bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Functional Testing to Characterize and Stratify PI3K Inhibitor Responses in Chronic Lymphocytic Leukemia
Authors: Yin Yanping , Athanasiadis Paschalis , Karlsen Linda , Urban Aleksandra , Xu Haifeng , Murali Ishwarya , Fernandes Stacey M. , Arribas Alberto J. , Hilli Abdul K. , Taskén Kjetil , Bertoni Francesco , Mato Anthony R. , Normant Emmanuel , Brown Jennifer R. , Tjønnfjord Geir E. , Aittokallio Tero , Skånland Sigrid S.
Published: April 2023

AbstractPurpose:
PI3K inhibitors (PI3Ki) are approved for relapsed chronic lymphocytic leukemia (CLL). Although patients may show an initial response to these therapies, development of treatment intolerance or resistance remain clinical challenges. To overcome these, prediction of individual treatment responses based on actionable biomarkers is needed. Here, we characterized the activity and cellular effects of 10 PI3Ki and investigated whether functional analyses can identify treatment vulnerabilities in PI3Ki-refractory/intolerant CLL and stratify responders to PI3Ki.
Experimental Design:
Peripheral blood mononuclear cell samples (n = 51 in total) from treatment-naïve and PI3Ki-treated patients with CLL were studied. Cells were profiled against 10 PI3Ki and the Bcl-2 antagonist venetoclax. Cell signaling and immune phenotypes were analyzed by flow cytometry. Cell viability was monitored by detection of cleaved caspase-3 and the CellTiter-Glo assay.
Results:
pan-PI3Kis were most effective at inhibiting PI3K signaling and cell viability, and showed activity in CLL cells from both treatment-naïve and idelalisib-refractory/intolerant patients. CLL cells from idelalisib-refractory/intolerant patients showed overall reduced protein phosphorylation levels. The pan-PI3Ki copanlisib, but not the p110δ inhibitor idelalisib, inhibited PI3K signaling in CD4+ and CD8+ T cells in addition to CD19+ B cells, but did not significantly affect T-cell numbers. Combination treatment with a PI3Ki and venetoclax resulted in synergistic induction of apoptosis. Analysis of drug sensitivities to 73 drug combinations and profiling of 31 proteins stratified responders to idelalisib and umbralisib, respectively.
Conclusions:
Our findings suggest novel treatment vulnerabilities in idelalisib-refractory/intolerant CLL, and indicate that ex vivo functional profiling may stratify PI3Ki responders.
Data from SPOP Mutations as a Predictive Biomarker for Androgen Receptor Axis–Targeted Therapy in De Novo Metastatic Castration-Sensitive Prostate Cancer
Authors: Swami Umang , Graf Ryon P. , Nussenzveig Roberto H. , Fisher Virginia , Tukachinsky Hanna , Schrock Alexa B. , Li Gerald , Ross Jeffrey S. , Sayegh Nicolas , Tripathi Nishita , Mathew Thomas Vinay , Oxnard Geoffrey R. , Antonarakis Emmanuel S. , Agarwal Neeraj
Published: April 2023

AbstractPurpose:
Intensification of androgen deprivation therapy (ADT) with either docetaxel or androgen receptor axis–targeted therapies (ARAT) are the current standard of care for patients with metastatic castration-sensitive prostate cancer (mCSPC). However, biomarkers guiding treatment selection are lacking. We hypothesized that ADT intensification with ARAT, but not with docetaxel, would be associated with improved outcomes in patients with de novo (dn)-mCSPC harboring SPOP mutations.
Experimental Design:
Patient-level data from a deidentified nationwide (U.S.-based) prostate cancer clinico-genomic database between January 2011 and December 2021 were extracted. Eligibility criteria: diagnosis of metastatic disease within 30 days of original prostate cancer diagnosis, genomic profiling of a tissue biopsy collected within 90 days of original diagnosis, and initiation of ARAT or docetaxel within 120 days of initial diagnosis. The log-rank test and Cox proportional hazards models were used to compare time to castration-resistant prostate cancer (TTCRPC) and overall survival (OS) for patients with and without SPOP mutations undergoing ADT intensification with ARAT or docetaxel.
Results:
In the ARAT cohort, presence of SPOP mutation compared with wild-type was associated with more favorable TTCRPC [not reached (NR) vs. 16.7 months; adjusted HR (aHR), 0.20; 95% confidence interval (CI), 0.06–0.63; P = 0.006] and OS (NR vs. 27.2 months; aHR, 0.19; 95% CI, 0.05–0.79; P = 0.022). In contrast, SPOP mutation status was not associated with TTCRPC or OS in docetaxel-treated cohort.
Conclusions:
In real-world settings, SPOP mutations were associated with improved outcomes to ADT plus ARAT (but not ADT plus docetaxel) in patients with dn-mCSPC. This may serve as a predictive biomarker to guide treatment selection for patients with mCSPC.
Data from Pharmacological Landscape of FDA-Approved Anticancer Drugs Reveals Sensitivities to Ixabepilone, Romidepsin, Omacetaxine, and Carfilzomib in Aggressive Meningiomas
Authors: Jungwirth Gerhard , Yu Tao , Liu Fang , Cao Junguo , Alaa Eddine Montadar , Moustafa Mahmoud , Abdollahi Amir , Warta Rolf , Unterberg Andreas , Herold-Mende Christel
Published: April 2023

