bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Prediction of Immunotherapy Response in Melanoma through Combined Modeling of Neoantigen Burden and Immune-Related Resistance Mechanisms
Authors: Abbott Charles W. , Boyle Sean M. , Pyke Rachel Marty , McDaniel Lee D. , Levy Eric , Navarro Fábio C.P. , Mellacheruvu Dattatreya , Zhang Simo V. , Tan Mengyao , Santiago Rose , Rusan Zeid M. , Milani Pamela , Bartha Gabor , Harris Jason , McClory Rena , Snyder Michael P. , Jang Sekwon , Chen Richard
Published: April 2023

AbstractPurpose:
While immune checkpoint blockade (ICB) has become a pillar of cancer treatment, biomarkers that consistently predict patient response remain elusive due to the complex mechanisms driving immune response to tumors. We hypothesized that a multi-dimensional approach modeling both tumor and immune-related molecular mechanisms would better predict ICB response than simpler mutation-focused biomarkers, such as tumor mutational burden (TMB).
Experimental Design:
Tumors from a cohort of patients with late-stage melanoma (n = 51) were profiled using an immune-enhanced exome and transcriptome platform. We demonstrate increasing predictive power with deeper modeling of neoantigens and immune-related resistance mechanisms to ICB.
Results:
Our neoantigen burden score, which integrates both exome and transcriptome features, more significantly stratified responders and nonresponders (P = 0.016) than TMB alone (P = 0.049). Extension of this model to include immune-related resistance mechanisms affecting the antigen presentation machinery, such as HLA allele-specific LOH, resulted in a composite neoantigen presentation score (NEOPS) that demonstrated further increased association with therapy response (P = 0.002).
Conclusions:
NEOPS proved the statistically strongest biomarker compared with all single-gene biomarkers, expression signatures, and TMB biomarkers evaluated in this cohort. Subsequent confirmation of these findings in an independent cohort of patients (n = 110) suggests that NEOPS is a robust, novel biomarker of ICB response in melanoma.
Data from Recurrent Mutations in Cyclin D3 Confer Clinical Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia
Authors: Smith Catherine C. , Viny Aaron D. , Massi Evan , Kandoth Cyriac , Socci Nicholas D. , Rapaport Franck , Najm Matthieu , Medina-Martinez Juan S. , Papaemmanuil Elli , Tarver Theodore C. , Hsu Henry H. , Le Mai H. , West Brian , Bollag Gideon , Taylor Barry S. , Levine Ross L. , Shah Neil P.
Published: April 2023

AbstractPurpose:
Biomarkers of response and resistance to FLT3 tyrosine kinase inhibitors (TKI) are still emerging, and optimal clinical combinations remain unclear. The purpose of this study is to identify co-occurring mutations that influence clinical response to the novel FLT3 inhibitor pexidartinib (PLX3397).
Experimental Design:
We performed targeted sequencing of pretreatment blasts from 29 patients with FLT3 internal tandem duplication (ITD) mutations treated on the phase I/II trial of pexidartinib in relapsed/refractory FLT3-ITD+ acute myeloid leukemia (AML). We sequenced 37 samples from 29 patients with available material, including 8 responders and 21 non-responders treated at or above the recommended phase II dose of 3,000 mg.
Results:
Consistent with other studies, we identified mutations in NRAS, TP53, IDH2, and a variety of epigenetic and transcriptional regulators only in non-responders. Among the most frequently mutated genes in non-responders was Cyclin D3 (CCND3). A total of 3 individual mutations in CCND3 (Q276*, S264R, and T283A) were identified in 2 of 21 non-responders (one patient had both Q276* and S264R). No CCND3 mutations were found in pexidartinib responders. Expression of the Q276* and T283A mutations in FLT3-ITD MV4;11 cells conferred resistance to apoptosis, decreased cell-cycle arrest, and increased proliferation in the presence of pexidartinib and other FLT3 inhibitors. Inhibition of CDK4/6 activity in CCND3 mutant MV4;11 cells restored pexidartinib-induced cell-cycle arrest but not apoptosis.
Conclusions:
Mutations in CCND3, a gene not commonly mutated in AML, are a novel cause of clinical primary resistance to FLT3 inhibitors in AML and may have sensitivity to CDK4/6 inhibition.
Data from TP53 Mutations with Low Variant Allele Frequency Predict Short Survival in Chronic Lymphocytic Leukemia
Authors: Bomben Riccardo , Rossi Francesca Maria , Vit Filippo , Bittolo Tamara , D'Agaro Tiziana , Zucchetto Antonella , Tissino Erika , Pozzo Federico , Vendramini Elena , Degan Massimo , Zaina Eva , Cattarossi Ilaria , Varaschin Paola , Nanni Paola , Berton Michele , Braida Alessandra , Polesel Jerry , Cohen Jared A. , Santinelli Enrico , Biagi Annalisa , Gentile Massimo , Morabito Fortunato , Fronza Gilberto , Pozzato Gabriele , D'Arena Giovanni , Olivieri Jacopo , Bulian Pietro , Pepper Chris , Hockaday Anna , Schuh Anna , Hillmen Peter , Rossi Davide , Chiarenza Annalisa , Zaja Francesco , Di Raimondo Francesco , Del Poeta Giovanni , Gattei Valter
Published: April 2023

