bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from The Capacity of the Ovarian Cancer Tumor Microenvironment to Integrate Inflammation Signaling Conveys a Shorter Disease-free Interval
Authors: Jordan Kimberly R. , Sikora Matthew J. , Slansky Jill E. , Minic Angela , Richer Jennifer K. , Moroney Marisa R. , Hu Junxiao , Wolsky Rebecca J. , Watson Zachary L. , Yamamoto Tomomi M. , Costello James C. , Clauset Aaron , Behbakht Kian , Kumar T. Rajendra , Bitler Benjamin G.
Published: April 2023

AbstractPurpose:
Ovarian cancer has one of the highest deaths to incidence ratios across all cancers. Initial chemotherapy is effective, but most patients develop chemoresistant disease. Mechanisms driving clinical chemo-response or -resistance are not well-understood. However, achieving optimal surgical cytoreduction improves survival, and cytoreduction is improved by neoadjuvant chemotherapy (NACT). NACT offers a window to profile pre- versus post-NACT tumors, which we used to identify chemotherapy-induced changes to the tumor microenvironment.
Experimental Design:
We obtained matched pre- and post-NACT archival tumor tissues from patients with high-grade serous ovarian cancer (patient, n = 6). We measured mRNA levels of 770 genes (756 genes/14 housekeeping genes, NanoString Technologies), and performed reverse phase protein array (RPPA) on a subset of matched tumors. We examined cytokine levels in pre-NACT ascites samples (n = 39) by ELISAs. A tissue microarray with 128 annotated ovarian tumors expanded the transcriptional, RPPA, and cytokine data by multispectral IHC.
Results:
The most upregulated gene post-NACT was IL6 (16.79-fold). RPPA data were concordant with mRNA, consistent with elevated immune infiltration. Elevated IL6 in pre-NACT ascites specimens correlated with a shorter time to recurrence. Integrating NanoString (n = 12), RPPA (n = 4), and cytokine (n = 39) studies identified an activated inflammatory signaling network and induced IL6 and IER3 (immediate early response 3) post-NACT, associated with poor chemo-response and time to recurrence.
Conclusions:
Multiomics profiling of ovarian tumor samples pre- and post-NACT provides unique insight into chemo-induced changes to the tumor microenvironment. We identified a novel IL6/IER3 signaling axis that may drive chemoresistance and disease recurrence.
Data from Concentration-dependent Early Antivascular and Antitumor Effects of Itraconazole in Non–Small Cell Lung Cancer
Authors: Gerber David E. , Putnam William C. , Fattah Farjana J. , Kernstine Kemp H. , Brekken Rolf A. , Pedrosa Ivan , Skelton Rachael , Saltarski Jessica M. , Lenkinski Robert E. , Leff Richard D. , Ahn Chul , Padmanabhan Chyndhri , Chembukar Vaidehi , Kasiri Sahba , Kallem Raja Reddy , Subramaniyan Indhumathy , Yuan Qing , Do Quyen N. , Xi Yin , Reznik Scott I. , Pelosof Lorraine , Faubert Brandon , DeBerardinis Ralph J. , Kim James
Published: April 2023

AbstractPurpose:
Itraconazole has been repurposed as an anticancer therapeutic agent for multiple malignancies. In preclinical models, itraconazole has antiangiogenic properties and inhibits Hedgehog pathway activity. We performed a window-of-opportunity trial to determine the biologic effects of itraconazole in human patients.
Experimental Design:
Patients with non–small cell lung cancer (NSCLC) who had planned for surgical resection were administered with itraconazole 300 mg orally twice daily for 10–14 days. Patients underwent dynamic contrast-enhanced MRI and plasma collection for pharmacokinetic and pharmacodynamic analyses. Tissues from pretreatment biopsy, surgical resection, and skin biopsies were analyzed for itraconazole and hydroxyitraconazole concentration, and vascular and Hedgehog pathway biomarkers.
Results:
Thirteen patients were enrolled in this study. Itraconazole was well-tolerated. Steady-state plasma concentrations of itraconazole and hydroxyitraconazole demonstrated a 6-fold difference across patients. Tumor itraconazole concentrations trended with and exceeded those of plasma. Greater itraconazole levels were significantly and meaningfully associated with reduction in tumor volume (Spearman correlation, −0.71; P = 0.05) and tumor perfusion (Ktrans; Spearman correlation, −0.71; P = 0.01), decrease in the proangiogenic cytokines IL1b (Spearman correlation, −0.73; P = 0.01) and GM-CSF (Spearman correlation, −1.00; P < 0.001), and reduction in tumor microvessel density (Spearman correlation, −0.69; P = 0.03). Itraconazole-treated tumors also demonstrated distinct metabolic profiles. Itraconazole treatment did not alter transcription of GLI1 and PTCH1 mRNA. Patient size, renal function, and hepatic function did not predict itraconazole concentrations.
Conclusions:
Itraconazole demonstrates concentration-dependent early antivascular, metabolic, and antitumor effects in patients with NSCLC. As the number of fixed dose cancer therapies increases, attention to interpatient pharmacokinetics and pharmacodynamics differences may be warranted.
Data from Molecular and Immunologic Signatures are Related to Clinical Benefit from Treatment with Vocimagene Amiretrorepvec (Toca 511) and 5-Fluorocytosine (Toca FC) in Patients with Glioma
Authors: Accomando William P. , Rao Aliz R. , Hogan Daniel J. , Newman Aaron M. , Nakao Aki , Alizadeh Ash A. , Diehn Maximilian , Diago Oscar R. , Gammon Dawn , Haghighi Ali , Gruber Harry E. , Jolly Douglas J. , Ostertag Derek
Published: April 2023

