bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from PD-1 Blockade Reinvigorates Bone Marrow CD8+ T Cells from Patients with Multiple Myeloma in the Presence of TGFβ Inhibitors
Authors: Kwon Minsuk , Kim Chang Gon , Lee Hoyoung , Cho Hyunsoo , Kim Youngun , Lee Eung Chang , Choi Seong Jin , Park Junsik , Seo In-Ho , Bogen Bjarne , Song Ik-Chan , Jo Deog-Yeon , Kim Jin Seok , Park Su-Hyung , Choi Inhak , Choi Yoon Seok , Shin Eui-Cheol
Published: April 2023

AbstractPurpose:
Immune-checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, anti-programmed death (PD)-1 therapy has not shown clinical efficacy in multiple myeloma.
Experimental Design:
Bone marrow (BM) mononuclear cells were obtained from 77 newly diagnosed multiple myeloma patients. We examined the expression of immune-checkpoint receptors in BM CD8+ T cells and their functional restoration by ex vivo treatment with anti–PD-1 and TGFβ inhibitors.
Results:
We confirmed the upregulation of PD-1 and PD-L1 expression in CD8+ T cells and myeloma cells, respectively, from the BM of multiple myeloma patients. PD-1–expressing CD8+ T cells from the BM of multiple myeloma patients coexpressed other checkpoint inhibitory receptors and exhibited a terminally differentiated phenotype. These results were also observed in BM CD8+ T cells specific to myeloma antigens NY-ESO-1 and HM1.24. BM CD8+ T cells from multiple myeloma patients exhibited reduced proliferation and cytokine production upon T-cell receptor stimulation. However, anti–PD-1 did not increase the proliferation of BM CD8+ T cells from multiple myeloma patients, indicating that T-cell exhaustion in multiple myeloma is hardly reversed by PD-1 blockade alone. Intriguingly, anti–PD-1 significantly increased the proliferation of BM CD8+ T cells from multiple myeloma patients in the presence of inhibitors of TGFβ, which was overexpressed by myeloma cells.
Conclusions:
Our findings indicate that combined blockade of PD-1 and TGFβ may be useful for the treatment of multiple myeloma.
Data from Radiation-Induced Amplification of TGFB1-Induced Mesenchymal Stem Cell–Mediated Sodium Iodide Symporter (NIS) Gene 131I Therapy
Authors: Schug Christina , Kitzberger Carolin , Sievert Wolfgang , Spellerberg Rebekka , Tutter Mariella , Schmohl Kathrin A. , Eberlein Bernadette , Biedermann Tilo , Steiger Katja , Zach Christian , Schwaiger Markus , Multhoff Gabriele , Wagner Ernst , Nelson Peter J. , Spitzweg Christine
Published: April 2023

AbstractPurpose:
The innate tumor homing potential of mesenchymal stem cells (MSCs) has been used for a targeted delivery of the theranostic sodium iodide symporter (NIS) transgene into solid tumors. We have previously shown that external beam radiotherapy (EBRT) results in the enhanced recruitment of NIS-expressing MSCs into human hepatocellular carcinoma (HuH7). In parallel, the tumor-associated cytokine TGFB1 becomes strongly upregulated in HuH7 tumors in response to EBRT.
Experimental Design:
We therefore evaluated the effects of combining focused EBRT (5 Gy) with MSC-mediated systemic delivery of the theranostic NIS transgene under control of a synthetic TGFB1-inducible SMAD-responsive promoter (SMAD-NIS-MSCs) using 123I-scintigraphy followed by 131I therapy in CD1 nu/nu mice harboring subcutaneous human hepatocellular carcinoma (HuH7).
Results:
Following tumor irradiation and SMAD-NIS-MSC application, tumoral iodide uptake monitored in vivo by 123I-scintigraphy was enhanced as compared with nonirradiated tumors. Combination of EBRT and SMAD-NIS-MSC–mediated 131I therapy resulted in a significantly improved delay in tumor growth and prolonged survival in therapy mice as compared with the combined therapy using CMV-NIS-MSCs or to control groups receiving EBRT or saline only, or EBRT together with SMAD-NIS-MSCs and saline applications.
Conclusions:
MSC-based NIS-mediated 131I therapy after EBRT treatment dramatically enhanced therapeutic efficacy when a TGFB1-inducible SMAD-responsive promoter was used to drive NIS expression in adoptively applied MSCs. The remarkable therapeutic effect seen is thought to be linked in large part to the enhanced TGFB1 produced in this context, which leads to a highly selective and focused amplification of MSC-based NIS expression within the tumor milieu.
Data from Tumor Characteristics Associated with Benefit from Pembrolizumab in Advanced Non–Small Cell Lung Cancer
Authors: Hu-Lieskovan Siwen , Lisberg Aaron , Zaretsky Jesse M. , Grogan Tristan R. , Rizvi Hira , Wells Daniel K. , Carroll James , Cummings Amy , Madrigal John , Jones Benjamin , Gukasyan Jacklin , Shintaku I. Peter , Slamon Dennis , Dubinett Steven , Goldman Jonathan W. , Elashoff David , Hellmann Matthew D. , Ribas Antoni , Garon Edward B.
Published: April 2023