AbstractPurpose:
In chronic lymphocytic leukemia (CLL), TP53 mutations are associated with reduced survival and resistance to standard chemoimmunotherapy (CIT). Nevertheless, the clinical impact of subclonal TP53 mutations below 10% to 15% variant allele frequency (VAF) remains unclear.
Experimental Design:
Using a training/validation approach, we retrospectively analyzed the clinical and biological features of TP53 mutations above (high-VAF) or below (low-VAF) the previously reported 10.0% VAF threshold, as determined by deep next-generation sequencing. Clinical impact of low-VAF TP53 mutations was also confirmed in a cohort (n = 251) of CLL treated with fludarabine-cyclophosphamide-rituximab (FCR) or FCR-like regimens from two UK trials.
Results:
In the training cohort, 97 of 684 patients bore 152 TP53 mutations, while in the validation cohort, 71 of 536 patients had 109 TP53 mutations. In both cohorts, patients with the TP53 mutation experienced significantly shorter overall survival (OS) than TP53 wild-type patients, regardless of the TP53 mutation VAF. By combining TP53 mutation and 17p13.1 deletion (del17p) data in the total cohort (n = 1,220), 113 cases were TP53 mutated only (73/113 with low-VAF mutations), 55 del17p/TP53 mutated (3/55 with low-VAF mutations), 20 del17p only, and 1,032 (84.6%) TP53 wild-type. A model including low-VAF cases outperformed the canonical model, which considered only high-VAF cases (c-indices 0.643 vs. 0.603, P < 0.0001), and improved the prognostic risk stratification of CLL International Prognostic Index. Clinical results were confirmed in CIT-treated cases (n = 552) from the retrospective cohort, and the UK trials cohort.
Conclusions:
TP53 mutations affected OS regardless of VAF. This finding can be used to update the definition of TP53 mutated CLL for clinical purposes.
Data from Dual Targeting of Chromatin Stability By The Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Shows Significant Preclinical Efficacy in Neuroblastoma
Authors: Xiao Lin , Somers Klaartje , Murray Jayne , Pandher Ruby , Karsa Mawar , Ronca Emma , Bongers Angelika , Terry Rachael , Ehteda Anahid , Gamble Laura D. , Issaeva Natalia , Leonova Katerina I. , O'Connor Aisling , Mayoh Chelsea , Venkat Pooja , Quek Hazel , Brand Jennifer , Kusuma Frances K. , Pettitt Jessica A. , Mosmann Erin , Kearns Adam , Eden Georgina , Alfred Stephanie , Allan Sophie , Zhai Lei , Kamili Alvin , Gifford Andrew J. , Carter Daniel R. , Henderson Michelle J. , Fletcher Jamie I. , Marshall Glenn , Johnstone Ricky W. , Cesare Anthony J. , Ziegler David S. , Gudkov Andrei V. , Gurova Katerina V. , Norris Murray D. , Haber Michelle
Published: April 2023

AbstractPurpose:
We investigated whether targeting chromatin stability through a combination of the curaxin CBL0137 with the histone deacetylase (HDAC) inhibitor, panobinostat, constitutes an effective multimodal treatment for high-risk neuroblastoma.
Experimental Design:
The effects of the drug combination on cancer growth were examined in vitro and in animal models of MYCN-amplified neuroblastoma. The molecular mechanisms of action were analyzed by multiple techniques including whole transcriptome profiling, immune deconvolution analysis, immunofluorescence, flow cytometry, pulsed-field gel electrophoresis, assays to assess cell growth and apoptosis, and a range of cell-based reporter systems to examine histone eviction, heterochromatin transcription, and chromatin compaction.
Results:
The combination of CBL0137 and panobinostat enhanced nucleosome destabilization, induced an IFN response, inhibited DNA damage repair, and synergistically suppressed cancer cell growth. Similar synergistic effects were observed when combining CBL0137 with other HDAC inhibitors. The CBL0137/panobinostat combination significantly delayed cancer progression in xenograft models of poor outcome high-risk neuroblastoma. Complete tumor regression was achieved in the transgenic Th-MYCN neuroblastoma model which was accompanied by induction of a type I IFN and immune response. Tumor transplantation experiments further confirmed that the presence of a competent adaptive immune system component allowed the exploitation of the full potential of the drug combination.
Conclusions:
The combination of CBL0137 and panobinostat is effective and well-tolerated in preclinical models of aggressive high-risk neuroblastoma, warranting further preclinical and clinical investigation in other pediatric cancers. On the basis of its potential to boost IFN and immune responses in cancer models, the drug combination holds promising potential for addition to immunotherapies.
Data from Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies
Authors: Tayari Mina M. , Santos Helena G. Dos , Kwon Deukwoo , Bradley Terrence J. , Thomassen Amber , Chen Charles , Dinh Yvonne , Perez Aymee , Zelent Arthur , Morey Lluis , Cimmino Luisa , Shiekhattar Ramin , Swords Ronan T. , Watts Justin M.
Published: April 2023

AbstractPurpose:
In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS).
Patients and Methods:
Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily).
Results:
ATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34+ cell phenotype at baseline, including decreased MYC and RARA expression, compared with nonresponders that exhibited a more proliferative CD34+ phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid–target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response.
Conclusions:
These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML.
Data from Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions
Authors: Singh Harshabad , Li Yvonne Y. , Spurr Liam F. , Shinagare Atul B. , Abhyankar Ritika , Reilly Emma , Brais Lauren K. , Nag Anwesha , Ducar Matthew D. , Thorner Aaron R. , Shapiro Geoffrey I. , Keller Rachel B. , Siletti Cheta , Clark Jeffrey W. , Farago Anna F. , Lin Jessica J. , Demetri George D. , Gujrathi Rahul , Kulke Matthew H. , MacConaill Laura E. , Ligon Azra H. , Sicinska Ewa , Meyerson Matthew L. , Meyerhardt Jeffrey A. , Cherniack Andrew D. , Wolpin Brian M. , Ng Kimmie , Giannakis Marios , Hornick Jason L. , Cleary James M.
Published: April 2023