AbstractPurpose:
High-grade gliomas (HGGs) are central nervous system tumors with poor prognoses and limited treatment options. Vocimagene amiretrorepvec (Toca 511) is a retroviral replicating vector encoding cytosine deaminase, which converts extended release 5-fluorocytosine (Toca FC) into the anticancer agent, 5-fluorouracil. According to preclinical studies, this therapy kills cancer cells and immunosuppressive myeloid cells in the tumor microenvironment, leading to T-cell–mediated antitumor immune activity. Therefore, we sought to elucidate this immune-related mechanism of action in humans, and to investigate potential molecular and immunologic indicators of clinical benefit from therapy.
Patients and Methods:
In a phase I clinical trial (NCT01470794), patients with recurrent HGG treated with Toca 511 and Toca FC showed improved survival relative to historical controls, and some had durable complete responses to therapy. As a part of this trial, we performed whole-exome DNA sequencing, RNA-sequencing, and multiplex digital ELISA measurements on tumor and blood samples.
Results:
Genetic analyses suggest mutations, copy-number variations, and neoantigens are linked to survival. Quantities of tumor immune infiltrates estimated by transcript abundance may potentially predict clinical outcomes. Peak values of cytokines in peripheral blood samples collected during and after therapy could indicate response.
Conclusions:
These results support an immune-related mechanism of action for Toca 511 and Toca FC, and suggest that molecular and immunologic signatures are related to clinical benefit from treatment.
Data from Long-term Follow-up of Standard-Dose Pembrolizumab Plus Reduced-Dose Ipilimumab in Patients with Advanced Melanoma: KEYNOTE-029 Part 1B
Authors: Carlino Matteo S. , Menzies Alexander M. , Atkinson Victoria , Cebon Jonathan S. , Jameson Michael B. , Fitzharris Bernard M. , McNeil Catriona M. , Hill Andrew G. , Ribas Antoni , Atkins Michael B. , Thompson John A. , Hwu Wen-Jen , Hodi F. Stephen , Guminski Alexander D. , Kefford Richard , Wu Haiyan , Ibrahim Nageatte , Homet Moreno Blanca , Long Georgina V.
Published: April 2023

AbstractPurpose:
Combination therapy with reduced-dose programmed death 1 inhibitor plus standard-dose cytotoxic T-lymphocyte–associated antigen 4 inhibitor demonstrated efficacy, but substantial toxicity, in melanoma. We present long-term results of part 1B of KEYNOTE-029, which assessed safety and efficacy of standard-dose pembrolizumab plus reduced-dose ipilimumab in advanced melanoma.
Patients and Methods:
Part 1B was an expansion cohort of the open-label, phase Ib portion of KEYNOTE-029. Eligible patients had advanced melanoma and no previous immune checkpoint inhibitor therapy. Patients received pembrolizumab 2 mg/kg (amended to 200 mg) every 3 weeks plus ipilimumab 1 mg/kg every 3 weeks (four cycles), then pembrolizumab alone for up to 2 years. Primary end point was safety; secondary end points included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS).
Results:
A total of 153 patients received at least one dose of pembrolizumab plus ipilimumab. At a median follow-up of 36.8 months, 71.9% had received four doses of ipilimumab and 30.7% had completed 2 years of pembrolizumab; 26.1% completed both treatments. Treatment-related adverse events occurred in 96.1% (47.1% grade 3/4; no deaths), leading to discontinuation of one or both study drugs in 35.9%. ORR was 62.1% with 42 (27.5%) complete and 53 (34.6%) partial responses. Median DOR was not reached; 36-month ongoing response rate was 84.2%. Median PFS and OS were not reached; 36-month rates were 59.1% and 73.4%, respectively.
Conclusions:
Standard-dose pembrolizumab plus reduced-dose ipilimumab demonstrated robust antitumor activity, durable response, and favorable long-term survival with manageable toxicity.
Data from FS118, a Bispecific Antibody Targeting LAG-3 and PD-L1, Enhances T-Cell Activation Resulting in Potent Antitumor Activity
Authors: Kraman Matthew , Faroudi Mustapha , Allen Natalie L. , Kmiecik Katarzyna , Gliddon Daniel , Seal Claire , Koers Alexander , Wydro Mateusz M. , Batey Sarah , Winnewisser Julia , Young Lesley , Tuna Mihriban , Doody Jacqueline , Morrow Michelle , Brewis Neil
Published: April 2023

AbstractPurpose:
Although programmed death-ligand 1 (PD-L1) antibody–based therapy has improved the outcome of patients with cancer, acquired resistance to these treatments limits their clinical efficacy. FS118 is a novel bispecific, tetravalent antibody (mAb2) against human lymphocyte activation gene-3 (LAG-3) and PD-L1 with the potential to reinvigorate exhausted immune cells and overcome resistance mechanisms to PD-L1 blockade. Here, using FS118 and a murine surrogate, we characterized the activity and report a novel mechanism of action of this bispecific antibody.
Experimental Design:
This study characterizes the binding activity and immune function of FS118 in cell lines and human peripheral blood mononuclear cells and further investigates its antitumor activity and mechanism of action using a surrogate murine bispecific antibody (mLAG-3/PD-L1 mAb2).
Results:
FS118 demonstrated simultaneous binding to LAG-3 and PD-L1 with high affinity and comparable or better activity than the combination of the single component parts of the mAb2 in blocking LAG-3- and PD-L1–mediated immune suppression and enhancing T-cell activity. In syngeneic tumor mouse models, mLAG-3/PD-L1 mAb2 significantly suppressed tumor growth. Mechanistic studies revealed decreased LAG-3 expression on T cells following treatment with the mouse surrogate mLAG-3/PD-L1 mAb2, whereas LAG-3 expression increased upon treatment with the combination of mAbs targeting LAG-3 and PD-L1. Moreover, following binding of mLAG-3/PD-L1 mAb2 to target-expressing cells, mouse LAG-3 is rapidly shed into the blood.
Conclusions:
This study demonstrates a novel benefit of the bispecific approach over a combination of mAbs and supports the further development of FS118 for the treatment of patients with cancer.
Data from Pan-cancer Transcriptomic Predictors of Perineural Invasion Improve Occult Histopathologic Detection
Authors: Guo Jimmy A. , Hoffman Hannah I. , Shroff Stuti G. , Chen Peter , Hwang Peter G. , Kim Daniel Y. , Kim Daniel W. , Cheng Stephanie W. , Zhao Daniel , Mahal Brandon A. , Alshalalfa Mohammed , Niemierko Andrzej , Wo Jennifer Y. , Loeffler Jay S. , Fernandez-del Castillo Carlos , Jacks Tyler , Aguirre Andrew J. , Hong Theodore S. , Mino-Kenudson Mari , Hwang William L.
Published: April 2023