AbstractPurpose:
Several biomarkers have been individually associated with response to PD-1 blockade, including PD-L1 and tumor mutational burden (TMB) in non–small cell lung cancer (NSCLC), and CD8 cells in melanoma. We sought to examine the relationship between these distinct variables with response to PD-1 blockade and long-term benefit.
Experimental Design:
We assessed the association between baseline tumor characteristics (TMB, PD-L1, CD4, and CD8) and clinical features and outcome in 38 patients with advanced NSCLC treated with pembrolizumab (median follow-up of 4.5 years, range 3.8–5.5 years).
Results:
PD-L1 expression and CD8 infiltration correlated with each other and each significantly associated with objective response rate (ORR) and progression-free survival (PFS). TMB was independent of PD-L1 and CD8 expression, and trended towards association with ORR and PFS. There was no association between CD4 infiltration and outcomes. Only PD-L1 expression was correlated with overall survival (OS). Among 5 patients with long-term survival >3 years with no additional systemic therapy, PD-L1 expression was the only discriminating feature. The increased predictive value for PFS and OS of composite biomarker inclusive of PD-L1, CD8, CD4, and TMB was limited.
Conclusions:
In patients with NSCLC treated with PD-1 blockade with long-term follow up, TMB, PD-L1, and CD8 were each associated with benefit from PD-1 blockade. Pretreatment PD-L1 expression was correlated with T lymphocyte infiltration and OS, whereas models incorporating TMB and infiltrating CD4 and CD8 lymphocytes did not substantially add to the predictive value of PD-L1 alone for OS.
Data from Intracellular Delivery of an Antibody Targeting Gasdermin-B Reduces HER2 Breast Cancer Aggressiveness
Authors: Molina-Crespo Ángela , Cadete Ana , Sarrio David , Gámez-Chiachio Manuel , Martinez Lidia , Chao Kinlin , Olivera Ana , Gonella Andrea , Díaz Eva , Palacios José , Dhal Pradeep K. , Besev Magnus , Rodríguez-Serrano Macarena , García Bermejo María Laura , Triviño Juan Carlos , Cano Amparo , García-Fuentes Marcos , Herzberg Osnat , Torres Dolores , Alonso Maria José , Moreno-Bueno Gema
Published: April 2023

AbstractPurpose:
Gasdermin B (GSDMB) overexpression/amplification occurs in about 60% of HER2 breast cancers, where it promotes cell migration, resistance to anti-HER2 therapies, and poor clinical outcome. Thus, we tackle GSDMB cytoplasmic overexpression as a new therapeutic target in HER2 breast cancers.
Experimental Design:
We have developed a new targeted nanomedicine based on hyaluronic acid–biocompatible nanocapsules, which allow the intracellular delivery of a specific anti-GSDMB antibody into HER2 breast cancer cells both in vitro and in vivo.
Results:
Using different models of HER2 breast cancer cells, we show that anti-GSDMB antibody loaded to nanocapsules has significant and specific effects on GSDMB-overexpressing cancer cells' behavior in ways such as (i) lowering the in vitro cell migration induced by GSDMB; (ii) enhancing the sensitivity to trastuzumab; (iii) reducing tumor growth by increasing apoptotic rate in orthotopic breast cancer xenografts; and (iv) diminishing lung metastasis in MDA-MB-231-HER2 cells in vivo. Moreover, at a mechanistic level, we have shown that AbGB increases GSDMB binding to sulfatides and consequently decreases migratory cell behavior and may upregulate the potential intrinsic procell death activity of GSDMB.
Conclusions:
Our findings portray the first evidence of the effectiveness and specificity of an antibody-based nanomedicine that targets an intracellular oncoprotein. We have proved that intracellular-delivered anti-GSDMB reduces diverse protumor GSDMB functions (migration, metastasis, and resistance to therapy) in an efficient and specific way, thus providing a new targeted therapeutic strategy in aggressive HER2 cancers with poor prognosis.
Data from Interferon Gamma Messenger RNA Signature in Tumor Biopsies Predicts Outcomes in Patients with Non–Small Cell Lung Carcinoma or Urothelial Cancer Treated with Durvalumab
Authors: Higgs Brandon W. , Morehouse Christopher A. , Streicher Katie , Brohawn Philip Z. , Pilataxi Fernanda , Gupta Ashok , Ranade Koustubh
Published: April 2023

Abstract
Purpose: To identify a predictive biomarker for durvalumab, an anti–programmed death ligand 1 (PD-L1) mAb.

Experimental Design: RNA sequencing of 97 advanced-stage non–small cell lung carcinoma (NSCLC) biopsies from a nonrandomized phase Ib/II clinical trial (1108/NCT01693562) were profiled to identify a predictive signature; 62 locally advanced or metastatic urothelial cancer tumors from the same study were profiled to confirm predictive utility of the signature. Thirty NSCLC patients provided pre- and posttreatment tumors for messenger RNA (mRNA) analysis. NSCLC with ≥25% tumor cells and urothelial cancer with ≥25% tumor or immune cells stained for PD-L1 at any intensity were scored PD-L1 positive (PD-L1+). Kaplan–Meier and Cox proportional hazards analyses were used to adjust for gender, age, prior therapies, histology, ECOG status, liver metastasis, and smoking. Tumor mutation burden (TMB) was calculated using data from The Cancer Genome Atlas (TCGA).

Results: In the NSCLC discovery set, a four-gene IFNγ-positive (IFNγ+) signature comprising IFNγ, CD274, LAG3, and CXCL9 was associated with higher overall response rates, longer median progression-free survival, and overall survival compared with signature-low patients. IFNγ+-signature NSCLC patients had improved survival regardless of IHC PD-L1 status. These associations were replicated in a urothelial cancer cohort. The IFNγ+ signature was induced 2-fold (P = 0.003) by durvalumab after 8 weeks of therapy in patients with NSCLC, and baseline signature was associated with TMB but not survival in TCGA data.

Conclusions: The IFNγ+ mRNA signature may assist in identifying patients with improved outcomes with durvalumab, independent of PD-L1 assessed by IHC. Clin Cancer Res; 24(16); 3857–66. ©2018 AACR.
Data from The Pharmacokinetic–Pharmacodynamic (PKPD) Relationships of AZD3229, a Novel and Selective Inhibitor of KIT, in a Range of Mouse Xenograft Models of GIST
Authors: Pilla Reddy Venkatesh , Anjum Rana , Grondine Michael , Smith Aaron , Bhavsar Deepa , Barry Evan , Guichard Sylvie M. , Shao Wenlin , Kettle Jason G. , Brown Crystal , Banks Erica , Jones Rhys D.O.
Published: April 2023

