces on-target toxicity for this previously undruggable target, supporting the PROBODY platform. Evidence of anti-tumor activity was observed. Dose escalation continues. Clinical trial information: NCT03543813 .
Pen-866, a miniature drug conjugate of a heat shock protein 90 (HSP90) ligand linked to SN38 for patients with advanced solid malignancies: Phase I and expansion cohort results.
Authors: Falchook Gerald Steven , Bendell Johanna C. , Ulahannan Susanna Varkey , Sen Shiraj , Vilimas Rasa , Kriksciukaite Kristina , Mei Laura , Jerkovic Goran , Sarapa Nenad , Bilodeau Mark , Bloss Jeffrey , Thomas Anish 
Published: May 2020

3515 Background: PEN-866 is a miniature drug conjugate which links a HSP90 binding small molecule to a SN-38 cytotoxic payload. HSP90 is highly expressed in advanced malignancies. PEN-866 targets and binds to activated tumor HSP90 protein, releases its cytotoxic payload, and results in complete tumor regressions in multiple xenograft models. This first-in-human study assessed safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of PEN-866. Methods: Patients (pts) with progressive, advanced solid malignancies were enrolled in escalating cohorts of 2-9 pts. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of PEN-866 given weekly (3 out of 4 weeks in a 28-day cycle). Results: 30 pts were treated in 8 cohorts (range 30-360 mg flat dosing or 150–200 mg/m2 BSA-based dosing). As of 9Jan20, the total median/mean exposure was 7.05/12.4 weeks. No dose limiting toxicities (DLTs) occurred in the first 4 cohorts (30-240 mg; 14 pts). In cohort 5 (360 mg), 1 of 3 pts had a DLT of grade (G) 3 transient diarrhea, and 2 other pts had G3 uncomplicated transient neutropenia. A change to BSA-based dosing was instituted for cohort 6 (175 mg/m2), on which no DLTs were observed, although 1 pt experienced G3 uncomplicated transient neutropenia. At 200 mg/m2, 2 of 5 pts experienced DLTs (G5 dehydration, G3 fatigue). The MTD and RP2D were determined to be 175 mg/m2. The most frequent (≥20% pts) related adverse events were nausea (50%), fatigue (43%), diarrhea (40%), vomiting (27%), and anemia (23%). PK was nonlinear. Plasma exposures increased greater than dose proportionally. Median t1/2 ~7 h. Cleaved SN38 never exceeded 3% of PEN-866 plasma AUC at all dose levels. Tissue PK confirmed tumor accumulation and retention of both the conjugate and released payload. As of 9Jan20, 26 pts were evaluable for response. 11 pts had stable disease at 8 weeks, of which 7 lasted 12–58 weeks. One pt with anal squamous cell carcinoma achieved a confirmed partial response. Decreased target lesion size was observed in 6 additional pts. Conclusions: PEN-866 was well tolerated and demonstrated preliminary evidence of antitumor activity. PEN-866 will be evaluated in Phase 2a expansion cohorts enrolling multiple solid tumors (NCT03221400). Clinical trial information: NCT03221400 .