AbstractPurpose:
To date, there are no systemic treatment options for patients with recurrent or refractory meningioma.
Experimental Design:
To identify effective drugs, we performed a large-scale drug screening using FDA-approved drugs on several meningioma cell lines. The impact of the top four compounds was assessed on cell viability, proliferation, colony formation, migration, and apoptosis. In addition, the antineoplastic effects of the selected drugs were validated in a heterotopic xenograft mouse model.
Results:
Analyses of the viability of meningioma cells treated with 119 antineoplastic FDA-approved drugs resulted in categorization into sensitive and resistant drug–response groups based on the mean IC50 values and peak serum concentrations (Cmax) in patients. Eighty drugs, including 15 alkylating agents, 14 antimetabolites, and 13 tyrosine kinase inhibitors, were classified as resistant (IC50 > Cmax). The sensitive drug–response group (n = 29, IC50 < Cmax) included RNA/protein synthesis inhibitors, proteasome inhibitors, topoisomerase, tyrosine-kinase, and partial histone deacetylase and microtubule inhibitors. The IC50 value of the four most effective compounds (carfilzomib, omacetaxine, ixabepilone, and romidepsin) ranged from 0.12 to 9.5 nmol/L. Most of them caused cell-cycle arrest in the G2–M-phase and induced apoptosis. Furthermore, all drugs except romidepsin significantly inhibited tumor growth in vivo. The strongest antineoplastic effect was observed for ixabepilone, which reduced tumor volume by 86%.
Conclusions:
In summary, a large-scale drug screening provides a comprehensive insight into the anti-meningioma activities of FDA-approved drugs, and identified carfilzomib, omacetaxine, ixabepilone, and romidepsin as novel potent antineoplastic agents for the treatment of aggressive meningiomas. The most pronounced effects were observed with ixabepilone mandating for further clinical investigation.
Data from [18F]FluorThanatrace ([18F]FTT) PET Imaging of PARP-Inhibitor Drug-Target Engagement as a Biomarker of Response in Ovarian Cancer, a Pilot Study
Authors: Pantel Austin R. , Gitto Sarah B. , Makvandi Mehran , Kim Hyoung , Medvedv Sergey , Weeks Joanna K. , Torigian Drew A. , Hsieh Chia-Ju , Ferman Benjamin , Latif Nawar A. , Tanyi Janos L. , Martin Lainie P. , Lanzo Shannon M. , Liu Fang , Cao Quy , Mills Gordon B. , Doot Robert K. , Mankoff David A. , Mach Robert H. , Lin Lilie L. , Simpkins Fiona
Published: April 2023

AbstractPurpose:
PARP inhibitors have become the standard-of-care treatment for homologous recombination deficient (HRD) high-grade serous ovarian cancer (HGSOC). However, not all HRD tumors respond to PARPi. Biomarkers to predict response are needed. [18F]FluorThanatrace ([18F]FTT) is a PARPi-analog PET radiotracer that noninvasively measures PARP-1 expression. Herein, we evaluate [18F]FTT as a biomarker to predict response to PARPi in patient-derived xenograft (PDX) models and subjects with HRD HGSOC.
Experimental Design:
In PDX models, [18F]FTT-PET was performed before and after PARPi (olaparib), ataxia-telangiectasia inhibitor (ATRi), or both (PARPi-ATRi). Changes in [18F]FTT were correlated with tumor volume changes. Subjects were imaged with [18F]FTT-PET at baseline and after ∼1 week of PARPi. Changes in [18F]FTT-PET uptake were compared with changes in tumor size (RECISTv1.1), CA-125, and progression-free survival (PFS).
Results:
A decrease in [18F]FTT tumor uptake after PARPi correlated with response to PARPi, or PARPi-ATRi treatment in PARPi-resistant PDX models (r = 0.77–0.81). In subjects (n = 11), percent difference in [18F]FTT-PET after ∼7 days of PARPi compared with baseline correlated with best RECIST response (P = 0.01), best CA-125 response (P = 0.033), and PFS (P = 0.027). All subjects with >50% reduction in [18F]FTT uptake had >6-month PFS and >50% reduction in CA-125. Utilizing only baseline [18F]FTT uptake did not predict such responses.
Conclusions:
The decline in [18F]FTT uptake shortly after PARPi initiation provides a measure of drug-target engagement and shows promise as a biomarker to guide PARPi therapies in this pilot study. These results support additional preclinical mechanistic and clinical studies in subjects receiving PARPi ± combination therapy.
Data from A Novel B7-H6–Targeted IgG-Like T Cell–Engaging Antibody for the Treatment of Gastrointestinal Tumors
Authors: Zhang Wei , Auguste Aurélie , Liao Xiaoyun , Walterskirchen Christian , Bauer Kathrin , Lin Yu-Hsi , Yang Ling , Sayedian Farzaneh , Fabits Markus , Bergmann Michael , Binder Carina , Corrales Leticia , Vogt Anne B. , Hudson Lindsey J. , Barnes Martin P. , Bisht Arnima , Giragossian Craig , Voynov Vladimir , Adam Paul J. , Hipp Susanne
Published: April 2023

AbstractPurpose:
Advanced-stage gastrointestinal cancers represent a high unmet need requiring new effective therapies. We investigated the antitumor activity of a novel T cell–engaging antibody (B7-H6/CD3 ITE) targeting B7-H6, a tumor-associated antigen that is expressed in gastrointestinal tumors.
Experimental Design:
Membrane proteomics and IHC analysis identified B7-H6 as a tumor-associated antigen in gastrointestinal tumor tissues with no to very little expression in normal tissues. The antitumor activity and mode of action of B7-H6/CD3 ITE was evaluated in in vitro coculture assays, in humanized mouse tumor models, and in colorectal cancer precision cut tumor slice cultures.
Results:
B7-H6 expression was detected in 98% of colorectal cancer, 77% of gastric cancer, and 63% of pancreatic cancer tissue samples. B7-H6/CD3 ITE-mediated redirection of T cells toward B7-H6–positive tumor cells resulted in B7-H6–dependent lysis of tumor cells, activation and proliferation of T cells, and cytokine secretion in in vitro coculture assays, and infiltration of T cells into tumor tissues associated with tumor regression in in vivo colorectal cancer models. In primary patient-derived colorectal cancer precision-cut tumor slice cultures, treatment with B7-H6/CD3 ITE elicited cytokine secretion by endogenous tumor-infiltrating immune cells. Combination with anti-PD-1 further enhanced the activity of the B7-H6/CD3 ITE.
Conclusion:
These data highlight the potential of the B7-H6/CD3 ITE to induce T cell–redirected lysis of tumor cells and recruitment of T cells into noninflamed tumor tissues, leading to antitumor activity in in vitro, in vivo, and human tumor slice cultures, which supports further evaluation in a clinical study.
Data from Mechanisms of MCL-1 Protein Stability Induced by MCL-1 Antagonists in B-Cell Malignancies
Authors: Tantawy Shady I. , Sarkar Aloke , Hubner Stefan , Tan Zhi , Wierda William G. , Eldeib Abdelraouf , Zhang Shuxing , Kornblau Steven , Gandhi Varsha
Published: April 2023