AbstractPurpose:
The emergence of secondary mutations is a cause of resistance to current KIT inhibitors used in the treatment of patients with gastrointestinal stromal tumors (GIST). AZD3229 is a selective inhibitor of wild-type KIT and a wide spectrum of primary and secondary mutations seen in patients with GIST. The objective of this analysis is to establish the pharmacokinetic–pharmacodynamic (PKPD) relationship of AZD3229 in a range of mouse GIST tumor models harboring primary and secondary KIT mutations, and to benchmark AZD3229 against other KIT inhibitors.
Experimental Design:
A PKPD model was developed for AZD3229 linking plasma concentrations to inhibition of phosphorylated KIT using data generated from several in vivo preclinical tumor models, and in vitro data generated in a panel of Ba/F3 cell lines.
Results:
AZD3229 drives inhibition of phosphorylated KIT in an exposure-dependent manner, and optimal efficacy is observed when >90% inhibition of KIT phosphorylation is sustained over the dosing interval. Integrating the predicted human pharmacokinetics into the mouse PKPD model predicts that an oral twice daily human dose greater than 34 mg is required to ensure adequate coverage across the mutations investigated. Benchmarking shows that compared with standard-of-care KIT inhibitors, AZD3229 has the potential to deliver the required target coverage across a wider spectrum of primary or secondary mutations.
Conclusions:
We demonstrate that AZD3229 warrants clinical investigation as a new treatment for patients with GIST based on its ability to inhibit both ATP-binding and A-loop mutations of KIT at clinically relevant exposures.
Data from Aurora Kinase A Inhibition Provides Clinical Benefit, Normalizes Megakaryocytes, and Reduces Bone Marrow Fibrosis in Patients with Myelofibrosis: A Phase I Trial
Authors: Gangat Naseema , Marinaccio Christian , Swords Ronan , Watts Justin M. , Gurbuxani Sandeep , Rademaker Alfred , Fought Angela J. , Frankfurt Olga , Altman Jessica K. , Wen Qiang Jeremy , Farnoud Noushin , Famulare Christopher A. , Patel Akshar , Tapia Roberto , Vallapureddy Rangit R. , Barath Stephanie , Graf Amy , Handlogten Amy , Zblewski Darci , Patnaik Mrinal M. , Al-kali Aref , Dinh Yvonne Trang , Englund Prahl Kristen , Patel Shradha , Nobrega Juan Carlos , Tejera Dalissa , Thomassen Amber , Gao Juehua , Ji Peng , Rampal Raajit K. , Giles Francis J. , Tefferi Ayalew , Stein Brady , Crispino John D.
Published: April 2023

AbstractPurpose:
Myelofibrosis is characterized by bone marrow fibrosis, atypical megakaryocytes, splenomegaly, constitutional symptoms, thrombotic and hemorrhagic complications, and a risk of evolution to acute leukemia. The JAK kinase inhibitor ruxolitinib provides therapeutic benefit, but the effects are limited. The purpose of this study was to determine whether targeting AURKA, which has been shown to increase maturation of atypical megakaryocytes, has potential benefit for patients with myelofibrosis.
Patients and Methods:
Twenty-four patients with myelofibrosis were enrolled in a phase I study at three centers. The objective of the study was to evaluate the safety and preliminary efficacy of alisertib. Correlative studies involved assessment of the effect of alisertib on the megakaryocyte lineage, allele burden, and fibrosis.
Results:
In addition to being well tolerated, alisertib reduced splenomegaly and symptom burden in 29% and 32% of patients, respectively, despite not consistently reducing the degree of inflammatory cytokines. Moreover, alisertib normalized megakaryocytes and reduced fibrosis in 5 of 7 patients for whom sequential marrows were available. Alisertib also decreased the mutant allele burden in a subset of patients.
Conclusions:
Given the limitations of ruxolitinib, novel therapies are needed for myelofibrosis. In this study, alisertib provided clinical benefit and exhibited the expected on-target effect on the megakaryocyte lineage, resulting in normalization of these cells and reduced fibrosis in the majority of patients for which sequential marrows were available. Thus, AURKA inhibition should be further developed as a therapeutic option in myelofibrosis.

See related commentary by Piszczatowski and Steidl, p. 4868
Data from The Anatomical Location Shapes the Immune Infiltrate in Tumors of Same Etiology and Affects Survival
Authors: Santegoets Saskia J. , van Ham Vanessa J. , Ehsan Ilina , Charoentong Pornpimol , Duurland Chantal L. , van Unen Vincent , Höllt Thomas , van der Velden Lilly-Ann , van Egmond Sylvia L. , Kortekaas Kim E. , de Vos van Steenwijk Peggy J. , van Poelgeest Mariëtte I.E. , Welters Marij J.P. , van der Burg Sjoerd H.
Published: April 2023

AbstractPurpose:
The tumor immune microenvironment determines clinical outcome. Whether the original tissue in which a primary tumor develops influences this microenvironment is not well understood.
Experimental Design:
We applied high-dimensional single-cell mass cytometry [Cytometry by Time-Of-Flight (CyTOF)] analysis and functional studies to analyze immune cell populations in human papillomavirus (HPV)–induced primary tumors of the cervix (cervical carcinoma) and oropharynx (oropharyngeal squamous cell carcinoma, OPSCC).
Results:
Despite the same etiology of these tumors, the composition and functionality of their lymphocytic infiltrate substantially differed. Cervical carcinoma displayed a 3-fold lower CD4:CD8 ratio and contained more activated CD8+CD103+CD161+ effector T cells and less CD4+CD161+ effector memory T cells than OPSCC. CD161+ effector cells produced the highest cytokine levels among tumor-specific T cells. Differences in CD4+ T-cell infiltration between cervical carcinoma and OPSCC were reflected in the detection rate of intratumoral HPV-specific CD4+ T cells and in their impact on OPSCC and cervical carcinoma survival. The peripheral blood mononuclear cell composition of these patients, however, was similar.
Conclusions:
The tissue of origin significantly affects the overall shape of the immune infiltrate in primary tumors.
Data from First-in-Human Phase I Trial of a Tumor-Targeted Cytokine (NHS-IL12) in Subjects with Metastatic Solid Tumors
Authors: Strauss Julius , Heery Christopher R. , Kim Joseph W. , Jochems Caroline , Donahue Renee N. , Montgomery Agnes S. , McMahon Sheri , Lamping Elizabeth , Marté Jennifer L. , Madan Ravi A. , Bilusic Marijo , Silver Matthew R. , Bertotti Elisa , Schlom Jeffrey , Gulley James L.
Published: April 2023

