bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Periostin and Epithelial–Mesenchymal Transition Score as Novel Prognostic Markers for Leiomyosarcoma, Myxofibrosarcoma, and Undifferentiated Pleomorphic Sarcoma
Authors: Piano Maria Assunta , Brunello Antonella , Cappellesso Rocco , Del Bianco Paola , Mattiolo Adriana , Fritegotto Chiara , Montini Barbara , Zamuner Carolina , Del Fiore Paolo , Rastrelli Marco , Sommariva Antonio , De Salvo Gian Luca , Montesco Maria Cristina , Rossi Carlo Riccardo , Zagonel Vittorina , Calabrò Maria Luisa
Published: April 2023

AbstractPurpose:
Interpatient clinical variability in soft-tissue sarcomas (STS) highlights the need for novel prognostic markers supporting patient risk stratification. As sarcomas might exhibit a more mesenchymal or a more epithelial state, we focused on epithelial–mesenchymal and mesenchymal–epithelial transitions (EMT/MET) for prognostic clues, and selected three histotypes with variable aggressiveness.
Experimental Design:
The expression of EMT/MET-related factors was measured by qRT-PCR in 55 tumor samples from patients with leiomyosarcoma, myxofibrosarcoma, or undifferentiated pleomorphic sarcoma. The identified marker was further evaluated by IHC in 31 leiomyosarcomas and by measuring its circulating levels in 67 patients. The prognostic value of a sarcoma-tailored EMT score was analyzed. Epirubicin chemosensitivity and migration were studied in primary STS cultures. Associations with overall survival (OS) were assessed using Kaplan–Meier and Cox regression methods.
Results:
High expression of periostin, a mesenchymal matricellular protein, in sarcoma tissues (P = 0.0024), its high stromal accumulation in leiomyosarcomas (P = 0.0075), and increased circulation (>20 ng/mL, P = 0.0008) were associated with reduced OS. High periostin expression [HR 2.9; 95% confidence interval (CI), 1.3–6.9; P = 0.0134] and circulation (HR 2.6; 95% CI, 1.3–5.1; P = 0.0086), and a mesenchymal EMT score (mesenchymal vs. transitioning; HR, 5.2; 95% CI, 2.1–13.0, P = 0.0005) were associated with increased risk in multivariable models. An intrinsic or induced mesenchymal state enhanced chemoresistance and migration in sarcoma cell lines.
Conclusions:
Although limited to a pilot study, these findings suggest that periostin might contribute prognostic information in the three studied STS histotypes. Moreover, a transitioning EMT score measured in the tumor might predict a less active and a more chemosensitive disease.
Data from Combining Vascular Normalization with an Oncolytic Virus Enhances Immunotherapy in a Preclinical Model of Advanced-Stage Ovarian Cancer
Authors: Matuszewska Kathy , Santry Lisa A. , van Vloten Jacob P. , AuYeung Amanda W.K. , Major Pierre P. , Lawler Jack , Wootton Sarah K. , Bridle Byram W. , Petrik Jim
Published: April 2023

AbstractPurpose:
Intravenous delivery of oncolytic viruses often leads to tumor vascular shutdown, resulting in decreased tumor perfusion and elevated tumor hypoxia. We hypothesized that using 3TSR to normalize tumor vasculature prior to administration of an oncolytic Newcastle disease virus (NDV) would enhance virus delivery and trafficking of immunologic cell subsets to the tumor core, resulting in systemically enhanced immunotherapy and regression of advanced-stage epithelial ovarian cancer (EOC).
Experimental Design:
Using an orthotopic, syngeneic mouse model of advanced-stage EOC, we pretreated mice with 3TSR (4 mg/kg per day) alone or followed by combination with fusogenic NDV(F3aa) (1.0 × 108 plaque-forming units).
Results:
Treatment with 3TSR normalized tumor vasculature, enhanced blood perfusion of primary EOC tumors, and induced disease regression. Animals treated with combination therapy had the greatest reduction in primary tumor mass, ascites accumulation, and secondary lesions (50% of mice were completely devoid of peritoneal metastases). Combining 3TSR + NDV(F3aa) led to enhanced trafficking of immunologic cells into the primary tumor core.
Conclusions:
We have shown, for the first time, that NDV, like other oncolytic viruses, is a potent mediator of acute vascular shutdown and that preventing this through vascular normalization can promote regression in a preclinical model of advanced-stage ovarian cancer. This challenges the current focus on induction of intravascular thrombosis as a requisite for successful oncolytic virotherapy.