AbstractPurpose:
Receptor tyrosine kinase fusions in colorectal cancers are rare, but potentially therapeutically relevant. We describe clinical, molecular, and pathologic attributes of RTK fusion–associated colorectal cancer.
Experimental Design:
We identified all cases with RTK fusions in patients with colorectal cancer seen at Dana-Farber Cancer Institute (Boston, MA) who underwent OncoPanel testing between 2013 and 2018. Clinical, histologic, and molecular features were extracted from the patient charts and molecular testing results.
Results:
We identified 12 driver oncogenic fusions in various RTKs. These fusions occurred exclusively in BRAF and RAS wild-type tumors and were enriched in right-sided and mismatch repair–deficient (MMR-D) colorectal cancers. All of the MMR-D colorectal cancers with RTK fusions were found in tumors with acquired MMR-D due to MLH1 promoter hypermethylation and one was associated with a sessile serrated polyp. Molecular profiles of MMR-D colorectal cancer with RTK fusions largely resembled BRAF V600E–mutated MMR-D colorectal cancer, rather than those secondary to Lynch syndrome. We describe two patients with fusion-associated microsatellite stable (MSS) colorectal cancer who derived clinical benefit from therapeutic targeting of their translocation. The first harbored an ALK-CAD fusion and received sequential crizotinib and alectinib therapy for a total of 7.5 months until developing an ALK L1196Q gatekeeper mutation. The second patient, whose tumor contained an ROS1-GOPC fusion, continues to benefit from entrectinib after 9 months of therapy.
Conclusions:
RTK fusions in colorectal cancer are a rare, but important disease subgroup that occurs in RAS and BRAF wild-type tumors. Despite enrichment in acquired MMR-D tumors, RTK fusions also occur in MSS colorectal cancer and provide an important therapeutic target.
Data from Abiraterone Acetate Induces CREB1 Phosphorylation and Enhances the Function of the CBP-p300 Complex, Leading to Resistance in Prostate Cancer Cells
Authors: Pan Wenting , Zhang Zhouwei , Kimball Hannah , Qu Fangfang , Berlind Kyler , Stopsack Konrad H. , Lee Gwo-Shu Mary , Choueiri Toni K. , Kantoff Philip W.
Published: April 2023

AbstractPurpose:
Abiraterone acetate (AA), an inhibitor of cytochrome P450 17alpha-hydroxylase/17, 20 lyase, is an FDA-approved drug for advanced prostate cancer. However, not all patients respond to AA, and AA resistance ultimately develops in patients who initially respond. We aimed to identify AA resistance mechanisms in prostate cancer cells.
Experimental Design:
We established several AA-resistant cell lines and performed a comprehensive study on mechanisms involved in AA resistance development. RNA sequencing and phospho-kinase array screenings were performed to discover that the cAMP-response element CRE binding protein 1 (CREB1) was a critical molecule in AA resistance development.
Results:
The drug-resistant cell lines are phenotypically stable without drug selection, and exhibit permanent global gene expression changes. The phosphorylated CREB1 (pCREB1) is increased in AA-resistant cell lines and is critical in controlling global gene expression. Upregulation of pCREB1 desensitized prostate cancer cells to AA, while blocking CREB1 phosphorylation resensitized AA-resistant cells to AA. AA treatment increases intracellular cyclic AMP (cAMP) levels, induces kinases activity, and leads to the phosphorylation of CREB1, which may subsequently augment the essential role of the CBP/p300 complex in AA-resistant cells because AA-resistant cells exhibit a relatively higher sensitivity to CBP/p300 inhibitors. Further pharmacokinetics studies demonstrated that AA significantly synergizes with CBP/p300 inhibitors in limiting the growth of prostate cancer cells.
Conclusions:
Our studies suggest that AA treatment upregulates pCREB1, which enhances CBP/p300 activity, leading to global gene expression alterations, subsequently resulting in drug resistance development. Combining AA with therapies targeting resistance mechanisms may provide a more effective treatment strategy.
Data from Co-Targeting of MDM2 and CDK4/6 with Siremadlin and Ribociclib for the Treatment of Patients with Well-Differentiated or Dedifferentiated Liposarcoma: Results from a Proof-of-Concept, Phase Ib Study
Authors: Abdul Razak Albiruni R. , Bauer Sebastian , Suarez Cristina , Lin Chia-Chi , Quek Richard , Hütter-Krönke Marie Luise , Cubedo Ricardo , Ferretti Stephane , Guerreiro Nelson , Jullion Astrid , Orlando Elena J. , Clementi Giorgia , Sand Dejmek Janna , Halilovic Ensar , Fabre Claire , Blay Jean-Yves , Italiano Antoine
Published: April 2023

AbstractPurpose:
Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are characterized by co-amplification of the murine double minute-2 (MDM2) and cyclin-dependent kinase-4 (CDK4) oncogenes. Siremadlin, a p53–MDM2 inhibitor, was combined with ribociclib, a CDK4/6 inhibitor, in patients with locally advanced/metastatic WDLPS or DDLPS who had radiologically progressed on, or despite, prior systemic therapy.
Patients and Methods:
In this proof-of-concept, phase Ib, dose-escalation study, patients received siremadlin and ribociclib across different regimens until unacceptable toxicity, disease progression, and/or treatment discontinuation: Regimen A [4-week cycle: siremadlin once daily (QD) and ribociclib QD (2 weeks on, 2 weeks off)], Regimen B [3-week cycle: siremadlin once every 3 weeks; ribociclib QD (2 weeks on, 1 week off)], and Regimen C [4-week cycle: siremadlin once every 4 weeks; ribociclib QD (2 weeks on, 2 weeks off)]. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of siremadlin plus ribociclib in one or more regimens.
Results:
As of October 16, 2019 (last patient last visit), 74 patients had enrolled. Median duration of exposure was 13 (range, 1–174) weeks. Dose-limiting toxicities occurred in 10 patients, most of which were Grade 3/4 hematologic events. The RDE was siremadlin 120 mg every 3 weeks plus ribociclib 200 mg QD (Regimen B). Three patients achieved a partial response, and 38 achieved stable disease. One patient (Regimen C) died as a result of treatment-related hematotoxicity.
Conclusions:
Siremadlin plus ribociclib demonstrated manageable toxicity and early signs of antitumor activity in patients with advanced WDLPS or DDLPS.
Data from G9a Inhibition Enhances Checkpoint Inhibitor Blockade Response in Melanoma
Authors: Kelly Gregory M. , Al-Ejeh Fares , McCuaig Robert , Casciello Francesco , Ahmad Kamal Nabilah , Ferguson Blake , Pritchard Antonia L. , Ali Sayed , Silva Ines P. , Wilmott James S. , Long Georgina V. , Scolyer Richard A. , Rao Sudha , Hayward Nicholas K. , Gannon Frank , Lee Jason S.
Published: April 2023