AbstractPurpose:
The NHS-IL12 immunocytokine is composed of two IL12 heterodimers fused to the NHS76 antibody. Preclinical studies have shown that this antibody targets IL12 to regions of tumor necrosis by binding histones on free DNA fragments in these areas, resulting in enhanced antitumor activity. The objectives of this phase I study were to determine the maximum tolerated dose (MTD) and pharmacokinetics of NHS-IL12 in subjects with advanced solid tumors.
Patients and Methods:
Subjects (n = 59) were treated subcutaneously with NHS-IL12 in a single ascending-dose cohort followed by a multiple ascending-dose cohort (n = 37 with every 4-week dosing).
Results:
The most frequently observed treatment-related adverse events (TRAE) included decreased circulating lymphocytes, increased liver transaminases, and flu-like symptoms. Of the grade ≥3 TRAEs, all were transient and only one was symptomatic (hyperhidrosis). The MTD is 16.8 μg/kg. A time-dependent rise in IFNγ and an associated rise in IL10 were observed following NHS-IL12. Of peripheral immune cell subsets evaluated, most noticeable were increases in frequencies of activated and mature natural killer (NK) cells and NKT cells. Based on T-cell receptor sequencing analysis, increases in T-cell receptor diversity and tumor-infiltrating lymphocyte density were observed after treatment where both biopsies and peripheral blood mononuclear cells were available. Although no objective tumor responses were observed, 5 subjects had durable stable disease (range, 6–30+ months).
Conclusions:
NHS-IL12 was well tolerated up to a dose of 16.8 μg/kg, which is the recommended phase II dose. Early clinical immune-related activity warrants further studies, including combination with immune checkpoint inhibitors.

See related commentary by Lyerly et al., p. 9
Data from Molecular Classification of Epithelial Ovarian Cancer Based on Methylation Profiling: Evidence for Survival Heterogeneity
Authors: Bodelon Clara , Killian J. Keith , Sampson Joshua N. , Anderson William F. , Matsuno Rayna , Brinton Louise A. , Lissowska Jolanta , Anglesio Michael S. , Bowtell David D.L. , Doherty Jennifer A. , Ramus Susan J. , Talhouk Aline , Sherman Mark E. , Wentzensen Nicolas
Published: April 2023

AbstractPurpose:
Ovarian cancer is a heterogeneous disease that can be divided into multiple subtypes with variable etiology, pathogenesis, and prognosis. We analyzed DNA methylation profiling data to identify biologic subgroups of ovarian cancer and study their relationship with histologic subtypes, copy number variation, RNA expression data, and outcomes.
Experimental Design:
A total of 162 paraffin-embedded ovarian epithelial tumor tissues, including the five major epithelial ovarian tumor subtypes (high- and low-grade serous, endometrioid, mucinous, and clear cell) and tumors of low malignant potential were selected from two different sources: The Polish Ovarian Cancer study, and the Surveillance, Epidemiology, and End Results Residual Tissue Repository (SEER RTR). Analyses were restricted to Caucasian women. Methylation profiling was conducted using the Illumina 450K methylation array. For 45 tumors array copy number data were available. NanoString gene expression data for 39 genes were available for 61 high-grade serous carcinomas (HGSC).
Results:
Consensus nonnegative matrix factorization clustering of the 1,000 most variable CpG sites showed four major clusters among all epithelial ovarian cancers. We observed statistically significant differences in survival (log-rank test, P = 9.1 × 10−7) and genomic instability across these clusters. Within HGSC, clustering showed three subgroups with survival differences (log-rank test, P = 0.002). Comparing models with and without methylation subgroups in addition to previously identified gene expression subtypes suggested that the methylation subgroups added significant survival information (P = 0.007).
Conclusions:
DNA methylation profiling of ovarian cancer identified novel molecular subgroups that had significant survival difference and provided insights into the molecular underpinnings of ovarian cancer.

See related commentary by Ishak et al., p. 5729
Data from Aberrant Thyroid-Stimulating Hormone Receptor Signaling Increases VEGF-A and CXCL8 Secretion of Thyroid Cancer Cells, Contributing to Angiogenesis and Tumor Growth
Authors: Song Young Shin , Kim Min Joo , Sun Hyun Jin , Kim Hwan Hee , Shin Hyo Shik , Kim Young A. , Oh Byung-Chul , Cho Sun Wook , Park Young Joo
Published: April 2023