See related commentary by Bykov and Zamarin, p. 1446
Data from ΔNp63γ/SRC/Slug Signaling Axis Promotes Epithelial-to-Mesenchymal Transition in Squamous Cancers
Authors: Srivastava Kirtiman , Pickard Adam , Craig Stephanie G. , Quinn Gerard P. , Lambe Shauna M. , James Jacqueline A. , McDade Simon S. , McCance Dennis J.
Published: April 2023

Abstract
Purpose: To investigate the regulation of epithelial-to-mesenchymal transition (EMT) in head and neck squamous cell carcinoma (HNSCC) and its importance in tumor invasion.

Experimental Design: We use a three-dimensional invasive organotypic raft culture model of human foreskin keratinocytes expressing the E6/E7 genes of the human papilloma virus-16, coupled with bioinformatic and IHC analysis of patient samples to investigate the role played by EMT in invasion and identify effectors and upstream regulatory pathways.

Results: We identify SNAI2 (Slug) as a critical effector of EMT-activated downstream of TP63 overexpression in HNSCC. Splice-form–specific depletion and rescue experiments further identify the ΔNp63γ isoform as both necessary and sufficient to activate the SRC signaling axis and SNAI2-mediated EMT and invasion. Moreover, elevated SRC levels are associated with poor outcome in patients with HNSCC in The Cancer Genome Atlas dataset. Importantly, the effects on EMT and invasions and SNAI2 expression can be reversed by genetic or pharmacologic inhibition of SRC.

Conclusions: Overexpression of ΔNp63γ modulates cell invasion by inducing targetable SRC-Slug–evoked EMT in HNSCC, which can be reversed by inhibitors of the SRC signaling. Clin Cancer Res; 24(16); 3917–27. ©2018 AACR.
Data from A PET Imaging Strategy for Interrogating Target Engagement and Oncogene Status in Pancreatic Cancer
Authors: Henry Kelly E. , Dacek Megan M. , Dilling Thomas R. , Caen Jonathan D. , Fox Ian L. , Evans Michael J. , Lewis Jason S.
Published: April 2023

AbstractPurpose:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers, with a 5-year survival rate of less than 10%. Physicians often rely on biopsy or CT to guide treatment decisions, but these techniques fail to reliably measure the actions of therapeutic agents in PDAC. KRAS mutations are present in >90% of PDAC and are connected to many signaling pathways through its oncogenic cascade, including extracellular regulated kinase (ERK) and MYC. A key downstream event of MYC is transferrin receptor (TfR), which has been identified as a biomarker for cancer therapeutics and imaging.
Experimental Design:
In this study, we aimed to test whether zirconium-89 transferrin ([89Zr]Zr-Tf) could measure changes in MYC depending on KRAS status of PDAC, and assess target engagement of anti-MYC and anti-ERK–targeted therapies.
Results:
Mice bearing iKras*p53* tumors showed significantly higher (P < 0.05) uptake of [89Zr]Zr-Tf in mice withdrawn from inducible oncogenic KRAS. A therapy study with JQ1 showed a statistically significant decrease (P < 0.05) of [89Zr]Zr-Tf uptake in drug versus vehicle-treated mice bearing Capan-2 and Suit-2 xenografts. IHC analysis of resected PDAC tumors reflects the data observed via PET imaging and radiotracer biodistribution.
Conclusions:
Our study demonstrates that [89Zr]Zr-Tf is a valuable tool to noninvasively assess oncogene status and target engagement of small-molecule inhibitors downstream of oncogenic KRAS, allowing a quantitative assessment of drug delivery.
Data from Immune Activation in Patients with Locally Advanced Cervical Cancer Treated with Ipilimumab Following Definitive Chemoradiation (GOG-9929)
Authors: Da Silva Diane M. , Enserro Danielle M. , Mayadev Jyoti S. , Skeate Joseph G. , Matsuo Koji , Pham Huyen Q. , Lankes Heather A. , Moxley Katherine M. , Ghamande Sharad A. , Lin Yvonne G. , Schilder Russell J. , Birrer Michael J. , Kast W. Martin
Published: April 2023