AbstractPurpose:
Perineural invasion (PNI) is associated with aggressive tumor behavior, recurrence, and metastasis, and can influence the administration of adjuvant treatment. However, standard histopathologic examination has limited sensitivity in detecting PNI and does not provide insights into its mechanistic underpinnings.
Experimental Design:
A multivariate Cox regression was performed to validate associations between PNI and survival in 2,029 patients across 12 cancer types. Differential expression and gene set enrichment analysis were used to learn PNI-associated programs. Machine learning models were applied to build a PNI gene expression classifier. A blinded re-review of hematoxylin and eosin (H&E) slides by a board-certified pathologist helped determine whether the classifier could improve occult histopathologic detection of PNI.
Results:
PNI associated with both poor overall survival [HR, 1.73; 95% confidence interval (CI), 1.27–2.36; P < 0.001] and disease-free survival (HR, 1.79; 95% CI, 1.38–2.32; P < 0.001). Neural-like, prosurvival, and invasive programs were enriched in PNI-positive tumors (Padj < 0.001). Although PNI-associated features likely reflect in part the increased presence of nerves, many differentially expressed genes mapped specifically to malignant cells from single-cell atlases. A PNI gene expression classifier was derived using random forest and evaluated as a tool for occult histopathologic detection. On a blinded H&E re-review of sections initially described as PNI negative, more specimens were reannotated as PNI positive in the high classifier score cohort compared with the low-scoring cohort (P = 0.03, Fisher exact test).
Conclusions:
This study provides salient biological insights regarding PNI and demonstrates a role for gene expression classifiers to augment detection of histopathologic features.
Data from Preoperative β-Blockade with Propranolol Reduces Biomarkers of Metastasis in Breast Cancer: A Phase II Randomized Trial
Authors: Hiller Jonathan G. , Cole Steven W. , Crone Elizabeth M. , Byrne David J. , Shackleford David M. , Pang Jia-Min B. , Henderson Michael A. , Nightingale Sophie S. , Ho Kwok M. , Myles Paul S. , Fox Stephen , Riedel Bernhard , Sloan Erica K.
Published: April 2023

AbstractPurpose:
The majority of deaths from breast cancer occur following the development of metastatic disease, a process inhibited by β-blockers in preclinical studies. This phase II randomized controlled trial evaluated the effect of preoperative β-blockade with propranolol on biomarkers of metastatic potential and the immune cell profile within the primary tumor of patients with breast cancer.
Patients and Methods:
In this triple-blind placebo-controlled clinical trial, 60 patients were randomly assigned to receive an escalating dose of oral propranolol (n = 30; 80–160 mg daily) or placebo (n = 30) for 7 days prior to surgery. The primary endpoint investigated the effect of propranolol on prometastatic and proinflammatory gene expression within the primary tumor.
Results:
Propranolol downregulated primary tumor expression of mesenchymal genes (P = 0.002) without affecting epithelial gene expression (P = 0.21). Bioinformatic analyses implicated downregulation of Snail/Slug (P = 0.03), NF-κB/Rel (P < 0.01), and AP-1 (P < 0.01) transcription factors in structuring the observed transcriptome alterations, and identified changes in intratumoral neutrophil, natural killer cell, and dendritic cell recruitment (all P < 0.01). Patients with clinical evidence of drug response (lowered heart rate and blood pressure) demonstrated elevated tumor infiltration of CD68+ macrophages and CD8+ T cells.
Conclusions:
One week of β-blockade with propranolol reduced intratumoral mesenchymal polarization and promoted immune cell infiltration in early-stage surgically-resectable breast cancer. These results show that β-blockade reduces biomarkers associated with metastatic potential, and support the need for larger phase III clinical trials powered to detect the impact of β-blockade on cancer recurrence and survival.

See related commentary by Blaes et al., p. 1781
Data from Molecular Biomarkers of Response to Eribulin in Patients with Leiomyosarcoma
Authors: Wozniak Agnieszka , Boeckx Bram , Modave Elodie , Weaver Amy , Lambrechts Diether , Littlefield Bruce A. , Schöffski Patrick
Published: April 2023

AbstractPurpose:
A randomized phase III study evaluated the efficacy of eribulin versus dacarbazine in patients with advanced liposarcoma and leiomyosarcoma. Improved overall survival (OS) led to approval of eribulin for liposarcoma, but not for leiomyosarcoma.
Experimental Design:
We explored the molecular profile of 77 archival leiomyosarcoma samples from this trial to identify potential predictive biomarkers, utilizing low-coverage whole-genome and whole-exome sequencing. Tumor molecular profiles were correlated with clinical data, and disease control was defined as complete/partial response or stable disease (RECIST v1.1).
Results:
Overall, 111 focal copy-number alterations were observed in leiomyosarcoma. Gain of chromosome 17q12 was the most common event, present in 43 of 77 cases (56%). In the eribulin-treated group, gains of 4q26, 20p12.2, 13q13.3, 8q22.2, and 8q13.2 and loss of 1q44 had a negative impact on progression-free survival (PFS), while loss of 2p12 correlated with better prognosis. Gains of 4q22.1 and losses of 3q14.2, 2q14.1, and 11q25 had a negative impact on OS in patients with leiomyosarcoma receiving eribulin. The most commonly mutated genes were TP53 (38%), MUC16 (32%), and ATRX (17%). The presence of ATRX mutations had a negative impact on PFS in both treatment arms; however, the correlation with worse OS was observed only in the eribulin-treated patients. TP53 mutations were associated with longer PFS on eribulin.
Conclusions:
Leiomyosarcoma has a complex genetic background, with multiple copy-number alterations and mutations affecting genes implicated in tumorigenesis. We identified several molecular changes with potential impact on survival of patients with leiomyosarcoma when treated with eribulin.
Data from BRCA2, ATM, and CDK12 Defects Differentially Shape Prostate Tumor Driver Genomics and Clinical Aggression
Authors: Warner Evan , Herberts Cameron , Fu Simon , Yip Steven , Wong Amanda , Wang Gang , Ritch Elie , Murtha Andrew J. , Vandekerkhove Gillian , Fonseca Nicolette M. , Angeles Arkhjamil , Beigi Arshia , Schönlau Elena , Beja Kevin , Annala Matti , Khalaf Daniel , Chi Kim N. , Wyatt Alexander W.
Published: April 2023