AbstractPurpose:
G9a histone methyltransferase exerts oncogenic effects in several tumor types and its inhibition promotes anticancer effects. However, the impact on checkpoint inhibitor blockade response and the utility of G9a or its target genes as a biomarker is poorly studied. We aimed to examine whether G9a inhibition can augment the efficacy of checkpoint inhibitor blockade and whether LC3B, a G9a target gene, can predict treatment response.
Experimental Design:
Clinical potential of LC3B as a biomarker of checkpoint inhibitor blockade was assessed using patient samples including tumor biopsies and circulating tumor cells from liquid biopsies. Efficacy of G9a inhibition to enhance checkpoint inhibitor blockade was examined using a mouse model.
Results:
Patients with melanoma who responded to checkpoint inhibitor blockade were associated with not only a higher level of tumor LC3B but also a higher proportion of cells expressing LC3B. A higher expression of MAP1LC3B or LC3B protein was associated with longer survival and lower incidence of acquired resistance to checkpoint inhibitor blockade, suggesting LC3B as a potential predictive biomarker. We demonstrate that G9a histone methyltransferase inhibition is able to not only robustly induce LC3B level to augment the efficacy of checkpoint inhibitor blockade, but also induces melanoma cell death.
Conclusions:
Checkpoint inhibitor blockade response is limited to a subset of the patient population. These results have implications for the development of LC3B as a predictive biomarker of checkpoint inhibitor blockade to guide patient selection, as well as G9a inhibition as a strategy to extend the proportion of patients responding to immunotherapy.
Data from Tadalafil Enhances Immune Signatures in Response to Neoadjuvant Nivolumab in Resectable Head and Neck Squamous Cell Carcinoma
Authors: Luginbuhl Adam J. , Johnson Jennifer M. , Harshyne Larry A. , Linnenbach Alban J. , Shukla Sanket K. , Alnemri Angela , Kumar Gaurav , Cognetti David M. , Curry Joseph M. , Kotlov Nikita , Antysheva Zoya , Degryse Sandrine , Mannion Kyle , Gibson Michael K. , Netterville James , Brown Brandee , Axelrod Rita , Zinner Ralph , Tuluc Madalina , Gargano Stacey , Leiby Benjamin E. , Shimada Ayako , Mahoney My G. , Martinez-Outschoorn Ubaldo , Rodeck Ulrich , Kim Young J. , South Andrew P. , Argiris Athanassios
Published: April 2023

AbstractPurpose:
We hypothesize that the addition of the phosphodiesterase-5 inhibitor tadalafil to the PD-1 inhibitor nivolumab, is safe and will augment immune-mediated antitumor responses in previously untreated squamous cell carcinoma of the head and neck (HNSCC).
Patients and Methods:
We conducted a two-arm multi-institutional neoadjuvant randomized trial in any-stage resectable HNSCC (NCT03238365). Patients were stratified at randomization by human papillomavirus (HPV) status. Patients in both arms received nivolumab 240 mg intravenously on days 1 and 15 followed by surgery on day 28. Those in the combination therapy arm also received tadalafil 10 mg orally once daily for 4 weeks. Imaging, blood, and tumor were obtained pretreatment and posttreatment for correlative analysis.
Results:
Neoadjuvant therapy was well-tolerated with no grade 3 to 5 adverse events and no surgical delays. Twenty-five of 46 (54%) evaluable patients had a pathologic treatment response of ≥20%, including three (7%) patients with a complete pathologic response. Regardless of HPV status, tumor proliferation rate was a negative predictor of response. A strong pretreatment T-cell signature in the HPV-negative cohort was a predictor of response. Tadalafil altered the immune microenvironment, as evidenced by transcriptome data identifying enriched B- and natural killer cell gene sets in the tumor and augmented effector T cells in the periphery.
Conclusions:
Preoperative nivolumab ± tadalafil is safe in HNSCC and results in more than 50% of the patients having a pathologic treatment response of at least 20% after 4 weeks of treatment. Pretreatment specimens identified HPV status-dependent signatures that predicted response to immunotherapy while posttreatment specimens showed augmentation of the immune microenvironment with the addition of tadalafil.
Data from Convection Enhanced Delivery of the Oncolytic Adenovirus Delta24-RGD in Patients with Recurrent GBM: A Phase I Clinical Trial Including Correlative Studies
Authors: van Putten Erik H.P. , Kleijn Anne , van Beusechem Victor W. , Noske David , Lamers Cor H.J. , de Goede Anna L. , Idema Sander , Hoefnagel Daphna , Kloezeman Jenneke J. , Fueyo Juan , Lang Frederick F. , Teunissen Charlotte E. , Vernhout René M. , Bakker Cathy , Gerritsen Winald , Curiel David T. , Vulto Arnold , Lamfers Martine L.M. , Dirven Clemens M.F.
Published: April 2023