AbstractPurpose:
A phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune-modulation therapy with the checkpoint inhibitor ipilimumab [anti–CTL antigen-4 (anti–CTLA-4)] following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunologic and viral correlates were assessed before, during, and after treatment.
Patients and Methods:
Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints. Circulating T-cell subsets were evaluated by multiparameter flow cytometry. Cytokines were evaluated by multiplex ELISA. HPV-specific T cells were evaluated in a subset of patients by IFNγ ELISpot.
Results:
Expression of the activation markers ICOS and PD-1 significantly increased on T-cell subsets following CRT and were sustained or increased following ipilimumab treatment. Combined CRT/ipilimumab treatment resulted in a significant expansion of both central and effector memory T-cell populations. Genotype-specific E6/E7-specific T-cell responses increased post-CRT in 1 of 8 HPV16+ patients and in 2 of 3 HPV18+ patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL6, IL8) post-CRT was significantly associated with worse progression-free survival.
Conclusions:
Our data indicate that CRT alone and combined with ipilimumab immunotherapy show immune-modulating activity in women with locally advanced cervical cancer and may be a promising therapeutic option for the enhancement of antitumor immune cell function after primary CRT for this population at high risk for recurrence and metastasis. Several key immune biomarkers were identified that were associated with clinical response.
Data from A Gene Expression–based Model to Predict Metabolic Response After Two Courses of ABVD in Hodgkin Lymphoma Patients
Authors: Luminari Stefano , Donati Benedetta , Casali Massimiliano , Valli Riccardo , Santi Raffaella , Puccini Benedetta , Kovalchuk Sofya , Ruffini Alessia , Fama Angelo , Berti Valentina , Fragliasso Valentina , Zanelli Magda , Vergoni Federica , Versari Annibale , Rigacci Luigi , Merli Francesco , Ciarrocchi Alessia
Published: April 2023

AbstractPurpose:
Early response to ABVD, assessed with interim FDG-PET (iPET), is prognostic for classical Hodgkin lymphoma (cHL) and supports the use of response adapted therapy. The aim of this study was to identify a gene-expression profile on diagnostic biopsy to predict iPET positivity (iPET+).
Experimental Design:
Consecutive untreated patients with stage I–IV cHL who underwent iPET after two cycles of ABVD were identified. Expression of 770 immune-related genes was analyzed by digital expression profiling (NanoString Technology). iPET was centrally reviewed according to the five-point Deauville scale (DS 1-5). An iPET+ predictive model was derived by multivariate regression analysis and assessed in a validation set identified using the same inclusion criteria.
Results:
A training set of 121 and a validation set of 117 patients were identified, with 23 iPET+ cases in each group. Sixty-three (52.1%), 19 (15.7%), and 39 (32.2%) patients had stage I–II, III, and IV, respectively. Diagnostic biopsy of iPET+ cHLs showed transcriptional profile distinct from iPET−. Thirteen genes were stringently associated with iPET+. This signature comprises two functionally stromal-related nodes. Lymphocytes/monocytes ratio (LMR) was also associated to iPET+. In the training cohort a 5-gene/LMR integrated score predicted iPET+ [AUC, 0.88; 95% confidence interval (CI), 0.80–0.96]. The score achieved a 100% sensitivity to identify DS5 cases. Model performance was confirmed in the validation set (AUC, 0.68; 95% CI, 0.52–0.84). Finally, iPET score was higher in patients with event versus those without.
Conclusions:
In cHL, iPET is associated with a genetic signature and can be predicted by applying an integrated gene-based model on the diagnostic biopsy.
Data from Immunomodulation in Pomalidomide, Dexamethasone, and Daratumumab-Treated Patients with Relapsed/Refractory Multiple Myeloma
Authors: Pierceall William E. , Amatangelo Michael D. , Bahlis Nizar J. , Siegel David S. , Rahman Adeeb , Van Oekelen Oliver , Neri Paola , Young Mary , Chung Weiyuan , Serbina Natalya , Parekh Samir , Agarwal Amit , Thakurta Anjan
Published: April 2023