AbstractPurpose:
DNA damage repair (DDR) defects are common across cancer types and can indicate therapeutic vulnerability. Optimal exploitation of DDR defects in prostate cancer requires new diagnostic strategies and a better understanding of associated clinical genomic features.
Experimental Design:
We performed targeted sequencing of 1,615 plasma cell-free DNA samples from 879 patients with metastatic prostate cancer. Depth-based copy-number calls and heterozygous SNP imbalance were leveraged to expose DDR-mutant allelic configuration and categorize mechanisms of biallelic loss. We used split-read structural variation analysis to characterize tumor suppressor rearrangements. Patient-matched archival primary tissue was analyzed identically.
Results:
BRCA2, ATM, and CDK12 were the most frequently disrupted DDR genes in circulating tumor DNA (ctDNA), collectively mutated in 15% of evaluable cases. Biallelic gene disruption via second somatic alteration or mutant allele–specific imbalance was identified in 79% of patients. A further 2% exhibited homozygous BRCA2 deletions. Tumor suppressors TP53, RB1, and PTEN were controlled via disruptive chromosomal rearrangements in BRCA2-defective samples, but via oncogene amplification in context of CDK12 defects. TP53 mutations were rare in cases with ATM defects. DDR mutations were re-detected across 94% of serial ctDNA samples and in all available archival primary tissues, indicating they arose prior to metastatic progression. Loss of BRCA2 and CDK12, but not ATM, was associated with poor clinical outcomes.
Conclusions:
BRCA2, ATM, and CDK12 defects are each linked to distinct prostate cancer driver genomics and aggression. The consistency of DDR status in longitudinal samples and resolution of allelic status underscores the potential for ctDNA as a diagnostic tool.
Data from Phase I Study of Stereotactic Body Radiotherapy plus Nivolumab and Urelumab or Cabiralizumab in Advanced Solid Tumors
Authors: Foster Corey C. , Fleming Gini F. , Karrison Theodore G. , Liao Chih-Yi , Desai Ami V. , Moroney John W. , Ratain Mark J. , Nanda Rita , Polite Blase N. , Hahn Olwen M. , O'Donnell Peter H. , Vokes Everett E. , Kindler Hedy L. , Hseu Robyn , Janisch Linda A. , Dai Julia , Hoffman Mark D. , Weichselbaum Ralph R. , Pitroda Sean P. , Chmura Steven J. , Luke Jason J.
Published: April 2023

AbstractPurpose:
CD137 agonism and CSF1R blockade augment stereotactic body radiotherapy (SBRT) and anti-programmed death-1 in preclinical models. We evaluated the safety and efficacy of SBRT with nivolumab+urelumab (CD137 agonist) or nivolumab+cabiralizumab (CSF1R inhibitor).
Patients and Methods:
This phase I clinical trial enrolled patients with advanced solid tumors that had progressed on standard therapies. SBRT was delivered to 1–4 metastases with nivolumab+urelumab or nivolumab+cabiralizumab given concurrently and following SBRT. Dose-limiting toxicity (DLT) was the primary endpoint with anatomic location-specific SBRT doses deemed safe if ≤33% DLT frequency was observed. Secondary endpoints included RECISTv1.1 response, progression-free survival (PFS), overall survival (OS), and molecular correlative studies.
Results:
Sixty patients were enrolled, and median follow-up for living patients is 13.8 months. Of these, 23 (38%) received SBRT+nivolumab+urelumab and 37 (62%) received SBRT+nivolumab+cabiralizumab. Seven patients (12%) experienced a DLT (n = 3 grade 3, n = 4 grade 4) in the following anatomic cohorts: abdominal/pelvic (3/17, 18%), liver (1/13, 8%), central lung (2/14, 14%), and peripheral lung (1/12, 8%). Of 41 patients radiographically evaluable for best overall response including 55 radiated and 23 unirradiated RECIST target lesions, 2 had complete responses (5%), 7 had partial responses (17%), 12 had stable disease (29%), and 20 had progression (49%). Median estimated PFS and OS are 3.0 months [95% confidence interval (CI), 2.9–4.8] and 17.0 months (95% CI, 6.8–undetermined), respectively. No patients with elevated pre-SBRT serum IL8 experienced a response.
Conclusions:
SBRT to ≤4 sites with nivolumab+urelumab or nivolumab+cabiralizumab for treating advanced solid tumors is feasible with acceptable toxicity and modest antitumor activity.

See related commentary by Rodriguez-Ruiz et al., p. 5443
Data from ZEBRA: A Multicenter Phase II Study of Pembrolizumab in Patients with Advanced Small-Bowel Adenocarcinoma
Authors: Pedersen Katrina S. , Foster Nathan R. , Overman Michael J. , Boland Patrick M. , Kim Sunnie S. , Arrambide Kathryn A. , Jaszewski Brandy L. , Bekaii-Saab Tanios , Graham Rondell P. , Welch Jack , Wilson Richard H. , McWilliams Robert R.
Published: April 2023