AbstractPurpose:
Several MCL-1 inhibitors (MCL-1i), including AMG-176 and AZD5991, have shown promise in preclinical studies and are being tested for the treatment of hematologic malignancies. A unique feature of these agents is induction and stability of Mcl-1 protein; however, the precise mechanism is unknown. We aim to study the mechanism of MCL-1i–induced Mcl-1 protein stability.
Experimental Design:
Using several B-cell leukemia and lymphoma cell lines and primary chronic lymphocytic leukemia (CLL) lymphocytes, we evaluated molecular events associated with Mcl-1 protein stability including protein half-life, reverse-phase protein array, protein–protein interaction, phosphorylation, ubiquitination, and de-ubiquitination, followed by molecular simulation and modeling.
Results:
Using both in vivo and in vitro analysis, we demonstrate that MCL-1i–induced Mcl-1 protein stability is predominantly associated with defective Mcl-1 ubiquitination and concurrent apoptosis induction in both cell lines and primary CLL subjects. These MCL1i also induced ERK-mediated Mcl-1Thr163 phosphorylation, which partially contributed to Mcl-1 stability. Disruption of Mcl-1:Noxa interaction followed by Noxa degradation, enhanced Mcl-1 de-ubiquitination by USP9x, and Mule destabilization are the major effects of these inhibitors. However, unlike other BH3 proteins, Mule:Mcl-1 interaction was unaffected by MCL-1i. WP1130, a global deubiquitinase (DUB) inhibitor, abrogated Mcl-1 induction reaffirming a critical role of DUBs in the observed Mcl-1 protein stability. Further, in vitro ubiquitination studies of Mcl-1 showed distinct difference among these inhibitors.
Conclusions:
We conclude that MCL-1i blocked Mcl-1 ubiquitination via enhanced de-ubiquitination and dissociation of Mcl-1 from Noxa, Bak and Bax, and Mule de-stabilization. These are critical events associated with increased Mcl-1 protein stability with AMG-176 and AZD5991.
Data from Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper
Authors: Illuzzi Giuditta , Staniszewska Anna D. , Gill Sonja J. , Pike Andy , McWilliams Lisa , Critchlow Susan E. , Cronin Anna , Fawell Stephen , Hawthorne Glen , Jamal Kunzah , Johannes Jeffrey , Leonard Emilyanne , Macdonald Ruth , Maglennon Gareth , Nikkilä Jenni , O'Connor Mark J. , Smith Aaron , Southgate Harriet , Wilson Joanne , Yates James , Cosulich Sabina , Leo Elisabetta
Published: April 2023

AbstractPurpose:
We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed to achieve selectivity over PARP2, which has been shown to play a role in the survival of hematopoietic/stem progenitor cells in animal models. We developed AZD5305 with the aim of achieving improved clinical efficacy and wider therapeutic window. This next-generation PARP inhibitor (PARPi) could provide a paradigm shift in clinical outcomes achieved by first-generation PARPi, particularly in combination.
Experimental Design:
AZD5305 was tested in vitro for PARylation inhibition, PARP-DNA trapping, and antiproliferative abilities. In vivo efficacy was determined in mouse xenograft and PDX models. The potential for hematologic toxicity was evaluated in rat models, as monotherapy and combination.
Results:
AZD5305 is a highly potent and selective inhibitor of PARP1 with 500-fold selectivity for PARP1 over PARP2. AZD5305 inhibits growth in cells with deficiencies in DNA repair, with minimal/no effects in other cells. Unlike first-generation PARPi, AZD5305 has minimal effects on hematologic parameters in a rat pre-clinical model at predicted clinically efficacious exposures. Animal models treated with AZD5305 at doses ≥0.1 mg/kg once daily achieved greater depth of tumor regression compared to olaparib 100 mg/kg once daily, and longer duration of response.
Conclusions:
AZD5305 potently and selectively inhibits PARP1 resulting in excellent antiproliferative activity and unprecedented selectivity for DNA repair deficient versus proficient cells. These data confirm the hypothesis that targeting only PARP1 can retain the therapeutic benefit of nonselective PARPi, while reducing potential for hematotoxicity. AZD5305 is currently in phase I trials (NCT04644068).
Data from An Enhancer Demethylator Phenotype Converged to Immune Dysfunction and Resistance to Immune Checkpoint Inhibitors in Clear-Cell Renal Cell Carcinomas
Authors: Lu Xiaofan , Vano Yann , Helleux Alexandra , Su Xiaoping , Lindner Véronique , Davidson Guillaume , Mouawad Roger , Spano Jean-Philippe , Rouprêt Morgan , Elaidi Reza , Compérat Eva , Verkarre Virginie , Sun Chengming , Chevreau Christine , Bennamoun Mostefa , Lang Hervé , Tricard Thibault , Cheng Wenxuan , Xu Li , Davidson Irwin , Yan Fangrong , Fridman Wolf Herman , Sautes-Fridman Catherine , Oudard Stéphane , Malouf Gabriel G.
Published: April 2023