AbstractPurpose:
Addition of daratumumab to pomalidomide and low-dose dexamethasone (LoDEX) is a safe and effective combination for relapsed/refractory multiple myeloma treatment. We sought to better understand immune combinational benefit of pomalidomide and daratumumab with LoDEX.
Patients and Methods:
Immunophenotypic changes were analyzed in peripheral blood from longitudinal sampling of patients treated with this triplet regimen from cohort B of the CC4047-MM-014 phase II trial (NCT01946477).
Results:
Consistent with the daratumumab mechanism, treatment led to decreased natural killer (NK) and B cells. In contrast, pronounced increases occurred in activated and proliferating NK and T cells, appreciably in CD8+ T cells, along with reduction in naïve and expansion of effector memory compartments. Timing of T-cell changes correlated with pomalidomide dosing schedule. Enhanced activation/differentiation did not result in increased exhausted T-cell phenotypes or increases in regulatory T cells. Similar immune enhancements were also observed in patients previously refractory to lenalidomide.
Conclusions:
These data support a potential mechanism for enhanced immune-mediated cytotoxicity in which daratumumab-mediated NK-cell diminution is partially offset by pomalidomide effects on the remaining NK-cell pool. Furthermore, daratumumab antimyeloma activity and elimination of CD38+ T cells (regulatory/activated) provide a rationale for therapeutic combination with direct tumoricidal activity and immunomodulation of pomalidomide-directed T-cell enhancements. These data highlight enhancements in immune subpopulations for the combination of daratumumab with pomalidomide and potentially with next-generation cereblon-targeting agents.
Data from A Multianalyte Panel Consisting of Extracellular Vesicle miRNAs and mRNAs, cfDNA, and CA19-9 Shows Utility for Diagnosis and Staging of Pancreatic Ductal Adenocarcinoma
Authors: Yang Zijian , LaRiviere Michael J. , Ko Jina , Till Jacob E. , Christensen Theresa , Yee Stephanie S. , Black Taylor A. , Tien Kyle , Lin Andrew , Shen Hanfei , Bhagwat Neha , Herman Daniel , Adallah Andrew , O'Hara Mark H. , Vollmer Charles M. , Katona Bryson W. , Stanger Ben Z. , Issadore David , Carpenter Erica L.
Published: April 2023

AbstractPurpose:
To determine whether a multianalyte liquid biopsy can improve the detection and staging of pancreatic ductal adenocarcinoma (PDAC).
Experimental Design:
We analyzed plasma from 204 subjects (71 healthy, 44 non-PDAC pancreatic disease, and 89 PDAC) for the following biomarkers: tumor-associated extracellular vesicle miRNA and mRNA isolated on a nanomagnetic platform that we developed and measured by next-generation sequencing or qPCR, circulating cell-free DNA (ccfDNA) concentration measured by qPCR, ccfDNA KRAS G12D/V/R mutations detected by droplet digital PCR, and CA19-9 measured by electrochemiluminescence immunoassay. We applied machine learning to training sets and subsequently evaluated model performance in independent, user-blinded test sets.
Results:
To identify patients with PDAC versus those without, we generated a classification model using a training set of 47 subjects (20 PDAC and 27 noncancer). When applied to a blinded test set (N = 136), the model achieved an AUC of 0.95 and accuracy of 92%, superior to the best individual biomarker, CA19-9 (89%). We next used a cohort of 20 patients with PDAC to train our model for disease staging and applied it to a blinded test set of 25 patients clinically staged by imaging as metastasis-free, including 9 subsequently determined to have had occult metastasis. Our workflow achieved significantly higher accuracy for disease staging (84%) than imaging alone (accuracy = 64%; P < 0.05).
Conclusions:
Algorithmically combining blood-based biomarkers may improve PDAC diagnostic accuracy and preoperative identification of nonmetastatic patients best suited for surgery, although larger validation studies are necessary.
Data from Addition of Antiestrogen Treatment in Patients with Malignant PEComa Progressing to mTOR Inhibitors
Authors: Sanfilippo Roberta , Fabbroni Chiara , Fucà Giovanni , Fumagalli Elena , Morosi Carlo , Sbaraglia Marta , Gronchi Alessandro , Collini Paola , Dei Tos Angelo P. , Casali Paolo G.
Published: April 2023