AbstractPurpose:
Thyroid-stimulating hormone (TSH) suppression is widely used to treat well-differentiated thyroid cancer, whereas its role in poorly differentiated thyroid cancer (PDTC) is undetermined. Besides thyrocytes, TSH also binds to stromal cells, comprising tumor microenvironments. This study aimed to investigate the effects of TSH on tumor microenvironments in PDTC.
Experimental Design:
An ectopic tumor model using PDTC cells (BHP10-3SCp and FRO), which exhibit TSH/cAMP-independent cell growth, was treated with TSH. IHC was performed using tissue microarrays from 13 PDTCs.
Results:
TSH treatment significantly enhanced tumor growth of PDTCs with increased vascularity but not that of breast cancer cells, suggesting this effect is unique to thyroid cancer cells, not stromal cells. TSH significantly upregulated VEGF-A and CXCL8 expressions in BHP10-3SCp cells via AKT and ERK signaling, resulting in higher concentrations of VEGF-A and CXCL8 in conditioned medium of TSH-treated BHP10-3SCp cells (TSH-CM) compared with controls. TSH-CM treatment enhanced tube formation potentials of endothelial cells, and blocking VEGF and/or CXCL8 reduced them. Blocking VEGF and/or CXCL8 also reduced TSH-dependent tumor growth with reduced tumor vasculature in vivo. TSH-treated tumors showed increased macrophage densities, and macrophage inhibition reduced TSH-dependent tumor growth in vivo. In human PDTCs, preoperative TSH levels were positively associated with VEGF-A and tumor size, and the expression of VEGF-A was positively correlated with CD31, CD163, and CXCL8, and their clinical poor prognosis.
Conclusions:
Aberrant TSH receptor signaling modulates tumor angiogenesis by stimulating VEGF-A and CXCL8 secretion from PDTC cells and enhances tumor growth; thus, TSH suppression is beneficial for treating PDTCs.
Data from Open-label, Phase I Study of Nivolumab Combined with nab-Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer
Authors: Wainberg Zev A. , Hochster Howard S. , Kim Edward J. , George Ben , Kaylan Aparna , Chiorean E. Gabriela , Waterhouse David M. , Guiterrez Martin , Parikh Aparna , Jain Rishi , Carrizosa Daniel Ricardo , Soliman Hatem H. , Lila Thomas , Reiss David J. , Pierce Daniel W. , Bhore Rafia , Banerjee Sibabrata , Lyons Larry , Louis Chrystal U. , Ong Teng Jin , O'Dwyer Peter J.
Published: April 2023

AbstractPurpose:
Assess safety and efficacy of nivolumab plus nab-paclitaxel and gemcitabine in patients with locally advanced/metastatic pancreatic cancer in a two-part, open-label, phase I trial.
Patients and Methods:
Fifty chemotherapy-naive patients received nab-paclitaxel 125 mg/m2 plus gemcitabine 1,000 mg/m2 (days 1, 8, and 15) and nivolumab 3 mg/kg (days 1 and 15) in 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs; part 1) and grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (parts 1/2). Secondary efficacy endpoints were progression-free survival (PFS), overall survival (OS), and response. Assessment of programmed cell death-ligand 1 (PD-L1) expression was an exploratory endpoint; additional biomarkers were assessed post hoc.
Results:
One DLT (hepatitis) was reported in part 1 among six DLT-evaluable patients; 48 of 50 patients experienced grade 3/4 TEAEs and 18 discontinued treatment due to TEAEs. One grade 5 TEAE (respiratory failure) was reported. Median [95% confidence interval (CI)] PFS/OS was 5.5 (3.25–7.20 months)/9.9 (6.74–12.16 months) months, respectively [median follow-up for OS, 13.6 months (95% CI, 12.06–23.49 months)]. Overall response rate (95% CI) was 18% (8.6%–31.4%). Median PFS/OS was 5.5/9.7 months (PD-L1 <5%) and 6.8/11.6 months (PD-L1 ≥5%), respectively. Proportion of peripheral Ki67+ CD8+/CD4+ cells increased significantly from baseline to cycle 3; median peak on-treatment Ki67+ CD8+ T-cell values were higher in responders than in nonresponders.
Conclusions:
The safety profile of nivolumab plus nab-paclitaxel and gemcitabine at standard doses in advanced pancreatic cancer was manageable, with no unexpected safety signals. Overall, the clinical results of this study do not support further investigation.
Data from PIK3CA Amplification Associates with Aggressive Phenotype but Not Markers of AKT-MTOR Signaling in Endometrial Carcinoma
Authors: Holst Frederik , Werner Henrica M.J. , Mjøs Siv , Hoivik Erling A. , Kusonmano Kanthida , Wik Elisabeth , Berg Anna , Birkeland Even , Gibson William J. , Halle Mari K. , Trovik Jone , Cherniack Andrew D. , Kalland Karl-Henning , Mills Gordon B. , Singer Christian F. , Krakstad Camilla , Beroukhim Rameen , Salvesen Helga B.
Published: April 2023

AbstractPurpose:
Amplification of PIK3CA, encoding the PI3K catalytic subunit alpha, is common in uterine corpus endometrial carcinoma (UCEC) and linked to an aggressive phenotype. However, it is unclear whether PIK3CA amplification acts via PI3K activation. We investigated the association between PIK3CA amplification, markers of PI3K activity, and prognosis in a large cohort of UCEC specimens.
Experimental Design:
UCECs from 591 clinically annotated patients including 83 tumors with matching metastasis (n = 188) were analyzed by FISH to determine PIK3CA copy-number status. These data were integrated with mRNA and protein expression and clinicopathologic data. Results were verified in The Cancer Genome Atlas dataset.
Results:
PIK3CA amplifications were associated with disease-specific mortality and with other markers of aggressive disease. PIK3CA amplifications were also associated with other amplifications characteristic of the serous-like somatic copy-number alteration (SCNA)–high subgroup of UCEC. Tumors with PIK3CA amplification also demonstrated an increase in phospho-p70S6K but had decreased levels of activated phospho-AKT1-3 as assessed by Reverse Phase Protein Arrays and an mRNA signature of MTOR inhibition.
Conclusions:
PIK3CA amplification is a strong prognostic marker and a potential marker for the aggressive SCNA-high subgroup of UCEC. Although PIK3CA amplification associates with some surrogate measures of increased PI3K activity, markers for AKT1-3 and MTOR signaling are decreased, suggesting that this signaling is not a predominant pathway to promote cancer growth of aggressive serous-like UCEC. Moreover, these associations may reflect features of the SCNA-high subgroup of UCEC rather than effects of PIK3CA amplification itself.
Data from Circulating Tumor Cells Are Associated with Recurrent Disease in Patients with Early-Stage Non–Small Cell Lung Cancer Treated with Stereotactic Body Radiotherapy
Authors: Frick Melissa A. , Feigenberg Steven J. , Jean-Baptiste Samuel R. , Aguarin Louise A. , Mendes Amberly , Chinniah Chimbu , Swisher-McClure Sam , Berman Abigail , Levin William , Cengel Keith A. , Hahn Stephen M. , Dorsey Jay F. , Simone Charles B. , Kao Gary D.
Published: April 2023