AbstractPurpose:
Immune checkpoint inhibitors (ICI) have revolutionized the treatment of patients with clear-cell renal cell carcinomas (ccRCC). Although analyses of transcriptome, genetic alterations, and the tumor microenvironment (TME) have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains fully unknown.
Experimental Design:
We investigated the methylome of six ccRCC cohorts as well as one cell line dataset. Of note, we took advantage of the BIONIKK trial aiming to tailor treatments according to Paris Descartes 4-gene expression subgroups, and performed Illumina EPIC profiling for 46 samples related to patients treated with ipilimumab plus nivolumab, and 17 samples related to patients treated with sunitinib.
Results:
A group of tumors associated with enhancer demethylation was discovered, namely TED. TED was associated with tumors with sarcomatoid differentiation and poor clinical outcome. TED harbored TET1 promoter demethylation, activated the gene expression signature of epithelial–mesenchymal transition and IL6/JAK/STAT3 pathways, and displayed a TME characterized by both immune activation and suppressive populations, fibroblast infiltration, and endothelial depletion. In addition, TED was a predictive factor of resistance to the combination of first-line ipilimumab-nivolumab in the BIONIKK clinical trial. Finally, TED was associated with activation of specific regulons, which we also found to be predictive of resistance to immunotherapy in an independent cohort.
Conclusions:
We report on the discovery of a novel epigenetic phenotype associated with resistance to ICIs that may pave the way to better personalizing patients’ treatments.
Data from A Phase I Trial of CT900, a Novel α-Folate Receptor–Mediated Thymidylate Synthase Inhibitor, in Patients with Solid Tumors with Expansion Cohorts in Patients with High-Grade Serous Ovarian Cancer
Authors: Banerjee Susana , Michalarea Vasiliki , Ang Joo Ern , Ingles Garces Alvaro , Biondo Andrea , Funingana Ionut-Gabriel , Little Martin , Ruddle Ruth , Raynaud Florence , Riisnaes Ruth , Gurel Bora , Chua Sue , Tunariu Nina , Porter Joanna C. , Prout Toby , Parmar Mona , Zachariou Anna , Turner Alison , Jenkins Ben , McIntosh Stuart , Ainscow Ed , Minchom Anna , Lopez Juanita , de Bono Johann , Jones Robert , Hall Emma , Cook Natalie , Basu Bristi , Banerji Udai
Published: April 2023

AbstractPurpose:
CT900 is a novel small molecule thymidylate synthase inhibitor that binds to α-folate receptor (α-FR) and thus is selectively taken up by α-FR–overexpressing tumors.
Patients and Methods:
A 3+3 dose escalation design was used. During dose escalation, CT900 doses of 1–6 mg/m2 weekly and 2–12 mg/m2 every 2 weeks (q2Wk) intravenously were evaluated. Patients with high-grade serous ovarian cancer were enrolled in the expansion cohorts.
Results:
109 patients were enrolled: 42 patients in the dose escalation and 67 patients in the expansion cohorts. At the dose/schedule of 12 mg/m2/q2Wk (with and without dexamethasone, n = 40), the most common treatment-related adverse events were fatigue, nausea, diarrhea, cough, anemia, and pneumonitis, which were predominantly grade 1 and grade 2. Levels of CT900 more than 600 nmol/L needed for growth inhibition in preclinical models were achieved for >65 hours at a dose of 12 mg/m2. In the expansion cohorts, the overall response rate (ORR), was 14/64 (21.9%). Thirty-eight response-evaluable patients in the expansion cohorts receiving 12 mg/m2/q2Wk had tumor evaluable for quantification of α-FR. Patients with high or medium expression had an objective response rate of 9/25 (36%) compared with 1/13 (7.7%) in patients with negative/very low or low expression of α-FR.
Conclusions:
The dose of 12 mg/m2/q2Wk was declared the recommended phase II dose/schedule. At this dose/schedule, CT900 exhibited an acceptable side effect profile with clinical benefit in patients with high/medium α-FR expression and warrants further investigation.
Data from 89Zr-panitumumab Combined With 18F-FDG PET Improves Detection and Staging of Head and Neck Squamous Cell Carcinoma
Authors: Lee Yu-Jin , van den Berg Nynke S. , Duan Heying , Azevedo E. Carmen , Ferri Valentina , Hom Marisa , Raymundo Roan C. , Valencia Alex , Castillo Jessa , Shen Bin , Zhou Quan , Freeman Laura , Koran Mary Ellen , Kaplan Michael J. , Colevas A. Dimitrios , Baik Fred M. , Chin Frederick T. , Martin Brock A. , Iagaru Andrei , Rosenthal Eben L.
Published: April 2023

AbstractPurpose:
Determine the safety and specificity of a tumor-targeted radiotracer (89Zr-pan) in combination with 18F-FDG PET/CT to improve diagnostic accuracy in head and neck squamous cell carcinoma (HNSCC).
Experimental Design:
Adult patients with biopsy-proven HNSCC scheduled for standard-of-care surgery were enrolled in a clinical trial and underwent systemic administration of 89Zirconium-panitumumab and panitumumab-IRDye800 followed by preoperative 89Zr-pan PET/CT and intraoperative fluorescence imaging. The sensitivity, specificity, and AUC were evaluated.
Results:
A total of fourteen patients were enrolled and completed the study. Four patients (28.5%) had areas of high 18F-FDG uptake outside the head and neck region with maximum standardized uptake values (SUVmax) greater than 2.0 that were not detected on 89Zr-pan PET/CT. These four patients with incidental findings underwent further workup and had no evidence of cancer on biopsy or clinical follow-up. Forty-eight lesions (primary tumor, LNs, incidental findings) with SUVmax ranging 2.0–23.6 were visualized on 18F-FDG PET/CT; 34 lesions on 89Zr-pan PET/CT with SUVmax ranging 0.9–10.5. The combined ability of 18F-FDG PET/CT and 89Zr-pan PET/CT to detect HNSCC in the whole body was improved with higher specificity of 96.3% [confidence interval (CI), 89.2%–100%] compared to 18F-FDG PET/CT alone with specificity of 74.1% (CI, 74.1%–90.6%). One possibly related grade 1 adverse event of prolonged QTc (460 ms) was reported but resolved in follow-up.
Conclusions:
89Zr-pan PET/CT imaging is safe and may be valuable in discriminating incidental findings identified on 18F-FDG PET/CT from true positive lesions and in localizing metastatic LNs.
Data from [89Zr]Zr-DFO-girentuximab and [18F]FDG PET/CT to Predict Watchful Waiting Duration in Patients with Metastatic Clear-cell Renal Cell Carcinoma
Authors: Verhoeff Sarah R. , Oosting Sjoukje F. , Elias Sjoerd G. , van Es Suzanne C. , Gerritse Sophie L. , Angus Lindsay , Heskamp Sandra , Desar Ingrid M.E. , Menke-van der Houven van Oordt C. Willemien , van der Veldt Astrid A.M. , Arens Anne I.J. , Brouwers Adrienne H. , Eisses Bertha , Mulders Peter F.A. , Hoekstra Otto S. , Zwezerijnen Gerben J.C. , van der Graaf Winette T.A. , Aarntzen Erik H.J.G. , Oyen Wim J.G. , van Herpen Carla M.L.
Published: April 2023