AbstractPurpose:
Perivascular epithelioid cell tumors (PEComa) are rare mesenchymal neoplasms. mTOR inhibitors are the most active agents in PEComa and in patients progressing to mTOR inhibitors, other available therapies have limited benefit. Preclinical evidences showed a cross-talk between the mTOR pathway and estrogen receptor signaling. This provided a rationale for adding an antiestrogen treatment in female patients becoming resistant to mTOR inhibitors.
Experimental Design:
Since April 2018, female patients with advanced/metastatic PEComa progressing to mTOR inhibitors were treated with a combination of sirolimus and exemestane with or without LHRH analogue (based on menopausal status). This case series was retrospectively reviewed. Survival analyses were performed using the Kaplan–Meier method.
Results:
A total of seven consecutive patients treated with the combination of sirolimus and antiestrogen treatment were retrospectively reviewed. Six (86%) received a combination of sirolimus and exemestane, whereas one patient (14%) received a combination of sirolimus, exemestane, and triptorelin since in premenopausal status. After a median follow-up of 13.1 months, three patients (43%) experienced a partial response, three patients (43%) experienced a stabilization of disease, and one patient (14%) had disease progression with an overall response rate of 43% and a disease control rate of 86%.
Conclusions:
In this small retrospective case series, the addition of antiestrogen treatment in female patients with advanced PEComa progressing to mTOR inhibitors resulted in a remarkable clinical benefit in a setting where no other options are available.
Data from Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1E17K-Mutant, ER-Positive Metastatic Breast Cancer
Authors: Smyth Lillian M. , Tamura Kenji , Oliveira Mafalda , Ciruelos Eva M. , Mayer Ingrid A. , Sablin Marie-Paule , Biganzoli Laura , Ambrose Helen J. , Ashton Jack , Barnicle Alan , Cashell Des D. , Corcoran Claire , de Bruin Elza C. , Foxley Andrew , Hauser Joana , Lindemann Justin P.O. , Maudsley Rhiannon , McEwen Robert , Moschetta Michele , Pass Martin , Rowlands Vicky , Schiavon Gaia , Banerji Udai , Scaltriti Maurizio , Taylor Barry S. , Chandarlapaty Sarat , Baselga José , Hyman David M.
Published: April 2023

AbstractPurpose:
The activating mutation AKT1E17K occurs in approximately 7% of estrogen receptor–positive (ER+) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of patients with AKT1E17K-mutant ER+ MBC.
Patients and Methods:
Patients with an AKT1E17K mutation, detected by local (next-generation sequencing) or central (plasma-based BEAMing) testing, received capivasertib 480 mg twice daily, 4 days on, 3 days off, weekly or 400 mg twice daily combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS), and clinical benefit rate at 24 weeks (CBR24). Biomarker analyses were conducted in the combination cohort.
Results:
From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although the latter group may have had more aggressive disease at baseline. AKT1E17K mutations were detectable in plasma by BEAMing (95%, 41/43), droplet digital PCR (80%, 33/41), and next-generation sequencing (76%, 31/41). A ≥50% decrease in AKT1E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy [most frequent grade ≥3 adverse events: rash (9% vs. 20%), hyperglycemia (5% vs. 30%), diarrhea (5% vs. 10%)].
Conclusions:
Capivasertib demonstrated clinically meaningful activity in heavily pretreated patients with AKT1E17K-mutant ER+ MBC, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination.
Data from Chloroquine Sensitizes GNAQ/11-mutated Melanoma to MEK1/2 Inhibition
Authors: Truong Amanda , Yoo Jae Hyuk , Scherzer Michael T. , Sanchez John Michael S. , Dale Kali J. , Kinsey Conan G. , Richards Jackson R. , Shin Donghan , Ghazi Phaedra C. , Onken Michael D. , Blumer Kendall J. , Odelberg Shannon J. , McMahon Martin
Published: April 2023