AbstractPurpose:
Although stereotactic body radiotherapy (SBRT) is effective in early-stage non–small cell lung cancer (NSCLC), approximately 10%–15% of patients will fail regionally and 20%–25% distantly. We evaluate a novel circulating tumor cell (CTC) assay as a prognostic marker for increased risk of recurrence following SBRT.
Experimental Design:
Ninety-two subjects (median age, 71 years) with T1a (64%), T1b (23%), or T2a (13%) stage I NSCLC treated with SBRT were prospectively enrolled. CTCs were enumerated by utilizing a GFP-expressing adenoviral probe that detects elevated telomerase activity in cancer cells. Samples were obtained before, during, and serially up to 24 months after treatment. SBRT was delivered to a median dose of 50 Gy (range, 40–60 Gy), mostly commonly in four to five fractions (92%).
Results:
Thirty-eight of 92 subjects (41%) had a positive CTC test prior to SBRT. A cutoff of ≥5 CTCs/mL before treatment defined favorable (n = 78) and unfavorable (n = 14) prognostic groups. Increased risk of nodal (P = 0.04) and distant (P = 0.03) failure was observed in the unfavorable group. Within 3 months following SBRT, CTCs continued to be detected in 10 of 35 (29%) subjects. Persistent detection of CTCs was associated with increased risk of distant failure (P = 0.04) and trended toward increased regional (P = 0.08) and local failure (P = 0.16).
Conclusions:
Higher pretreatment CTCs and persistence of CTCs posttreatment is significantly associated with increased risk of recurrence outside the targeted treatment site. This suggests that CTC analysis may potentially identify patients at higher risk for regional or distant recurrences and who may benefit from either systemic therapy and/or timely locoregional salvage treatment.
Data from Serum Sex Steroids as Prognostic Biomarkers in Patients Receiving Androgen Deprivation Therapy for Recurrent Prostate Cancer: A Post Hoc Analysis of the PR.7 Trial
Authors: Toren Paul , Hoffman Azik , Ding Keyue , Joncas France-Hélène , Turcotte Véronique , Caron Patrick , Pouliot Frédéric , Fradet Yves , Lévesque Éric , Guillemette Chantal , Klotz Laurence
Published: April 2023

Abstract
Purpose: Phenotypic biomarkers are a high priority for patients receiving androgen deprivation therapy (ADT) for prostate cancer given the increasing number of treatment options. This study evaluates serum sex steroids as prognostic biomarkers in men receiving ADT for recurrent prostate cancer.

Experimental Design: Retrospective cohort study of Canadian patients in the PR.7 trial (accrual 1999–2005) who received continuous ADT for biochemical recurrence postradiotherapy. Patients were excluded with follow-up <2 years or who received estrogens or corticosteroids. Kaplan–Meier and multivariable Cox regression analyses adjusted for baseline prognostic factors assessed time to castration-resistant prostate cancer (CRPC), prostate cancer survival, and overall survival according to tertile of sex steroid measured by mass spectrometry.

Results: Post-ADT initiation, we measured samples in 219 patients as well as two subsequent annual samples in a subset of 101 patients. Testosterone levels correlated with androstenedione (AD) and DHT, while DHT, AD, androsterone (AST), dehydroepiandrosterone (DHEA), and androstenediol (A5diol) were highly correlated to each other and negatively associated with age. Higher tertiles of estrone (E1) and estradiol (E2) were significantly associated with sooner time to CRPC. In patients with longitudinal samples, increases in serum DHEA and AST were significantly associated with sooner time to CRPC. Limitations include the number of events for some groups.

Conclusions: Our data suggest the patient hormonal milieu has long-term prognostic value in men receiving ADT for recurrent prostate cancer, including increased levels of E1 and E2 and rising DHEA and AST levels, which predict a shorter time to CRPC. Clin Cancer Res; 24(21); 5305–12. ©2018 AACR.
Data from Metformin Targets Mitochondrial Glycerophosphate Dehydrogenase to Control Rate of Oxidative Phosphorylation and Growth of Thyroid Cancer In Vitro and In Vivo
Authors: Thakur Shilpa , Daley Brianna , Gaskins Kelli , Vasko Vasyl V. , Boufraqech Myriem , Patel Dhaval , Sourbier Carole , Reece Jeff , Cheng Sheue-Yann , Kebebew Electron , Agarwal Sunita , Klubo-Gwiezdzinska Joanna
Published: April 2023

Abstract
Purpose: Mitochondrial glycerophosphate dehydrogenase (MGPDH) is the key enzyme connecting oxidative phosphorylation (OXPHOS) and glycolysis as well as a target of the antidiabetic drug metformin in the liver. There are no data on the expression and role of MGPDH as a metformin target in cancer. In this study, we evaluated MGPDH as a potential target of metformin in thyroid cancer and investigated its contribution in thyroid cancer metabolism.

Experimental Design: We analyzed MGPDH expression in 253 thyroid cancer and normal tissues by immunostaining and examined its expression and localization in thyroid cancer–derived cell lines (FTC133, BCPAP) by confocal microscopy. The effects of metformin on MGPDH expression were determined by qRT-PCR and Western blot analysis. Seahorse analyzer was utilized to assess the effects of metformin on OXPHOS and glycolysis in thyroid cancer cells. We analyzed the effects of metformin on tumor growth and MGPDH expression in metastatic thyroid cancer mouse models.

Results: We show for the first time that MGPDH is overexpressed in thyroid cancer compared with normal thyroid. We demonstrate that MGPDH regulates human thyroid cancer cell growth and OXPHOS rate in vitro. Metformin treatment is associated with downregulation of MGPDH expression and inhibition of OXPHOS in thyroid cancer in vitro. Cells characterized by high MGPDH expression are more sensitive to OXPHOS-inhibitory effects of metformin in vitro and growth-inhibitory effects of metformin in vitro and in vivo.