AbstractPurpose:
Watchful waiting (WW) can be considered for patients with metastatic clear-cell renal cell carcinoma (mccRCC) with good or intermediate prognosis, especially those with <2 International Metastatic RCC Database Consortium criteria and ≤2 metastatic sites [referred to as watch and wait (“W&W”) criteria]. The IMaging PAtients for Cancer drug SelecTion-Renal Cell Carcinoma study objective was to assess the predictive value of [18F]FDG PET/CT and [89Zr]Zr-DFO-girentuximab PET/CT for WW duration in patients with mccRCC.
Experimental Design:
Between February 2015 and March 2018, 48 patients were enrolled, including 40 evaluable patients with good (n = 14) and intermediate (n = 26) prognosis. Baseline contrast-enhanced CT, [18F]FDG and [89Zr]Zr-DFO-girentuximab PET/CT were performed. Primary endpoint was the time to disease progression warranting systemic treatment. Maximum standardized uptake values (SUVmax) were measured using lesions on CT images coregistered to PET/CT. High and low uptake groups were defined on the basis of median geometric mean SUVmax of RECIST-measurable lesions across patients.
Results:
The median WW time was 16.1 months [95% confidence interval (CI): 9.0–31.7]. The median WW period was shorter in patients with high [18F]FDG tumor uptake than those with low uptake (9.0 vs. 36.2 months; HR, 5.6; 95% CI: 2.4–14.7; P < 0.001). Patients with high [89Zr]Zr-DFO-girentuximab tumor uptake had a median WW period of 9.3 versus 21.3 months with low uptake (HR, 1.7; 95% CI: 0.9–3.3; P = 0.13). Patients with “W&W criteria” had a longer median WW period of 21.3 compared with patients without: 9.3 months (HR, 1.9; 95% CI: 0.9–3.9; Pone-sided = 0.034). Adding [18F]FDG uptake to the “W&W criteria” improved the prediction of WW duration (P < 0.001); whereas [89Zr]Zr-DFO-girentuximab did not (P = 0.53).
Conclusions:
In patients with good- or intermediate-risk mccRCC, low [18F]FDG uptake is associated with prolonged WW. This study shows the predictive value of the “W&W criteria” for WW duration and shows the potential of [18F]FDG-PET/CT to further improve this.
Data from FDA Approval Summary: Ripretinib for Advanced Gastrointestinal Stromal Tumor
Authors: Kumar Vaibhav , Doros Leslie , Thompson Margaret , Mushti Sirisha L. , Charlab Rosane , Spehalski Elizabeth I. , Zhao Hong , Thompson Matthew D. , Tang Shenghui , Pazdur Richard , Lemery Steven J. , Theoret Marc R. , Fashoyin-Aje Lola A.
Published: April 2023

Abstract
On May 15, 2020, the FDA approved ripretinib for adult patients with advanced gastrointestinal stromal tumor who have received prior treatment with three or more kinase inhibitors, including imatinib. The approval was based on results from INVICTUS (NCT03353753), an international, multi-center, double-blind, placebo-controlled trial. Patients were randomly allocated (2:1) to receive either ripretinib 150 mg once daily (n = 85) or matching placebo (n = 44). The trial demonstrated a statistically significant improvement in progression-free survival (PFS) as assessed by modified RECIST v1.1 by blinded independent central review for patients randomized to ripretinib, with a median PFS of 6.3 months [95% confidence interval (CI): 4.6–6.9] compared with 1.0 month (95% CI: 0.9–1.7) for placebo [HR: 0.15 (95% CI: 0.09–0.25); P < 0.0001, stratified log-rank test]. There was no statistically significant difference in objective response rate in the ripretinib arm, 9% (95% CI: 4.2–18) compared with placebo 0% [(95% CI: 0–8); P = 0.0504, Fisher exact test]. The median overall survival (OS) in the ripretinib arm was 15.1 months (95% CI: 12.3–15.1) compared with 6.6 months (95% CI: 4.1–11.6) in the placebo arm. A formal statistical comparison of OS was not made due to the prespecified hierarchical analysis plan. The most common (≥20%) adverse events with ripretinib, in order of decreasing frequency, were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia, and vomiting. Other important risks of ripretinib include new primary cutaneous malignancies, hypertension, and cardiac dysfunction.
Data from Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and BRCA1, BRCA2, or ATM Alterations Identified by Testing Circulating Tumor DNA
Authors: Matsubara Nobuaki , de Bono Johann , Olmos David , Procopio Giuseppe , Kawakami Satoru , Ürün Yüksel , van Alphen Robbert , Flechon Aude , Carducci Michael A. , Choi Young Deuk , Hotte Sebastien J. , Korbenfeld Ernesto , Kramer Gero , Agarwal Neeraj , Chi Kim N. , Dearden Simon , Gresty Christopher , Kang Jinyu , Poehlein Christian , Harrington Elizabeth A. , Hussain Maha
Published: April 2023