AbstractPurpose:
Testing safety of Delta24-RGD (DNX-2401), an oncolytic adenovirus, locally delivered by convection enhanced delivery (CED) in tumor and surrounding brain of patients with recurrent glioblastoma.
Patients and Methods:
Dose-escalation phase I study with 3+3 cohorts, dosing 107 to 1 × 1011 viral particles (vp) in 20 patients. Besides clinical parameters, adverse events, and radiologic findings, blood, cerebrospinal fluid (CSF), brain interstitial fluid, and excreta were sampled over time and analyzed for presence of immune response, viral replication, distribution, and shedding.
Results:
Of 20 enrolled patients, 19 received the oncolytic adenovirus Delta24-RGD, which was found to be safe and feasible. Four patients demonstrated tumor response on MRI, one with complete regression and still alive after 8 years. Most serious adverse events were attributed to increased intracranial pressure caused by either an inflammatory reaction responding to steroid treatment or viral meningitis being transient and self-limiting. Often viral DNA concentrations in CSF increased over time, peaking after 2 to 4 weeks and remaining up to 3 months. Concomitantly Th1- and Th2-associated cytokine levels and numbers of CD3+ T and natural killer cells increased. Posttreatment tumor specimens revealed increased numbers of macrophages and CD4+ and CD8+ T cells. No evidence of viral shedding in excreta was observed.
Conclusions:
CED of Delta24-RGD not only in the tumor but also in surrounding brain is safe, induces a local inflammatory reaction, and shows promising clinical responses.
Data from Continuation of Pembrolizumab with Additional Chemotherapy after Progression with PD-1/PD-L1 Inhibitor Monotherapy in Patients with Advanced NSCLC: A Randomized, Placebo-Controlled Phase II Study
Authors: Jung Hyun Ae , Park Sehhoon , Choi Yoon-La , Lee Se-Hoon , Ahn Jin Seok , Ahn Myung-Ju , Sun Jong-Mu
Published: April 2023

AbstractPurpose:
Although programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors have shown survival benefits in patients with non–small cell lung cancer (NSCLC), most patients progress. This study evaluated whether continuing pembrolizumab with additional chemotherapy after failure of prior PD-1/PD-L1 inhibitor extends survival.
Patients and Methods:
This placebo-controlled, double-blind, randomized phase II study enrolled patients with NSCLC who received one or two cytotoxic chemotherapy, including at least one platinum-doublet regimen, and progressed on second- or third-line PD-1/PD-L1 inhibitor monotherapy as the last systemic therapy. Patients were randomized (1:1) to pembrolizumab or placebo plus chemotherapy, stratified by histology and clinical outcomes to prior PD-1/PD-L1 inhibitor. The primary endpoint was progression-free survival (PFS).
Results:
A total of 98 patients were randomized to the pembrolizumab-chemotherapy (N = 47) and placebo-chemotherapy arm (N = 51). At the median follow-up duration of 10.5 months, there was no statistical difference in PFS [median 4.1 months vs. 5.9 months; HR = 1.06; 95% confidence interval (CI), 0.69–1.62; P = 0.78) and overall survival (median 11.5 months vs. 12.0 months; HR = 1.09; 95% CI, 0.66–1.83; P = 0.73) between the pembrolizumab-chemotherapy and placebo-chemotherapy arms. In a subgroup with PD-L1 expression in ≥50% of tumor cells and favorable clinical outcomes to prior PD-1/PD-L1 inhibitor (partial response or 6 months or longer of stable disease), the pembrolizumab-chemotherapy arm showed a higher 24-month survival rate than the placebo-chemotherapy arm (74% vs. 38%; HR = 0.52; 95% CI, 0.13–2.1; P = 0.34).
Conclusions:
This study did not show a survival benefit with the continuation of pembrolizumab with chemotherapy in patients whose NSCLC progressed on second- or third-line PD-1/PD-L1 inhibitors.

See related commentary by Tseng and Gainor, p. 2206
Data from Safety and Activity of PolyPEPI1018 Combined with Maintenance Therapy in Metastatic Colorectal Cancer: an Open-Label, Multicenter, Phase Ib Study
Authors: Hubbard Joleen M. , Tőke Enikő R. , Moretto Roberto , Graham Rondell P. , Youssoufian Hagop , Lőrincz Orsolya , Molnár Levente , Csiszovszki Zsolt , Mitchell Jessica L. , Wessling Jaclynn , Tóth József , Cremolini Chiara
Published: April 2023