Conclusions: Our study established MGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin. Clin Cancer Res; 24(16); 4030–43. ©2018 AACR.
Data from CD8+ T-Cell Density Imaging with 64Cu-Labeled Cys-Diabody Informs Immunotherapy Protocols
Authors: Seo Jai Woong , Tavaré Richard , Mahakian Lisa M. , Silvestrini Matthew T. , Tam Sarah , Ingham Elizabeth S. , Salazar Felix B. , Borowsky Alexander D. , Wu Anna M. , Ferrara Katherine W.
Published: April 2023

Abstract
Purpose: Noninvasive and quantitative tracking of CD8+ T cells by PET has emerged as a potential technique to gauge response to immunotherapy. We apply an anti-CD8 cys-diabody, labeled with 64Cu, to assess the sensitivity of PET imaging of normal and diseased tissue.

Experimental Design: Radiolabeling of an anti-CD8 cys-diabody (169cDb) with 64Cu was developed. The accumulation of 64Cu-169cDb was evaluated with PET/CT imaging (0, 5, and 24 hours) and biodistribution (24 hours) in wild-type mouse strains (n = 8/group studied with imaging and IHC or flow cytometry) after intravenous administration. Tumor-infiltrating CD8+ T cells in tumor-bearing mice treated with CpG and αPD-1 were quantified and mapped (n = 6–8/group studied with imaging and IHC or flow cytometry).

Results: We demonstrate the ability of immunoPET to detect small differences in CD8+ T-cell distribution between mouse strains and across lymphoid tissues, including the intestinal tract of normal mice. In FVB mice bearing a syngeneic HER2-driven model of mammary adenocarcinoma (NDL), 64Cu-169cDb PET imaging accurately visualized and quantified changes in tumor-infiltrating CD8+ T cells in response to immunotherapy. A reduction in the circulation time of the imaging probe followed the development of treatment-related liver and splenic hypertrophy and provided an indication of off-target effects associated with immunotherapy protocols.

Conclusions: 64Cu-169cDb imaging can spatially map the distribution of CD8+ T cells in normal organs and tumors. ImmunoPET imaging of tumor-infiltrating cytotoxic CD8+ T cells detected changes in T-cell density resulting from adjuvant and checkpoint immunotherapy protocols in our preclinical evaluation. Clin Cancer Res; 24(20); 4976–87. ©2018 AACR.
Data from Tyrosine Kinase Inhibitors Increase MCL1 Degradation and in Combination with BCLXL/BCL2 Inhibitors Drive Prostate Cancer Apoptosis
Authors: Arai Seiji , Jonas Oliver , Whitman Matthew A. , Corey Eva , Balk Steven P. , Chen Sen
Published: April 2023

Abstract
Purpose: Clinically available BH3 mimetic drugs targeting BCLXL and/or BCL2 (navitoclax and venetoclax, respectively) are effective in some hematologic malignancies, but have limited efficacy in solid tumors. This study aimed to identify combination therapies that exploit clinical BH3 mimetics for prostate cancer.

Experimental Design: Prostate cancer cells or xenografts were treated with BH3 mimetics as single agents or in combination with other agents, and effects on MCL1 and apoptosis were assessed. MCL1 was also targeted directly using RNAi, CRISPR, or an MCL1-specific BH3 mimetic, S63845.

Results: We initially found that MCL1 depletion or inhibition markedly sensitized prostate cancer cells to apoptosis mediated by navitoclax, but not venetoclax, in vitro and in vivo, indicating that they are primed to undergo apoptosis and protected by MCL1 and BCLXL. Small-molecule EGFR kinase inhibitors (erlotinib, lapatinib) also dramatically sensitized to navitoclax-mediated apoptosis, and this was associated with markedly increased proteasome-dependent degradation of MCL1. This increased MCL1 degradation appeared to be through a novel mechanism, as it was not dependent upon GSK3β-mediated phosphorylation and subsequent ubiquitylation by the ubiquitin ligases βTRCP and FBW7, or through other previously identified MCL1 ubiquitin ligases or deubiquitinases. Inhibitors targeting additional kinases (cabozantinib and sorafenib) similarly caused GSK3β-independent MCL1 degradation, and in combination with navitoclax drove apoptosis in vitro and in vivo.

Conclusions: These results show that prostate cancer cells are primed to undergo apoptosis and that cotargeting BCLXL and MCL1, directly or indirectly through agents that increase MCL1 degradation, can induce dramatic apoptotic responses. Clin Cancer Res; 24(21); 5458–70. ©2018 AACR.
Data from Immune Checkpoint Blockade in Combination with Stereotactic Body Radiotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma
Authors: Xie Changqing , Duffy Austin G. , Brar Gagandeep , Fioravanti Suzanne , Mabry-Hrones Donna , Walker Melissa , Bonilla Cecilia Monge , Wood Bradford J. , Citrin Deborah E. , Gil Ramirez Elizabeth M. , Escorcia Freddy E. , Redd Bernadette , Hernandez Jonathan M. , Davis Jeremy L. , Gasmi Billel , Kleiner David , Steinberg Seth M. , Jones Jennifer C. , Greten Tim F.
Published: April 2023