AbstractPurpose:
The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations. We present exploratory analyses on the use of circulating tumor DNA (ctDNA) testing as an additional method to identify patients with mCRPC with HRR gene alterations who may be eligible for olaparib treatment.
Patients and Methods:
Plasma samples collected during screening in PROfound were retrospectively sequenced using the FoundationOne®Liquid CDx test for BRCA1, BRCA2 (BRCA), and ATM alterations in ctDNA. Only patients from Cohort A (BRCA/ATM alteration positive by tissue testing) were evaluated. We compared clinical outcomes, including radiographic progression-free survival (rPFS) between the ctDNA subgroup and Cohort A.
Results:
Of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control. Patients’ baseline demographics and characteristics, and the prevalence of HRR alterations were comparable with the Cohort A intention-to-treat (ITT) population. rPFS was longer in the olaparib group versus control [median 7.4 vs. 3.5 months; hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21–0.53; nominal P < 0.0001], which is consistent with Cohort A ITT population (HR, 0.34; 95% CI, 0.25–0.47).
Conclusions:
When tumor tissue testing is not feasible or has failed, ctDNA testing may be a suitable alternative to identify patients with mCRPC carrying BRCA/ATM alterations who may benefit from olaparib treatment.
Data from Longitudinal Outcome over Two Decades of Unrelated Allogeneic Stem Cell Transplantation for Relapsed/Refractory Acute Myeloid Leukemia: An ALWP/EBMT Analysis
Authors: Nagler Arnon , Ngoya Maud , Galimard Jacques-Emmanuel , Labopin Myriam , Bornhäuser Martin , Stelljes Matthias , Finke Jürgen , Ganser Arnold , Einsele Herman , Kröger Nicolaus , Brecht Arne , Bethge Wolfgang , Edinger Matthias , Kulagin Aleksandr , Passweg Jakob , Blau Igor Wolfgang , Elmaagacli Ahmet , Schäfer-Eckart Kerstin , Platzbecker Uwe , Schroeder Thomas , Bunjes Donald , Tischer Johanna , Martin Sonja , Spyridonidis Alexandros , Giebel Sebastian , Savani Bipin , Mohty Mohamad
Published: April 2023

AbstractPurpose:
We evaluated outcomes of unrelated transplantation for primary refractory/relapsed (ref/rel) acute myeloid leukemia (AML), comparing two cohorts according to the year of transplant, 2000–2009 and 2010–2019.
Patients and Methods:
Multivariable analyses were performed using the Cox proportional-hazards regression model.
Results:
3,430 patients were included; 876 underwent a transplant between 2000–2009 and 2554 in 2010–2019. Median follow-up was 8.7 (95% CI, 7.8–9.4) and 3.4 (95% CI, 3.1–3.6) years (P < 0.001). Median age was 52 (18–77) and 56 (18–79) years (P > 0.0001); 45.5% and 55.5% had refractory AML while 54.5% and 44.5% had relapsed AML. Conditioning was myeloablative in 60% and 52%, respectively. Neutrophil recovery and day 100 incidence of acute and 2-year incidence of chronic graft-versus-host disease (GvHD) were similar between the two periods. Two-year relapse incidence was higher for patients undergoing transplant in the 2000–2009 period versus those undergoing transplant in 2010–2019: 50.2% versus 45.1% (HR, 0.85; 95% CI, 0.74–0.97; P = 0. 002). Leukemia-free survival; overall survival; and GvHD-free, relapse-free survival were lower for the 2000–2009 period: 26% versus 32.1% (HR, 0.87; 95% CI, 0.78–0.97; P = 0.01), 32.1% versus 38.1% (HR, 0.86; 95% CI, 0.77–0.96; P = 0.01), and 21.5% versus 25.3% (HR, 0.89; 95% CI, 0.81–0.99; P = 0.03), respectively. Two-year nonrelapse mortality was not significantly different (23.8% vs. 23.7%; HR, 0.91; 95% CI, 0.76–1.11; P = 0.34).
Conclusions:
Outcome of unrelated transplantation for patients with ref/rel AML has improved in the last two decades, rescuing about one third of the patients.

See related commentary by Adrianzen-Herrera and Shastri, p. 4167
Data from Activation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors
Authors: Nash Amanda M. , Aghlara-Fotovat Samira , Castillio Bertha , Hernandez Andrea , Pugazenthi Aarthi , Lee Hyun-Sung , Jang Hee-Jin , Nguyen Annie , Lu Alexander , Burt Bryan M. , Ghanta Ravi K. , Veiseh Omid
Published: April 2023

AbstractPurpose:
IL2 immunotherapy has the potential to elicit immune-mediated tumor lysis via activation of effector immune cells, but clinical utility is limited due to pharmacokinetic challenges as well as vascular leak syndrome and other life-threatening toxicities experienced by patients. We developed a safe and clinically translatable localized IL2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure.
Experimental Design:
We evaluated the therapeutic efficacy of IL2 cytokine factories in a mouse model of malignant mesothelioma. Changes in immune populations were analyzed using time-of-flight mass cytometry (CyTOF), and the safety and translatability of the platform were evaluated using complete blood counts and serum chemistry analysis.
Results:
IL2 cytokine factories enabled 150× higher IL2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after 1 week of monotherapy treatment, and 7 of 7 of animals exhibited tumor eradication without recurrence when IL2 cytokine factories were combined with anti–programmed cell death protein 1 (aPD1). Furthermore, CyTOF analysis showed an increase in CD69+CD44+ and CD69−CD44+CD62L− T cells, reduction of CD86−PD-L1− M2-like macrophages, and a corresponding increase in CD86+PD-L1+ M1-like macrophages and MHC-II+ dendritic cells after treatment. Finally, blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use.
Conclusions:
IL2 cytokine factories led to the eradication of aggressive mouse malignant mesothelioma tumors and protection from tumor recurrence, and increased the therapeutic efficacy of aPD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL2-based delivery system.