AbstractPurpose:
Small-bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic disease beyond first-line FOLFOX/CAPOX. SBA has higher rates of microsatellite instability (MSI-H) and T-lymphocyte infiltration than other gastrointestinal cancers. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response.
Patients and Methods:
Patients with previously treated advanced SBA received pembrolizumab 200 mg i.v. every 3 weeks until disease progression (PD), toxicity, or 35 doses maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary progression-free survival (PFS), overall survival (OS), and toxicity assessment endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level.
Results:
Forty patients were treated for a median duration of four cycles (range, 1–35). All patients are off study treatment due to PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AEs, 5%). Three confirmed partial responses [PRs; 8%; 95% confidence interval (CI), 2–20] did not meet predefined success criteria of ORR 30%. Median OS (7.1 months; 95% CI, 5.1–17.1) and median PFS (2.8 months; 95% CI, 2.7–4.2) were similar across primary tumor sites. One confirmed PR (3%) was seen in patients with low MSS/MSI tumors and correlated with high tumor mutation burden (TMB). Fifty percent of patients with MSI-H tumors achieved PR and remain alive without progression. Twenty-five patients (63%) had grade ≥3 AEs and 11 patients (28%) had grade 4/5 AEs.
Conclusions:
In the largest study of SBA to date, pembrolizumab did not induce the hypothesized response rate; however, we did identify responses in key biomarker-selected cohorts.
Data from CD40 Agonist Targeted to Fibroblast Activation Protein α Synergizes with Radiotherapy in Murine HPV-Positive Head and Neck Tumors
Authors: Labiano Sara , Roh Vincent , Godfroid Céline , Hiou-Feige Agnès , Romero Jackeline , Sum Eva , Rapp Moritz , Boivin Gael , Wyss Tania , Simon Christian , Bourhis Jean , Umaña Pablo , Trumpfheller Christine , Tolstonog Genrich V. , Vozenin Marie-Catherine , Romero Pedro
Published: April 2023

AbstractPurpose:
The incidence of human papillomavirus–associated head and neck squamous cell carcinoma (HPV+-HNSCC) is rising worldwide and although current therapeutic modalities are efficient in the majority of patients, there is a high rate of treatment failures. Thus, novel combination approaches are urgently needed to achieve better disease control in patients with HPV+-HNSCC. We investigated the safety and therapeutic efficacy of a novel fibroblast activation protein (FAP)-targeted CD40 agonist (FAP-CD40) in combination with local hypofractionated radiation in a syngeneic HPV+-HNSCC model.
Experimental Design:
Using an established orthotopic model, we treated tumor-bearing mice with local hypofractionated radiotherapy (2 × 6 Gy) alone or in combination with a systemic administration of the FAP-CD40 antibody. Following up the mice, we evaluated the changes in the tumor microenvironment (TME) by immunofluorescence, FACS, and NanoString RNA analysis.
Results:
The suboptimal radiotherapy regimen chosen failed to control tumors in the treated mice. The FAP-CD40 administered in monotherapy transiently controlled tumor growth, whereas the combined therapy induced durable complete responses in more than 80% of the tumor-bearing mice. This notable efficacy relied on the radiotherapy-induced remodeling of the TME and activation of the CD8+ T-cell-cDC1 axis and was devoid of the systemic toxicity frequently associated with CD40-targeted therapy. Moreover, the robust immunologic memory developed effectively prevented tumor relapses, a common feature in patients with HNSCC.
Conclusions:
Our study provides proof of concept, as well as mechanistic insights of the therapeutic efficacy of a bispecific FAP-CD40 combined with local radiotherapy in a FAP+-HNSCC model increasing overall survival and inducing long-term antitumor immunity.
Data from A Phase Ib Study of Atezolizumab with Radium-223 Dichloride in Men with Metastatic Castration-Resistant Prostate Cancer
Authors: Fong Lawrence , Morris Michael J. , Sartor Oliver , Higano Celestia S. , Pagliaro Lance , Alva Ajjai , Appleman Leonard J. , Tan Winston , Vaishampayan Ulka , Porcu Raphaelle , Tayama Darren , Kadel Edward E. , Yuen Kobe C. , Datye Asim , Armstrong Andrew J. , Petrylak Daniel P.
Published: April 2023

AbstractPurpose:
Men with metastatic castration-resistant prostate cancer (mCRPC) have limited treatment options after progressing on hormonal therapy and chemotherapy. Here, we evaluate the safety and efficacy of atezolizumab (anti–PD-L1) + radium-223 dichloride (radium-223) in men with mCRPC.
Patients and Methods:
This phase Ib study evaluated atezolizumab + radium-223 in men with mCRPC and bone and lymph node and/or visceral metastases that progressed after androgen pathway inhibitor treatment. Following safety assessment of concurrent dosing, 45 men were randomized 1:1:1 to concurrent or one of two staggered dosing schedules with either agent introduced one cycle before the other. This was followed by a safety–efficacy expansion cohort (randomized 1:1:1). The primary endpoints were safety and objective response rate (ORR) by RECIST 1.1. Secondary endpoints included radiographic progression-free survival (rPFS), PSA responses, and overall survival (OS).
Results:
As of October 4, 2019, 44 of 45 men were evaluable. All 44 had ≥1 all-cause adverse event (AE); 23 (52.3%) had a grade 3/4 AE. Fifteen (34.1%) grade 3/4 and 3 (6.8%) grade 5 AEs were related to atezolizumab; none were related to radium-223. Confirmed ORR was 6.8% [95% confidence interval (CI), 1.4–18.7], median rPFS was 3.0 months (95% CI, 2.8–4.6), median PSA progression was 3.0 months (95% CI, 2.8–3.3), and median OS was 16.3 months (95% CI, 10.9–22.3).
Conclusions:
This phase Ib study demonstrated that atezolizumab + radium-223, regardless of administration schedule, had greater toxicity than either drug alone, with no clear evidence of additional clinical benefit for patients with mCRPC and bone and lymph node and/or visceral metastases.
Data from Bone Marrow Mesenchymal Stromal Cells Can Render Multiple Myeloma Cells Resistant to Cytotoxic Machinery of CAR T Cells through Inhibition of Apoptosis
Authors: Holthof Lisa C. , van der Schans Jort J. , Katsarou Afroditi , Poels Renée , Gelderloos Anne T. , Drent Esther , van Hal-van Veen Susan E. , Li Fengzhi , Zweegman Sonja , van de Donk Niels W.C.J. , Themeli Maria , Groen Richard W.J. , Mutis Tuna
Published: April 2023