AbstractPurpose:
The effectiveness of immune checkpoint inhibitors (ICI) is limited in pancreatic ductal adenocarcinoma (PDAC). We conducted a phase I study to evaluate the safety of ICI with stereotactic body radiation therapy (SBRT) in patients with metastatic PDAC.
Patients and Methods:
Patients enrolled must have received at least one line of prior systemic chemotherapy for metastatic disease. Cohorts A1 and A2 received durvalumab every 2 weeks plus either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day −3 to +1. Cohorts B1 and B2 received durvalumab plus tremelimumab every 4 weeks and either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day −3 to +1. ICIs were continued until unacceptable toxicity or disease progression. The primary objective was the safety and feasibility of treatment. Objective response was assessed in lesions not subjected to SBRT.
Results:
Fifty-nine patients were enrolled and 39 were evaluable for efficacy. No dose-limiting toxicities were seen. The most common adverse event was lymphopenia. Two patients achieved a partial response (one confirmed and the other unconfirmed). The overall response rate was 5.1%. Median PFS and OS was 1.7 months [95% confidence intervals (CI), 0.8–2.0 months] and 3.3 months (95% CI, 1.2–6.6 months) in cohort A1; 2.5 months (95% CI, 0.1–3.7 months) and 9.0 months (95% CI, 0.5–18.4 months) in A2; 0.9 months (95% CI, 0.7–2.1 months) and 2.1 months (95% CI, 1.1–4.3 months) in B1; and 2.3 months (95% CI, 1.9–3.4 months) and 4.2 months (95% CI, 2.9–9.3 months) in B2.
Conclusions:
The combination of ICI and SBRT has an acceptable safety profile and demonstrates a modest treatment benefit in patients with metastatic PDAC.
Data from Safety and Clinical Activity of MEDI1873, a Novel GITR Agonist, in Advanced Solid Tumors
Authors: Balmanoukian Ani S. , Infante Jeffrey R. , Aljumaily Raid , Naing Aung , Chintakuntlawar Ashish V. , Rizvi Naiyer A. , Ross Helen J. , Gordon Michael , Mallinder Philip R. , Elgeioushi Nairouz , González-García Ignacio , Standifer Nathan , Cann Jennifer , Durham Nicholas , Rahimian Shahram , Kumar Rakesh , Denlinger Crystal S.
Published: April 2023

AbstractPurpose:
The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor–related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors.
Patients and Methods:
Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.
Results:
Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug–antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks.
Conclusions:
MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.
Data from Low-Dose Hsp90 Inhibitor Selectively Radiosensitizes HNSCC and Pancreatic Xenografts
Authors: Mehta Ranjit K. , Pal Sanjima , Kondapi Koushik , Sitto Merna , Dewar Cuyler , Devasia Theresa , Schipper Matthew J. , Thomas Dafydd G. , Basrur Venkatesha , Pai Manjunath P. , Morishima Yoshihiro , Osawa Yoichi , Pratt William B. , Lawrence Theodore S. , Nyati Mukesh K.
Published: April 2023

AbstractPurpose:
Treatment approaches using Hsp90 inhibitors at their maximum tolerated doses (MTDs) have not produced selective tumor toxicity. Inhibition of Hsp90 activity causes degradation of client proteins including those involved in recognizing and repairing DNA lesions. We hypothesized that if DNA repair proteins were degraded by concentrations of an Hsp90 inhibitor below those required to cause nonspecific cytotoxicity, significant tumor-selective radiosensitization might be achieved.
Experimental Design:
Tandem mass tagged-mass spectrometry was performed to determine the effect of a subcytotoxic concentration of the Hsp90 inhibitor, AT13387 (onalespib), on global protein abundance. The effect of AT13387 on in vitro radiosensitization was assessed using a clonogenic assay. Pharmacokinetics profiling was performed in mice bearing xenografts. Finally, the effect of low-dose AT13387 on the radiosensitization of three tumor models was assessed.
Results:
A subcytotoxic concentration of AT13387 reduced levels of DNA repair proteins, without affecting the majority of Hsp90 clients. The pharmacokinetics study using one-third of the MTD showed 40-fold higher levels of AT13387 in tumors compared with plasma. This low dose enhanced Hsp70 expression in peripheral blood mononuclear cells (PBMCs), which is a biomarker of Hsp90 inhibition. Low dose monotherapy was ineffective, but when combined with radiotherapy, produced significant tumor growth inhibition.
Conclusions:
This study shows that a significant therapeutic ratio can be achieved by a low dose of Hsp90 inhibitor in combination with radiotherapy. Hsp90 inhibition, even at a low dose, can be monitored by measuring Hsp70 expression in PBMCs in human studies.
Data from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia
Authors: Laurent Anouchka P. , Siret Aurélie , Ignacimouttou Cathy , Panchal Kunjal , Diop M'Boyba , Jenni Silvia , Tsai Yi-Chien , Roos-Weil Damien , Aid Zakia , Prade Nais , Lagarde Stephanie , Plassard Damien , Pierron Gaelle , Daudigeos Estelle , Lecluse Yann , Droin Nathalie , Bornhauser Beat C. , Cheung Laurence C. , Crispino John D. , Gaudry Muriel , Bernard Olivier A. , Macintyre Elizabeth , Barin Bonnigal Carole , Kotecha Rishi S. , Geoerger Birgit , Ballerini Paola , Bourquin Jean-Pierre , Delabesse Eric , Mercher Thomas , Malinge Sebastien
Published: April 2023

AbstractPurpose:
Children with Down syndrome (constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared with other children with B-cell acute lymphoblastic leukemia (B-ALL). This highlights the lack of suitable treatment for Down syndrome children with B-ALL.
Experimental Design:
To facilitate the translation of new therapeutic agents into clinical trials, we built the first preclinical cohort of patient-derived xenograft (PDX) models of DS-ALL, comprehensively characterized at the genetic and transcriptomic levels, and have proven its suitability for preclinical studies by assessing the efficacy of drug combination between the MEK inhibitor trametinib and conventional chemotherapy agents.
Results:
Whole-exome and RNA-sequencing experiments revealed a high incidence of somatic alterations leading to RAS/MAPK pathway activation in our cohort of DS-ALL, as well as in other pediatric B-ALL presenting somatic gain of the chromosome 21 (B-ALL+21). In murine and human B-cell precursors, activated KRASG12D functionally cooperates with trisomy 21 to deregulate transcriptional networks that promote increased proliferation and self renewal, as well as B-cell differentiation blockade. Moreover, we revealed that inhibition of RAS/MAPK pathway activation using the MEK1/2 inhibitor trametinib decreased leukemia burden in several PDX models of B-ALL+21, and enhanced survival of DS-ALL PDX in combination with conventional chemotherapy agents such as vincristine.
Conclusions:
Altogether, using novel and suitable PDX models, this study indicates that RAS/MAPK pathway inhibition represents a promising strategy to improve the outcome of Down syndrome children with B-cell precursor leukemia.