See related commentary by Palanki et al., p. 5010
Data from Meta-Analysis of the Test–Retest Repeatability of [18F]-Fluorodeoxyglucose Standardized Uptake Values: Implications for Assessment of Tumor Response
Authors: Shankar Lalitha K. , Huang Erich , Litiere Saskia , Hoekstra Otto S. , Schwartz Larry , Collette Sandra , Boellaard Ronald , Bogaerts Jan , Seymour Lesley , deVries Elisabeth G.E.
Published: April 2023

AbstractPurpose:
Currently, guidelines for PET with 18F-fluorodeoxyglucose (FDG-PET) interpretation for assessment of therapy response in oncology primarily involve visual evaluation of FDG-PET/CT scans. However, quantitative measurements of the metabolic activity in tumors may be even more useful in evaluating response to treatment. Guidelines based on such measurements, including the European Organization for Research and Treatment of Cancer Criteria and PET Response Criteria in Solid Tumors, have been proposed. However, more rigorous analysis of response criteria based on FDG-PET measurements is needed to adopt regular use in practice.
Experimental Design:
Well-defined boundaries of repeatability and reproducibility of quantitative measurements to discriminate noise from true signal changes are a needed initial step. An extension of the meta-analysis from de Langen and colleagues (2012) of the test–retest repeatability of quantitative FDG-PET measurements, including mean, maximum, and peak standardized uptake values (SUVmax, SUVmean, and SUVpeak, respectively), was performed. Data from 11 studies in the literature were used to estimate the relationship between the variance in test–retest measurements with uptake level and various study-level, patient-level, and lesion-level characteristics.
Results:
Test–retest repeatability of percentage fluctuations for all three types of SUV measurement (max, mean, and peak) improved with higher FDG uptake levels. Repeatability in all three SUV measurements varied for different lesion locations. Worse repeatability in SUVmean was also associated with higher tumor volumes.
Conclusions:
On the basis of these results, recommendations regarding SUV measurements for assessing minimal detectable changes based on repeatability and reproducibility are proposed. These should be applied to differentiate between response categories for a future set of FDG-PET–based criteria that assess clinically significant changes in tumor response.
Data from Multi-omic Characterization of Pancreatic Ductal Adenocarcinoma Relates CXCR4 mRNA Expression Levels to Potential Clinical Targets
Authors: Kocher Florian , Puccini Alberto , Untergasser Gerold , Martowicz Agnieszka , Zimmer Kai , Pircher Andreas , Baca Yasmine , Xiu Joanne , Haybaeck Johannes , Tymoszuk Piotr , Goldberg Richard M. , Petrillo Angelica , Shields Anthony F. , Salem Mohamed E. , Marshall John L. , Hall Michael , Korn W. Michael , Nabhan Chadi , Battaglin Francesca , Lenz Heinz-Josef , Lou Emil , Choo Su-Pin , Toh Chee-Keong , Gasteiger Silvia , Pichler Renate , Wolf Dominik , Seeber Andreas
Published: April 2023

AbstractPurpose:
Chemokines are essential for immune cell trafficking and are considered to have a major impact on the composition of the tumor microenvironment. CX-chemokine receptor 4 (CXCR4) is associated with poor differentiation, metastasis, and prognosis in pancreatic ductal adenocarcinoma (PDAC). This study provides a comprehensive molecular portrait of PDAC according to CXCR4 mRNA expression levels.
Experimental Design:
The Cancer Genome Atlas database was used to explore molecular and immunologic features associated with CXCR4 mRNA expression in PDAC. A large real-word dataset (n = 3,647) served for validation and further exploratory analyses. Single-cell RNA analyses on a publicly available dataset and in-house multiplex immunofluorescence (mIF) experiments were performed to elaborate cellular localization of CXCR4.
Results:
High CXCR4 mRNA expression (CXCR4high) was associated with increased infiltration of regulatory T cells, CD8+ T cells, and macrophages, and upregulation of several immune-related genes, including immune checkpoint transcripts (e.g., TIGIT, CD274, PDCD1). Analysis of the validation cohort confirmed the CXCR4-dependent immunologic TME composition in PDAC irrespective of microsatellite instability–high/mismatch repair–deficient or tumor mutational burden. Single-cell RNA analysis and mIF revealed that CXCR4 was mainly expressed by macrophages and T-cell subsets. Clinical relevance of our finding is supported by an improved survival of CXCR4high PDAC.
Conclusions:
High intratumoral CXCR4 mRNA expression is linked to a T cell– and macrophage-rich PDAC phenotype with high expression of inhibitory immune checkpoints. Thus, our findings might serve as a rationale to investigate CXCR4 as a predictive biomarker in patients with PDAC undergoing immune checkpoint inhibition.
Data from Necroptosis-dependent Immunogenicity of Cisplatin: Implications for Enhancing the Radiation-induced Abscopal Effect
Authors: Luo Ren , Onyshchenko Kateryna , Wang Liqun , Gaedicke Simone , Grosu Anca-Ligia , Firat Elke , Niedermann Gabriele
Published: April 2023