AbstractPurpose:
Mutational activation of GNAQ or GNA11 (GNAQ/11), detected in >90% of uveal melanomas, leads to constitutive activation of oncogenic pathways, including MAPK and YAP. To date, chemo- or pathway-targeted therapies, either alone or in combination, have proven ineffective in the treatment of patients with metastatic uveal melanoma.
Experimental Design:
We tested the efficacy of chloroquine or hydroxychloroquine, in combination with MAPK pathway inhibition in GNAQ/11-mutated cells in vitro and in vivo and identified mechanisms of MEK1/2 inhibitor plus chloroquine-induced cytotoxicity.
Results:
Inhibition of GNAQ/11-mediated activation of MAPK signaling resulted in the induction of autophagy. Combined inhibition of Gα and autophagy or lysosome function resulted in enhanced cell death. Moreover, the combination of MEK1/2 inhibition, using trametinib, with the lysosome inhibitor, chloroquine, also increased cytotoxicity. Treatment of mice bearing GNAQ/11-driven melanomas with trametinib plus hydroxychloroquine resulted in inhibition of tumor growth and significantly prolonged survival. Interestingly, lysosomal- and autophagy-specific inhibition with bafilomycin A1 was not sufficient to promote cytotoxicity in combination with trametinib. However, the addition of YAP inhibition with trametinib plus bafilomycin A1 resulted in cell death at comparable levels to trametinib plus chloroquine (T/CQ) treatment. Furthermore, T/CQ-treated cells displayed decreased YAP nuclear localization and decreased YAP transcriptional activity. Expression of a constitutively active YAP5SA mutant conferred resistance to T/CQ-induced cell death.
Conclusions:
These results suggest that YAP, MEK1/2, and lysosome function are necessary and critical targets for the therapy of GNAQ/11-driven melanoma, and identify trametinib plus hydroxychloroquine as a potential treatment strategy for metastatic uveal melanoma.
Data from Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma
Authors: Middleton Mark R. , McAlpine Cheryl , Woodcock Victoria K. , Corrie Pippa , Infante Jeffrey R. , Steven Neil M. , Evans Thomas R. Jeffry , Anthoney Alan , Shoushtari Alexander N. , Hamid Omid , Gupta Avinash , Vardeu Antonella , Leach Emma , Naidoo Revashnee , Stanhope Sarah , Lewis Sion , Hurst Jacob , O’Kelly Ita , Sznol Mario
Published: April 2023

AbstractPurpose:
Tebentafusp is a first-in-class bispecific fusion protein designed to target gp100 (a melanoma-associated antigen) through a high affinity T-cell receptor (TCR) binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Here, we report a multicenter phase I/II trial of tebentafusp in metastatic melanoma (NCT01211262) focusing on the mechanism of action of tebentafusp.
Patients and Methods:
Eighty-four patients with advanced melanoma received tebentafusp. Treatment efficacy, treatment-related adverse events, and biomarker assessments were performed for blood-derived and tumor biopsy samples obtained at baseline and on-treatment.
Results:
Tebentafusp was generally well-tolerated and active in both patients with metastatic uveal melanoma and patients with metastatic cutaneous melanoma. A 1-year overall survival rate of 65% was achieved for both patient cohorts. On-treatment cytokine measurements were consistent with the induction of IFNγ pathway–related markers in the periphery and tumor. Notably, tebentafusp induced an increase in serum CXCL10 (a T-cell attractant) and a reduction in circulating CXCR3+ CD8+ T cells together with an increase in cytotoxic T cells in the tumor microenvironment. Furthermore, increased serum CXCL10 or the appearance of rash (likely due to cytotoxic T cells targeting gp100-expressing skin melanocytes) showed a positive association with patient survival.
Conclusions:
These data suggest that redirecting T cells using a gp100-targeting TCR/anti-CD3 bispecific fusion protein may provide benefit to patients with metastatic melanoma. Furthermore, the activity observed in these two molecularly disparate melanoma classes hints at the broad therapeutic potential of tebentafusp.
Data from DNA Methylation Profiling Identifies Distinct Clusters in Angiosarcomas
Authors: Weidema Marije E. , van de Geer Ellen , Koelsche Christian , Desar Ingrid M.E. , Kemmeren Patrick , Hillebrandt-Roeffen Melissa H.S. , Ho Vincent K.Y. , van der Graaf Winette T.A. , Versleijen-Jonkers Yvonne M.H. , von Deimling Andreas , Flucke Uta E.
Published: April 2023