AbstractPurpose:
Although chemotherapy is standard of care for metastatic colorectal cancer (mCRC), immunotherapy has no role in microsatellite stable (MSS) mCRC, a “cold” tumor. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine derived from 7 tumor-associated antigens (TAA) frequently expressed in mCRC. This study assessed PolyPEPI1018 combined with first-line maintenance therapy in patients with MSS mCRC.
Patients and Methods:
Eleven patients with MSS mCRC received PolyPEPI1018 and Montanide ISA51VG adjuvant subcutaneously, combined with fluoropyrimidine/biologic following first-line induction with chemotherapy and a biologic (NCT03391232). In Part A of the study, 5 patients received a single dose; in Part B, 6 patients received up to three doses of PolyPEPI1018 every 12 weeks. The primary objective was safety; secondary objectives were preliminary efficacy, immunogenicity at peripheral and tumor level, and immune correlates.
Results:
PolyPEPI1018 vaccination was safe and well tolerated. No vaccine-related serious adverse event occurred. Eighty percent of patients had CD8+ T-cell responses against ≥3 TAAs. Increased density of tumor-infiltrating lymphocytes were detected post-treatment for 3 of 4 patients’ liver biopsies, combined with increased expression of immune-related gene signatures. Three patients had objective response according to RECISTv1.1, and 2 patients qualified for curative surgery. Longer median progression-free survival for patients receiving multiple doses compared with a single dose (12.5 vs. 4.6 months; P = 0.017) suggested a dose–efficacy correlation. The host HLA genotype predicted multi-antigen–specific T-cell responses (P = 0.01) indicative of clinical outcome.
Conclusions:
PolyPEPI1018 added to maintenance chemotherapy for patients with unresectable, MSS mCRC was safe and associated with specific immune responses and antitumor activity warranting further confirmation in a randomized, controlled setting.
Data from Telaglenastat plus Everolimus in Advanced Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled, Phase II ENTRATA Trial
Authors: Lee Chung-Han , Motzer Robert , Emamekhoo Hamid , Matrana Marc , Percent Ivor , Hsieh James J. , Hussain Arif , Vaishampayan Ulka , Liu Sandy , McCune Steven , Patel Vijay , Shaheen Montaser , Bendell Johanna , Fan Alice C. , Gartrell Benjamin A. , Goodman Oscar B. , Nikolinakos Petros G. , Kalebasty Arash Rezazadeh , Zakharia Yousef , Zhang Zhentao , Parmar Hema , Akella Lalith , Orford Keith , Tannir Nizar M.
Published: April 2023

AbstractPurpose:
Glutaminase is a key enzyme, which supports elevated dependency of tumors on glutamine-dependent biosynthesis of metabolic intermediates. Dual targeting of glucose and glutamine metabolism by the mTOR inhibitor everolimus plus the oral glutaminase inhibitor telaglenastat showed preclinical synergistic anticancer effects, which translated to encouraging safety and efficacy findings in a phase I trial of 2L+ renal cell carcinoma (RCC). This study evaluated telaglenastat plus everolimus (TelaE) versus placebo plus everolimus (PboE) in patients with advanced/metastatic RCC (mRCC) in the 3L+ setting (NCT03163667).
Patients and Methods:
Eligible patients with mRCC, previously treated with at least two prior lines of therapy [including ≥1 VEGFR-targeted tyrosine kinase inhibitor (TKI)] were randomized 2:1 to receive E, plus Tela or Pbo, until disease progression or unacceptable toxicity. Primary endpoint was investigator-assessed progression-free survival (PFS; one-sided α <0.2).
Results:
Sixty-nine patients were randomized (46 TelaE, 23 PboE). Patients had a median three prior lines of therapy, including TKIs (100%) and checkpoint inhibitors (88%). At median follow-up of 7.5 months, median PFS was 3.8 months for TelaE versus 1.9 months for PboE [HR, 0.64; 95% confidence interval (CI), 0.34–1.20; one-sided P = 0.079]. One TelaE patient had a partial response and 26 had stable disease (SD). Eleven patients on PboE had SD. Treatment-emergent adverse events included fatigue, anemia, cough, dyspnea, elevated serum creatinine, and diarrhea; grade 3 to 4 events occurred in 74% TelaE patients versus 61% PboE.
Conclusions:
TelaE was well tolerated and improved PFS versus PboE in patients with mRCC previously treated with TKIs and checkpoint inhibitors.
Data from Safety and Efficacy of 90Y-FAPI-46 Radioligand Therapy in Patients with Advanced Sarcoma and Other Cancer Entities
Authors: Fendler Wolfgang P. , Pabst Kim M. , Kessler Lukas , Fragoso Costa Pedro , Ferdinandus Justin , Weber Manuel , Lippert Maria , Lueckerath Katharina , Umutlu Lale , Kostbade Karina , Mavroeidi Ilektra A. , Schuler Martin , Ahrens Marit , Rischpler Christoph , Bauer Sebastian , Herrmann Ken , Siveke Jens T. , Hamacher Rainer
Published: April 2023

AbstractPurpose:
We report efficacy and safety of 90Y-labeled FAPI-46 (90Y-FAPI-46-RLT) in patients with advanced sarcoma, pancreatic cancer, and other cancer entities.
Experimental Design:
Up to four cycles of radioligand therapy (RLT) were offered to patients with (i) progressive metastatic malignancy, (ii) exhaustion of approved therapies, and (iii) high fibroblast activation protein (FAP) expression, defined as SUVmax ≥ 10 in more than 50% of tumor. Primary endpoint was RECIST response after RLT. Secondary endpoints included PET response (PERCIST), overall survival (OS), dosimetry, and safety of FAP-RLT.
Results:
Among 119 screened patients, 21 (18%) were found eligible [n = 16/3/1/1 sarcoma/pancreatic cancer/prostate/gastric cancer; 38% Eastern Cooperative Oncology Group (ECOG) ≥ 2] and received 47 90Y-FAPI-46-RLT cycles; 16 of 21 (76%) patients underwent repeat RLT. By RECIST, disease control was confirmed in 8 of 21 patients [38%; 8/16 (50%) of evaluable patients). There was one partial response (PR) and seven stable diseases after RLT. Disease control was associated with prolonged OS (P = 0.013). PERCIST response was noted in 8 of 21 patients [38%; 8/15 (53%) of evaluable patients]. Dosimetry was acquired in 19 (90%) patients. Mean absorbed dose was 0.53 Gy/GBq in kidney, 0.04 Gy/GBq in bone marrow, and <0.14 Gy/GBq in liver and lung. Treatment-related grade 3 or 4 adverse events were observed in 8 (38%) patients with thrombocytopenia (n = 6) and anemia (n = 6) being most prevalent.
Conclusions:
90Y-FAPI-46-RLT was safe and led to RECIST PR in one case as well as stable disease in about one third of patients with initially progressive sarcomas, pancreatic cancer, and other cancers. Discontinuation after the first cycle and a low rate of PR requires future improvement of FAP-RLT.
Data from Predictive Markers of Response to Neoadjuvant Durvalumab with Nab-Paclitaxel and Dose-Dense Doxorubicin/Cyclophosphamide in Basal-Like Triple-Negative Breast Cancer
Authors: Blenman Kim R.M. , Marczyk Michal , Karn Thomas , Qing Tao , Li Xiaotong , Gunasekharan Vignesh , Yaghoobi Vesal , Bai Yalai , Ibrahim Eiman Y. , Park Tristen , Silber Andrea , Wolf Denise M. , Reisenbichler Emily , Denkert Carsten , Sinn Bruno V. , Rozenblit Mariya , Foldi Julia , Rimm David L. , Loibl Sibylle , Pusztai Lajos
Published: April 2023