AbstractPurpose:
Cisplatin is increasingly used in chemoimmunotherapy and may enhance the T cell–dependent radiation-induced abscopal effect, but how it promotes antitumor immunity is poorly understood. We investigated whether and why cisplatin is immunogenic, and the implications for the cisplatin-enhanced abscopal effect.
Experimental Design:
Cisplatin, carboplatin, and the well-known immunogenic cell death (ICD) inducer oxaliplatin were compared for their potency to enhance the abscopal effect and induce type I IFN (IFN-I) and extracellular ATP, danger signals of ICD. The hypothetical role of necroptosis and associated damage-associated molecular patterns for cisplatin-induced ICD was investigated by inhibitors and knockout cells in vitro and in two tumor models in mice. A novel necroptosis signature for tumor immune cell infiltration and therapy response was developed.
Results:
Cisplatin enhanced the abscopal effect more strongly than oxaliplatin or carboplatin. This correlated with higher induction of IFN-I and extracellular ATP by cisplatin, in a necroptosis-dependent manner. Cisplatin triggered receptor-interacting protein kinase 3 (RIPK3)-dependent tumor cell necroptosis causing cytosolic mitochondrial DNA (mtDNA) release, initiating the cyclic GMP–AMP synthase–stimulator of interferon genes pathway and IFN-I secretion promoting T-cell cross-priming by dendritic cells (DC). Accordingly, tumor cell RIPK3 or mtDNA deficiency and loss of IFN-I or ATP signaling diminished the cisplatin-enhanced abscopal effect. Cisplatin-treated tumor cells were immunogenic in vaccination experiments, depending on RIPK3 and mtDNA. In human tumor transcriptome analysis, necroptotic features correlated with abundant CD8+ T cells/DCs, sparse immunosuppressive cells, and immunotherapy response.
Conclusions:
Cisplatin induces antitumor immunity through necroptosis-mediated ICD. Our findings may help explain the benefits of cisplatin in chemo(radio)immunotherapies and develop clinical trials to investigate whether cisplatin enhances the abscopal effect in patients.
Data from Randomized Phase II Study of Physiologic MRI-Directed Adaptive Radiation Boost in Poor Prognosis Head and Neck Cancer
Authors: Mierzwa Michelle L. , Aryal Madhava , Lee Choonik , Schipper Matthew , VanTil Monica , Morales Krystal , Swiecicki Paul L. , Casper Keith A. , Malloy Kelly M. , Spector Matthew E. , Shuman Andrew G. , Chinn Steven B. , Prince Mark E.P. , Stucken Chaz L. , Rosko Andrew J. , Lawrence Theodore S. , Brenner J. Chad , Rosen Benjamin , Schonewolf Caitlin A. , Shah Jennifer , Eisbruch Avraham , Worden Francis P. , Cao Yue
Published: April 2023

AbstractPurpose:
We conducted a randomized phase II multicenter clinical trial to test the hypothesis that physiologic MRI-based radiotherapy (RT) dose escalation would improve the outcome of patients with poor prognosis head and neck cancer.
Patients and Methods:
MRI was acquired at baseline and at RT fraction 10 to create low blood volume/apparent diffusion coefficient maps for RT boost subvolume definition in gross tumor volume. Patients were randomized to receive 70 Gy (standard RT) or 80 Gy to the boost subvolume (RT boost) with concurrent weekly platinum. The primary endpoint was disease-free survival (DFS) with significance defined at a one-sided 0.1 level, and secondary endpoints included locoregional failure (LRF), overall survival (OS), comparison of adverse events and patient reported outcomes (PRO).
Results:
Among 81 randomized patients, neither the primary endpoint of DFS (HR = 0.849, P = 0.31) nor OS (HR = 1.19, P = 0.66) was significantly improved in the RT boost arm. However, the incidence of LRF was significantly improved with the addition of the RT boost (HR = 0.43, P = 0.047). Two-year estimates [90% confidence interval (CI)] of the cumulative incidence of LRF were 40% (27%–53%) in the standard RT arm and 18% (10%–31%) in the RT boost arm. Two-year estimates (90% CI) for DFS were 48% (34%–60%) in the standard RT arm and 57% (43%–69%) in the RT boost arm. There were no significant differences in toxicity or longitudinal differences seen in EORTC QLQ30/HN35 subscales between treatment arms in linear mixed-effects models.
Conclusions:
Physiologic MRI-based RT boost decreased LRF without a significant increase in grade 3+ toxicity or longitudinal PRO differences, but did not significantly improve DFS or OS. Additional improvements in systemic therapy are likely necessary to realize improvements in DFS and OS.
Data from First-in-Maintenance Therapy for Localized High-Grade Osteosarcoma: An Open-Label Phase I/II Trial of the Anti–PD-L1 Antibody ZKAB001
Authors: Zhou Yan , Yang Qingcheng , Dong Yang , Ji Tong , Zhang Bing , Yang Cheng , Zheng Shuier , Tang Lina , Zhou Chenliang , Qian Guowei , Huang Yujing , Yu Wenxi , Li Hongtao , Wang Yonggang , He Aina , Shen Zan , Bao Qiyuan , Hua Yingqi , Bai Hongyu , Zhao Jiayi , Li Xiaoyi , Dai Xiangrong , Zhang Jianjun , Hu Haiyan , Yao Yang
Published: April 2023

AbstractPurpose:
We investigated the safety and preliminary efficacy of anti–PD-L1 antibody (ZKAB001) as maintenance therapy for localized patients with high-grade osteosarcoma to reduce the risk of recurrence and metastasis.
Patients and Methods:
This open-label Phase I/II study was divided into dose-escalation Phase I and expansion Phase II. Phase I used a 3+3 design with ZKAB001 at three escalating doses ranging: 5, 10, 15 mg/kg every 2 weeks in 9 patients with localized high-grade osteosarcoma and Phase II tested 10 mg/kg in 12 patients for up to 24 cycles. Primary endpoints were safety and tolerability assessed using CTCAE4.0.3.
Results:
Between October 2018 and 2019, 21 eligible patients were enrolled and accepted ZKAB001 treatment: 9 in the dose-escalation phase, and 12 in expansion phase. Six patients with disease progression withdrew from this study and follow-up is ongoing. The MTD was not defined in Phase I. All doses had a manageable safety profile. The recommended dose in Phase II was set at 10 mg/kg. Most frequent immune-related adverse events were thyroiditis (76.2%) and dermatitis (42.9%). Only 1 (4.8%) of 21 patients had a Grade 3 skin rash. The median 3-year event-free survival (EFS) and overall survival (OS) were not established; however, 24-month EFS was 71.4% (95% confidence interval, 47.2–86.0) and 2-year OS was 100%. Preliminary efficacy data showed EFS benefits in patients with PD-L1 positive or an MSI-H sub-population.
Conclusions:
Switching to maintenance using ZKAB001 showed an acceptable safety profile and provided preliminary evidence of clinical activity in localized patients with osteosarcoma.