AbstractPurpose:
DNA methylation profiling has previously uncovered biologically and clinically meaningful subgroups within many tumor types, but was not yet performed in angiosarcoma. Angiosarcoma is a rare sarcoma with very heterogeneous clinical presentations, which may be based on differences in biological background. In this exploratory study, DNA methylation profiling of 36 primary angiosarcoma samples from visceral, deep soft tissue, radiation-induced, and UV-induced localizations was performed.
Experimental Design:
Primary angiosarcoma formalin-fixed paraffin-embedded samples from visceral, soft tissue, radiation-induced, and UV-induced origin were collected from a nationwide search for angiosarcoma in the Netherlands. DNA was extracted for methylation profiling with the Illumina Infinium MethylationEPIC array. Quality control assessment and unsupervised hierarchical clustering were performed. Copy-number profiles were generated and analyzed for chromosomal stability. Clinical data were obtained from the Netherlands Cancer Registry.
Results:
DNA methylation profiling by unsupervised hierarchical clustering of 36 angiosarcoma samples (6 visceral, 5 soft tissue, 14 radiation-induced, 11 UV-induced) revealed two main clusters (A and B), which were divided into four subclusters. The clusters largely corresponded with clinical subtypes, showing enrichment of UV-induced cases in cluster A1 and radiation-induced cases in cluster A2. Visceral and soft tissue cases almost exclusively fell into cluster B. Cluster A showed significantly increased chromosomal instability and better overall survival (22 vs. 6 months, P = 0.046) compared with cluster B.
Conclusions:
In this novel methylation profiling study, we demonstrated for the first time four different angiosarcoma clusters. These clusters correlated with clinical subtype, overall survival, and chromosomal stability.
Data from Integration of Antiangiogenic Therapy with Cisplatin and Gemcitabine Chemotherapy in Patients with Nasopharyngeal Carcinoma
Authors: Chong Wan Qin , Lim Chwee Ming , Sinha Arvind Kumar , Tan Chee Seng , Chan Gloria Hui Jia , Huang Yiqing , Kumarakulasinghe Nesaretnam Barr , Sundar Raghav , Jeyasekharan Anand D. , Loh Woei Shyang , Tay Joshua K. , Yadav Kritika , Wang Lingzhi , Wong Andrea L. , Kong Li Ren , Soo Ross Andrew , Lau Jieying Amelia , Soon Yu Yang , Goh Robby Miguel , Ho Francis Cho Hao , Chong Siew Meng , Lee Soo Chin , Loh Kwok Seng , Tai Bee Choo , Lim Yaw Chyn , Goh Boon Cher
Published: April 2023

AbstractPurpose:
Induction cisplatin and gemcitabine chemotherapy is a standard treatment for locally advanced nasopharyngeal carcinoma (NPC). Inhibition of VEGF axis has been shown to promote maturation of microvasculature and improve perfusion. We conducted a four-arm study to assess the effect of two doses of either sunitinib or bevacizumab with chemotherapy in NPC.
Patients and Methods:
Patients with treatment-naïve locally advanced NPC were treated with three cycles of 3-weekly cisplatin and gemcitabine preceded by 1 week of anti-VEGF therapy for each cycle, followed by standard concurrent chemoradiation: arm A patients received 7 days of 12.5 mg/day sunitinib; arm B 7 days of 25 mg/day sunitinib; arm C bevacizumab 7.5 mg/kg infusion; arm D bevacizumab 2.5 mg/kg infusion. Patients with metastatic NPC were treated with up to six cycles of similar treatment without concurrent chemoradiation.
Results:
Complete metabolic response (mCR) by whole body 18FDG PET was highest in arm C (significant difference in four groups Fisher exact test P = 0.001; type 1 error = 0.05), with 42% mCR (95% confidence interval, 18–67) and 3-year relapse-free survival of 88% in patients with locally advanced NPC. Significant increase in pericyte coverage signifying microvascular maturation and increased immune cell infiltration was observed in posttreatment tumor biopsies in Arm C. Myelosuppression was more profound in sunitinib containing arms, and tolerability was established in arm C where hypertension was the most significant toxicity.
Conclusions:
Bevacizumab 7.5 mg/kg with cisplatin and gemcitabine was well tolerated. Promising tumor response was observed and supported mechanistically by positive effects on tumor perfusion and immune cell trafficking into the tumor.
Data from AZD4320, A Dual Inhibitor of Bcl-2 and Bcl-xL, Induces Tumor Regression in Hematologic Cancer Models without Dose-limiting Thrombocytopenia
Authors: Balachander Srividya B. , Criscione Steven W. , Byth Kate F. , Cidado Justin , Adam Ammar , Lewis Paula , Macintyre Terry , Wen Shenghua , Lawson Deborah , Burke Kathleen , Lubinski Tristan , Tyner Jeffrey W. , Kurtz Stephen E. , McWeeney Shannon K. , Varnes Jeffrey , Diebold R. Bruce , Gero Thomas , Ioannidis Stephanos , Hennessy Edward J. , McCoull William , Saeh Jamal C. , Tabatabai Areya , Tavana Omid , Su Nancy , Schuller Alwin , Garnett Mathew J. , Jaaks Patricia , Coker Elizabeth A. , Gregory Gareth P. , Newbold Andrea , Johnstone Ricky W. , Gangl Eric , Wild Martin , Zinda Michael , Secrist J. Paul , Davies Barry R. , Fawell Stephen E. , Gibbons Francis D.
Published: April 2023