AbstractPurpose:
The microenvironment of multiple myeloma (MM) can critically impair therapy outcome, including immunotherapies. In this context, we have earlier demonstrated that bone marrow mesenchymal stromal cells (BMMSC) protect MM cells against the lytic machinery of MM-reactive cytotoxic T cells (CTL) and daratumumab-redirected natural killer (NK) cells through the upregulation of antiapoptotic proteins Survivin and Mcl-1 in MM cells. Here, we investigated the significance of this mode of immune escape on T cells engineered to express chimeric antigen receptors (CAR T cells).
Experimental Design:
We tested the cytolytic ability of a panel of 10 BCMA-, CD38-, and CD138-specific CAR T cells with different affinities against a model MM cell line and against patient-derived MM cells in the presence versus absence of BMMSCs.
Results:
Although BMMSCs hardly protected MM cells from lysis by high-affinity, strongly lytic BCMA- and CD38-CAR T cells, they significantly protected against lower affinity, moderately lytic BCMA-, CD38-, and CD138-specific CAR T cells in a cell–cell contact-dependent manner. Overall, there was a remarkable inverse correlation between the protective ability of BMMSCs and the lytic activity of all CAR T cells, which was dependent on CAR affinity and type of costimulation. Furthermore, BMMSC-mediated resistance against CAR T cells was effectively modulated by FL118, an inhibitor of antiapoptotic proteins Survivin, Mcl-1, and XIAP.
Conclusions:
These results extend our findings on the negative impact of the microenvironment against immunotherapies and suggest that outcome of CAR T cell or conventional CTL therapies could benefit from inhibition of antiapoptotic proteins upregulated in MM cells through BMMSC interactions.
Data from Combined EZH2 Inhibition and IKAROS Degradation Leads to Enhanced Antitumor Activity in Diffuse Large B-cell Lymphoma
Authors: Tong Kit I. , Yoon Sharon , Isaev Keren , Bakhtiari Mehran , Lackraj Tracy , He Michael Y. , Joynt Jesse , Silva Anjali , Xu Maria C. , Privé Gilbert G. , He Housheng Hansen , Tiedemann Rodger E. , Chavez Elizabeth A. , Chong Lauren C. , Boyle Merrill , Scott David W. , Steidl Christian , Kridel Robert
Published: April 2023

AbstractPurpose:
The efficacy of EZH2 inhibition has been modest in the initial clinical exploration of diffuse large B-cell lymphoma (DLBCL), yet EZH2 inhibitors are well tolerated. Herein, we aimed to uncover genetic and pharmacologic opportunities to enhance the clinical efficacy of EZH2 inhibitors in DLBCL.
Experimental Design:
We conducted a genome-wide sensitizing CRISPR/Cas9 screen with tazemetostat, a catalytic inhibitor of EZH2. The sensitizing effect of IKZF1 loss of function was then validated and leveraged for combination treatment with lenalidomide. RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing analyses were performed to elucidate transcriptomic and epigenetic changes underlying synergy.
Results:
We identified IKZF1 knockout as the top candidate for sensitizing DLBCL cells to tazemetostat. Treating cells with tazemetostat and lenalidomide, an immunomodulatory drug that selectively degrades IKAROS and AIOLOS, phenocopied the effects of the CRISPR/Cas9 screen. The combined drug treatment triggered either cell-cycle arrest or apoptosis in a broad range of DLBCL cell lines, regardless of EZH2 mutational status. Cell-line–based xenografts also showed slower tumor growth and prolonged survival in the combination treatment group. RNA-seq analysis revealed strong upregulation of interferon signaling and antiviral immune response signatures. Gene expression of key immune response factors such as IRF7 and DDX58 were induced in cells treated with lenalidomide and tazemetostat, with a concomitant increase of H3K27 acetylation at their promoters. Furthermore, transcriptome analysis demonstrated derepression of endogenous retroviruses after combination treatment.
Conclusions:
Our data underscore the synergistic interplay between IKAROS degradation and EZH2 inhibition on modulating epigenetic changes and ultimately enhancing antitumor effects in DLBCL.
Data from Imaging of Cancer γ-Secretase Activity Using an Inhibitor-Based PET Probe
Authors: Nie Pengju , Kalidindi Teja , Nagle Veronica L. , Wu Xianzhong , Li Thomas , Liao George P. , Frost Georgia , Henry Kelly E. , Punzalan Blesida , Carter Lukas M. , Lewis Jason S. , Pillarsetty Naga Vara Kishore , Li Yue-Ming
Published: April 2023

AbstractPurpose:
Abnormal Notch signaling promotes cancer cell growth and tumor progression in various cancers. Targeting γ-secretase, a pivotal regulator in the Notch pathway, has yielded numerous γ-secretase inhibitors (GSIs) for clinical investigation in the last 2 decades. However, GSIs have demonstrated minimal success in clinical trials in part due to the lack of specific and precise tools to assess γ-secretase activity and its inhibition in vivo.
Experimental Design:
We designed an imaging probe based on GSI Semagacestat structure and synthesized the radioiodine-labeled analogues [131I]- or [124I]-PN67 from corresponding trimethyl-tin precursors. Both membrane- and cell-based ligand-binding assays were performed using [131I]-PN67 to determine the binding affinity and specificity for γ-secretase in vitro. Moreover, we evaluated [124I]-PN67 by PET imaging in mammary tumor and glioblastoma mouse models.
Results:
The probe was synthesized through iodo-destannylation using chloramine-T as an oxidant with a high labeling yield and efficiency. In vitro binding results demonstrate the high specificity of this probe and its ability for target replacement study by clinical GSIs. PET imaging studies demonstrated a significant (P < 0.05) increased in the uptake of [124I]-PN67 in tumors versus blocking or sham control groups across multiple mouse models, including 4T1 allograft, MMTV-PyMT breast cancer, and U87 glioblastoma allograft. Ex vivo biodistribution and autoradiography corroborate these results, indicating γ-secretase specific tumor accumulation of [124I]-PN67.
Conclusions:
[124I]-PN67 is a novel PET imaging agent that enables assessment of γ-secretase activity and target engagement of clinical GSIs.
Data from A Phase I Study of Autologous Dendritic Cell Vaccine Pulsed with Allogeneic Stem-like Cell Line Lysate in Patients with Newly Diagnosed or Recurrent Glioblastoma
Authors: Hu Jethro L. , Omofoye Oluwaseun A. , Rudnick Jeremy D. , Kim Sungjin , Tighiouart Mourad , Phuphanich Surasak , Wang Hongqiang , Mazer Mia , Ganaway Toni , Chu Ray M. , Patil Chirag G. , Black Keith L. , Shiao Stephen L. , Wang Rongfu , Yu John S.
Published: April 2023