AbstractPurpose:
We examined gene expression, germline variant, and somatic mutation features associated with pathologic response to neoadjuvant durvalumab plus chemotherapy in basal-like triple-negative breast cancer (bTNBC).
Experimental Design:
Germline and somatic whole-exome DNA and RNA sequencing, programmed death ligand 1 (PD-L1) IHC, and stromal tumor-infiltrating lymphocyte scoring were performed on 57 patients. We validated our results using 162 patients from the GeparNuevo randomized trial.
Results:
Gene set enrichment analysis showed that pathways involved in immunity (adaptive, humoral, innate), JAK–STAT signaling, cancer drivers, cell cycle, apoptosis, and DNA repair were enriched in cases with pathologic complete response (pCR), whereas epithelial–mesenchymal transition, extracellular matrix, and TGFβ pathways were enriched in cases with residual disease (RD). Immune-rich bTNBC with RD was enriched in CCL-3, -4, -5, -8, -23, CXCL-1, -3, -6, -10, and IL1, -23, -27, -34, and had higher expression of macrophage markers compared with immune-rich cancers with pCR that were enriched in IFNγ, IL2, -12, -21, chemokines CXCL-9, -13, CXCR5, and activated T- and B-cell markers (GZMB, CD79A). In the validation cohort, an immune-rich five-gene signature showed higher expression in pCR cases in the durvalumab arm (P = 0.040) but not in the placebo arm (P = 0.923) or in immune-poor cancers. Independent of immune markers, tumor mutation burden was higher, and PI3K, DNA damage repair, MAPK, and WNT/β-catenin signaling pathways were enriched in germline and somatic mutations in cases with pCR.
Conclusions:
The TGFβ pathway is associated with immune-poor phenotype and RD in bTNBC. Among immune-rich bTNBC RD, macrophage/neutrophil chemoattractants dominate the cytokine milieu, and IFNγ and activated B cells and T cells dominate immune-rich cancers with pCR.
Data from Safety and Efficacy of Irradiation Boost Based on 18F-FET-PET in Patients with Newly Diagnosed Glioblastoma
Authors: Harat Maciej , Blok Maciej , Miechowicz Izabela , Wiatrowska Izabela , Makarewicz Karolina , Małkowski Bogdan
Published: April 2023

AbstractPurpose:
Dual timepoint fluoro-ethyl-tyrosine (FET)-PET acquisition (10 and 60 minutes after FET injection) improves the definition of glioblastoma (GBM) location and shape. Here we evaluated the safety and efficacy of simultaneous integrated boost (SIB) planned using dual FET-PET for postoperative GBM treatment.
Patients and Methods:
In this prospective pilot study (March 2017–December 2020), 17 patients qualified for FET-PET–based SIB intensity-modulated radiotherapy after resection. The prescribed dose was 78 and 60 Gy (2.6 and 2.0 Gy per fraction, respectively) for the FET-PET– and magnetic resonance (MR)-based target volumes. Eleven patients had FET-PET within 9 months to precisely define biological responses. Progression-free survival (PFS), overall survival (OS), toxicities, and radiation necrosis were evaluated. Six patients (35%) had tumors with MGMT promoter methylation.
Results:
The 1- and 2-year OS and PFS rates were 73% and 43% and 53% and 13%, respectively. The median OS and PFS were 24 [95% confidence interval (CI), 9–26] and 12 (95% CI, 6–18) months, respectively. Two patients developed uncontrolled seizures during radiotherapy and could not receive treatment per protocol. In patients treated per protocol, 7 of 15 presented with new or increased neurologic deficits in the first month after irradiation. Radiation necrosis was diagnosed by MRI 3 months after SIB in 5 patients and later in another 2 patients. In 2 patients, the tumor was larger in FET-PET images after 6 months.
Conclusions:
Survival outcomes using our novel dose-escalation concept (total 78 Gy) were promising, even within the MGMT unmethylated subgroup. Excessive neurotoxicity was not observed, but radionecrosis was common and must be considered in future trials.
Data from Circulating Tumor DNA–Based MRD Assessment in Patients with CLL Treated with Obinutuzumab, Acalabrutinib, and Venetoclax
Authors: Fürstenau Moritz , Weiss Jonathan , Giza Adam , Franzen Fabian , Robrecht Sandra , Fink Anna-Maria , Fischer Kirsten , Schneider Christof , Tausch Eugen , Stilgenbauer Stephan , Ritgen Matthias , Schilhabel Anke , Brüggemann Monika , Eichhorst Barbara , Hallek Michael , Cramer Paula
Published: April 2023