AbstractPurpose:
Glioblastoma (GBM) is a heterogeneous malignancy with multiple subpopulations of cancer cells present within any tumor. We present the results of a phase I clinical trial using an autologous dendritic cell (DC) vaccine pulsed with lysate derived from a GBM stem-like cell line.
Patients and Methods:
Patients with newly diagnosed and recurrent GBM were enrolled as separate cohorts. Eligibility criteria included a qualifying surgical resection or minimal tumor size, ≤ 4-mg dexamethasone daily dose, and Karnofsky score ≥70. Vaccine treatment consisted of two phases: an induction phase with vaccine given weekly for 4 weeks, and a maintenance phase with vaccines administered every 8 weeks until depletion of supply or disease progression. Patients with newly diagnosed GBM also received standard-of-care radiation and temozolomide. The primary objective for this open-label, single-institution trial was to assess the safety and tolerability of the autologous DC vaccine.
Results:
For the 11 patients with newly diagnosed GBM, median progression-free survival (PFS) was 8.75 months, and median overall survival was 20.36 months. For the 25 patients with recurrent GBM, median PFS was 3.23 months, 6-month PFS was 24%, and median survival was 11.97 months. A subset of patients developed a cytotoxic T-cell response as determined by an IFNγ ELISpot assay.
Conclusions:
In this trial, treatment of newly diagnosed and recurrent GBM with autologous DC vaccine pulsed with lysate derived from an allogeneic stem-like cell line was safe and well tolerated. Clinical outcomes add to the body of evidence suggesting that immunotherapy plays a role in the treatment of GBM.
Data from A Phase I and Surgical Study of Ribociclib and Everolimus in Children with Recurrent or Refractory Malignant Brain Tumors: A Pediatric Brain Tumor Consortium Study
Authors: DeWire Mariko D. , Fuller Christine , Campagne Olivia , Lin Tong , Pan Haitao , Young Poussaint Tina , Baxter Patricia A. , Hwang Eugene I. , Bukowinski Andrew , Dorris Kathleen , Hoffman Lindsey , Waanders Angela J. , Karajannis Matthias A. , Stewart Clinton F. , Onar-Thomas Arzu , Fouladi Maryam , Dunkel Ira J.
Published: April 2023

AbstractPurpose:
Genomic aberrations in cell cycle and PI3K pathways are commonly observed in pediatric brain tumors. This study determined the MTD/recommended phase II dose (RP2D) of ribociclib and everolimus and characterized single-agent ribociclib concentrations in plasma and tumor in children undergoing resection.
Patients and Methods:
Patients were enrolled in the phase I study according to a rolling 6 design and received ribociclib and everolimus daily for 21 and 28 days, respectively. Surgical patients received ribociclib at the pediatric RP2D (350 mg/m2) for 7–10 days preoperatively followed by enrollment on the phase I study. Pharmacokinetics were analyzed for both cohorts.
Results:
Sixteen patients were enrolled on the phase I study (median age, 10.3 years; range, 3.9–20.4) and 6 patients in the surgical cohort (median age, 11.4 years; range: 7.2–17.1). Thirteen patients were enrolled at dose level 1 without dose-limiting toxicities (DLT). Two of the 3 patients at dose level 2 experienced DLTs (grade 3 hypertension and grade 4 alanine aminotransferase). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leukopenia. The RP2D of ribociclib and everolimus was 120 and 1.2 mg/m2 for 21 and 28 days, respectively. Steady-state everolimus exposures with ribociclib were 2.5-fold higher than everolimus administered alone. Ribociclib plasma, tumor concentrations, and cerebrospinal fluid (CSF) samples were collected. The mean tumor-to-plasma ratio of ribociclib was 19.8 (range, 2.22–53.4).
Conclusions:
Ribociclib and everolimus were well-tolerated and demonstrated pharmacokinetic properties similar to those in adults. Potential therapeutic ribociclib concentrations could be achieved in CSF and tumor tissue, although interpatient variability was observed.
Data from ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with ALK-Positive Non–Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges
Authors: Chow Laura Q.M. , Barlesi Fabrice , Bertino Erin M. , van den Bent Martin J. , Wakelee Heather A. , Wen Patrick Y. , Chiu Chao-Hua , Orlov Sergey , Chiari Rita , Majem Margarita , McKeage Mark , Yu Chong-Jen , Garrido Pilar , Hurtado Felipe K. , Arratia Pilar Cazorla , Song Yuanbo , Branle Fabrice , Shi Michael , Kim Dong-Wan
Published: April 2023

AbstractPurpose:
Central nervous system metastases are a prominent cause of morbidity and mortality in patients with ALK-positive (ALK+) non–small cell lung cancer (NSCLC). The phase II ASCEND-7 (NCT02336451) study was specifically designed to assess the efficacy and safety of the ALK inhibitor (ALKi) ceritinib in patients with ALK+ NSCLC metastatic to the brain and/or leptomeninges.
Patients and Methods:
Patients with active brain metastases were allocated to study arms 1 to 4 based on prior exposure to an ALKi and/or prior brain radiation (arm 1: prior radiotherapy/ALKi-pretreated; arm 2: no radiotherapy/ALKi-pretreated; arm 3: prior radiotherapy/ALKi-naïve; arm 4: no radiotherapy/ALKi-naïve). Arm 5 included patients with leptomeningeal carcinomatosis. Patients received ceritinib 750 mg once daily (fasted condition). Primary endpoint was investigator-assessed whole-body overall response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR) and intracranial/extracranial responses.
Results:
Per investigator assessment, in arms 1 (n = 42), 2 (n = 40), 3 (n = 12), and 4 (n = 44), respectively: whole-body ORRs [95% confidence interval (CI)] were 35.7% (21.6–52.0), 30.0% (16.6–46.5), 50.0% (21.1–78.9), and 59.1% (43.2–73.7); whole-body DCR (95% CI): 66.7% (50.5–80.4), 82.5% (67.2–92.7), 66.7% (34.9–90.1), and 70.5% (54.8–83.2); intracranial ORRs (95% CI): 39.3% (21.5–59.4), 27.6% (12.7–47.2), 28.6% (3.7–71.0), and 51.5% (33.5–69.2). In arm 5 (n = 18), whole-body ORR was 16.7% (95% CI, 3.6–41.4) and DCR was 66.7% (95% CI, 41.0–86.7). Paired cerebrospinal fluid and plasma sampling revealed that ceritinib penetrated the human blood–brain barrier.
Conclusions:
Ceritinib showed antitumor activity in patients with ALK+ NSCLC with active brain metastases and/or leptomeningeal disease, and could be considered in the management of intracranial disease.

See related commentary by Murciano-Goroff et al., p. 2477
Data from ESMO Scale for Clinical Actionability of Molecular Targets Driving Targeted Treatment in Patients with Cholangiocarcinoma
Authors: Verdaguer Helena , Saurí Tamara , Acosta Daniel Alejandro , Guardiola Magdalena , Sierra Alexandre , Hernando Jorge , Nuciforo Paulo , Miquel Josep M. , Molero Cristina , Peiró Sandra , Serra-Camprubí Queralt , Villacampa Guillermo , Aguilar Susana , Vivancos Ana , Tabernero Josep , Dienstmann Rodrigo , Macarulla Teresa
Published: April 2023

AbstractPurpose:
Treatment options for advanced cholangiocarcinoma are limited and prognosis is poor. Cholangiocarcinomas are highly heterogeneous at the molecular level, with divergent patterns between intrahepatic and extrahepatic forms, intrahepatic being particularly rich in actionable alterations. We compared survival in patients with advanced cholangiocarcinoma harboring alterations matched to targeted drugs, with patients harboring nonactionable alterations.
Experimental Design:
Patients with cholangiocarcinoma treated between 2011 and 2020 at one institution, with available molecular analyses, were retrospectively reviewed. Genomic alteration actionability was classified according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) and correlated with efficacy endpoints.
Results:
Of 327 patients included, 78.9% had intrahepatic cholangiocarcinoma, 97.9% had received chemotherapy for metastatic disease. Actionable molecular alterations per ESCAT were identified in 184 patients (56.3%), including IDH1 mutations and FGFR2 fusions (23.1% and 8.0% of patients with intrahepatic cholangiocarcinoma, respectively). Median overall survival in 50 patients with ESCAT I-IV alterations who received matched therapy (48 with intrahepatic cholangiocarcinoma) was 22.6 months [95% confidence interval (CI), 20.1–32.8], compared with 14.3 months (95% CI 11.9–18.1) in 130 patients without actionable ESCAT alterations (HR, 0.58; 95% CI, 0.40–0.85; P = 0.005). Among patients receiving matched targeted therapy, median progression-free survival was longer for patients with alterations classified as ESCAT I-II compared with ESCAT III-IV (5.0 vs. 1.9 months; HR, 0.36; 95% CI, 0.15–0.87; P = 0.02).
Conclusions:
ESCAT represents a tool to guide clinicians in fine-tuning use of molecular profiling data to choose matched targeted therapies. Our data demonstrate that targeted treatment administered per alteration actionability according to ESCAT is associated with improved survival in cholangiocarcinoma, particularly in ESCAT I-II intrahepatic cholangiocarcinoma.
Data from Immunogenicity and Safety of COVID-19 Vaccine BNT162b2 for Patients with Solid Cancer: A Large Cohort Prospective Study from a Single Institution
Authors: Di Noia Vincenzo , Pimpinelli Fulvia , Renna Davide , Barberi Vittoria , Maccallini Maria Teresa , Gariazzo Ludovica , Pontone Martina , Monti Alessandro , Campo Flaminia , Taraborelli Emanuela , Di Santo Maria , Petrone Fabrizio , Mandoj Chiara , Ferraresi Virginia , Ferretti Gianluigi , Carlini Paolo , Di Bella Ornella , Conti Laura , La Malfa Antonia Marina , Pellini Raul , Bracco Domenico , Giannarelli Diana , Morrone Aldo , Cognetti Francesco
Published: April 2023

AbstractPurpose:
We assessed the immunogenicity and safety of the BNT162b2 vaccine in a large cohort of patients with cancer (CP).
Experimental Design:
From March 1, 2021 to March 20, 2021, this prospective cohort study included 816 CP afferent to our institution and eligible for the vaccination. A cohort of 274 health care workers (HCW) was used as age- and sex-matched control group. BNT162b2 was administered as a two-dose regimen given 21 days apart. Blood samples to analyze anti-Spike (S) IgG antibodies (Ab) were collected prevaccination [timepoint (TP) 0], and at 3 weeks (TP1) and 7 weeks (TP2) after the first dose.
Results:
Patients characteristics: median age 62 (range, 21–97); breast/lung cancer/others (31/21/48%); active treatment/follow-up (90/10%). In the whole CP cohort, the serologic response rate (RR) and the titre of anti-S IgG significantly increased across the TPs; at TP2, the responders (IgG >15 AU/mL) were 94.2%. Active chemotherapy and chronic use of steroids were independent predictors of lower RR. Adverse events (AE) after the booster predicted higher likelihood of response (OR, 4.04; 95% confidence interval, 1.63–9.99; P = 0.003). Comparing the matched cohorts, the responders were significantly lower in CP than in HCW at TP1 (61.2% vs. 93.2%) and TP2 (93.3% vs. 100%), while the geometric mean concentration of IgG did not significantly differ at TP2 being significantly lower in CP (23.3) than in HCW (52.1) at TP1. BNT162b2 was well tolerated in CP; severe-grade AEs were 3.5% and 1.3% after the first and second doses, respectively.
Conclusions:
BNT162b2 assures serologic immunization without clinically significant toxicity in CP. The second dose is needed to reach a satisfactory humoral response.