AbstractPurpose:
With the advent of highly efficacious time-limited combination treatments of targeted agents in chronic lymphocytic leukemia (CLL), minimal residual disease (MRD) assessment has gained importance as a measure for therapeutic success and as a surrogate for progression-free survival. The currently most widely used method is multicolor flow cytometry, which detects circulating CLL cells in the peripheral blood. However, it seems to be less sensitive for the detection of MRD in the lymph node compartment.
Patients and Methods:
To evaluate whether a cell-free approach can overcome this limitation, we performed serial assessments of circulating tumor DNA (ctDNA) in patients with CLL treated with obinutuzumab, acalabrutinib, and venetoclax in the phase II CLL2-BAAG trial. Patient-specific variability, diversity, joining (VDJ) rearrangements as well as somatic driver mutations were tracked before, during and after treatment by digital droplet PCR in blood plasma. Furthermore, these were systematically compared to matched flow cytometry data.
Results:
In the 381 sample pairs, ctDNA and flow cytometry yielded highly concordant results. However, clone-specific ctDNA was detected in 44 of 152 samples (29%) that were assessed as undetectable MRD (uMRD) by flow cytometry (defined as less than one CLL cell in 10,000 normal leukocytes). 29 ctDNA-negative samples showed detectable MRD >10–4 by flow cytometry. Also, somatic driver mutations were detected with a similar sensitivity compared with patient-specific VDJ rearrangements in plasma. In patients with predominantly nodal residual disease, ctDNA compared favorably with 4-color flow cytometry and seemed to more accurately reflect the entire disease burden across compartments.
Conclusions:
On the basis of these findings, ctDNA-based MRD assessment appears to be a promising method to complement cell-based MRD approaches like flow cytometry that focus on circulating CLL cells in the peripheral blood.
Data from Tumor Immunogenomic Features Determine Outcomes in Patients with Metastatic Colorectal Cancer Treated with Standard-of-Care Combinations of Bevacizumab and Cetuximab
Authors: Innocenti Federico , Yazdani Akram , Rashid Naim , Qu Xueping , Ou Fang-Shu , Van Buren Scott , Bertagnolli Monica M. , Kabbarah Omar , Blanke Charles David , Venook Alan P. , Lenz Heinz-Josef , Vincent Benjamin G.
Published: April 2023

AbstractPurpose:
CALGB/SWOG 80405 was a randomized phase III trial in first-line patients with metastatic colorectal cancer treated with bevacizumab, cetuximab, or both, plus chemotherapy. We tested the effect of tumor immune features on overall survival (OS).
Experimental Design:
Primary tumors (N = 554) were profiled by RNA sequencing. Immune signatures of macrophages, lymphocytes, TGFβ, IFNγ, wound healing, and cytotoxicity were measured. CIBERSORTx scores of naive and memory B cells, plasma cells, CD8+ T cells, resting and activated memory CD4+ T cells, M0 and M2 macrophages, and activated mast cells were measured.
Results:
Increased M2 macrophage score [HR, 6.30; 95% confidence interval (CI), 3.0–12.15] and TGFβ signature expression (HR, 1.35; 95% CI, 1.05–1.77) were associated with shorter OS. Increased scores of plasma cells (HR, 0.55; 95% CI, 0.38–0.87) and activated memory CD4+ T cells (HR, 0.34; 95% CI, 0.16–0.65) were associated with longer OS. Using optimal cutoffs from these four features, patients were categorized as having either 4, 3, 2, or 0–1 beneficial features associated with longer OS, and the median (95% CI) OS decreased from 42.5 (35.8–47.8) to 31.0 (28.8–34.4), 25.2 (20.6–27.9), and 17.7 (13.5–20.4) months respectively (P = 3.48e–11).
Conclusions:
New immune features can be further evaluated to improve patient response. They provide the rationale for more effective immunotherapy strategies.
Data from Long-term Safety of Treatment with Autologous Mesenchymal Stem Cells in Patients with Radiation-Induced Xerostomia: Primary Results of the MESRIX Phase I/II Randomized Trial
Authors: Lynggaard Charlotte Duch , Grønhøj Christian , Jensen Siri B. , Christensen Robin , Specht Lena , Andersen Elo , Andersen Tobias T. , Ciochon Urszula M. , Rathje Gulla S. , Hansen Adam E. , Stampe Helene , Fischer-Nielsen Anne , von Buchwald Christian
Published: April 2023

AbstractPurpose:
Mesenchymal stem/stromal cell therapy may reduce radiation-induced xerostomia. We investigated the long-term safety of autologous adipose tissue-derived mesenchymal stem/stromal cell (ASC) injections into the submandibular glands.
Experimental Design:
An investigator-initiated, randomized, single-center, placebo-controlled trial. Previous patients with oropharyngeal squamous cell carcinoma with radiation-induced xerostomia were randomly (1:1) allocated to receive a 2.8 million ASCs/cm3 injection or placebo in both submandibular glands and followed for a minimum of 2 years. The primary endpoint was number of serious adverse events (SAE). Secondary endpoints included whole saliva flow rates and xerostomia-related symptoms. Data analysis was based on the intention-to-treat population using repeated measures mixed-effects linear models.
Results:
Thirty-three patients were randomized; 30 patients were treated (ASC group, n = 15; placebo group, n = 15). Long-term safety data were collected from all 30 patients. During follow-up, 6 of 15 (40%) of the ASC-treated patients versus 5 of 15 (33%) of the placebo patients experienced an SAE; no SAEs appeared to be treatment related. Unstimulated whole saliva flow rate increased to 0.20 and 0.16 mL/minute in the ASC and placebo group, respectively, yielding a 0.05 mL/minute (95% confidence interval: 0.00–0.10; P = 0.051) difference between groups. Patient-reported xerostomia symptoms diminished according to a decreased xerostomia questionnaire summary score of 35.0 and 45.1, respectively [−10.1 (−18.1 to −2.2); P = 0.013]. Three of the visual analog scale xerostomia measures indicated clinical benefit following use of ASC.
Conclusions:
Our data show that ASC therapy is safe with a clinically relevant effect on xerostomia-related symptoms. Confirmation in larger randomized controlled trials is warranted.