AbstractPurpose:
Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2–selective inhibitor, has had success in the clinic, another family member, Bcl-xL, has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-xL inhibitor that broadens the therapeutic activity while minimizing Bcl-xL–mediated thrombocytopenia.
Experimental Design:
We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-xL and assessed the activity against in vitro cell lines, patient samples, and in vivo models. We applied pharmacokinetic/pharmacodynamic (PK/PD) modeling to integrate our understanding of on-target activity of the dual inhibitor in tumors and platelets across dose levels and over time.
Results:
We discovered AZD4320, which has nanomolar affinity for Bcl-2 and Bcl-xL, and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2– and Bcl-xL–dependent hematologic cancer cell lines and enhanced activity in acute myeloid leukemia (AML) patient samples compared with the Bcl-2–selective agent venetoclax. A single intravenous bolus dose of AZD4320 induces tumor regression with transient thrombocytopenia, which recovers in less than a week, suggesting a clinical weekly schedule would enable targeting of Bcl-2/Bcl-xL–dependent tumors without incurring dose-limiting thrombocytopenia. AZD4320 demonstrates monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models.
Conclusions:
AZD4320 is a potent molecule with manageable thrombocytopenia risk to explore the utility of a dual Bcl-2/Bcl-xL inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins.
Data from Capturing Hyperprogressive Disease with Immune-Checkpoint Inhibitors Using RECIST 1.1 Criteria
Authors: Matos Ignacio , Martin-Liberal Juan , García-Ruiz Alonso , Hierro Cinta , Ochoa de Olza Maria , Viaplana Cristina , Azaro Analia , Vieito Maria , Braña Irene , Mur Gemma , Ros Javier , Mateos Jose , Villacampa Guillermo , Berché Roger , Oliveira Mafalda , Alsina Maria , Elez Elena , Oaknin Ana , Muñoz-Couselo Eva , Carles Joan , Felip Enriqueta , Rodón Jordi , Tabernero Josep , Dienstmann Rodrigo , Perez-Lopez Raquel , Garralda Elena
Published: April 2023

AbstractPurpose:
Most hyperprogression disease (HPD) definitions are based on tumor growth rate (TGR). However, there is still no consensus on how to evaluate this phenomenon.
Patients and Methods:
We investigated two independent cohorts of patients with advanced solid tumors treated in phase I trials with (i) programmed cell death 1 (PD-1)/PD-L1 antibodies in monotherapy or combination and (ii) targeted agents (TA) in unapproved indications. A Response Evaluation Criteria in Solid Tumors (RECIST) 1.1–based definition of hyperprogression was developed. The primary endpoint was the assessment of the rate of HPD in patients treated with ICIs or TAs using both criteria (RECIST and TGR) and the impact on overall survival (OS) in patients who achieved PD as best response.
Results:
Among 270 evaluable patients treated with PD-1/PD-L1 inhibitors, 29 PD-1/PD-L1–treated patients (10.7%) had HPD by RECIST definition. This group had a significantly lower OS (median of 5.23 months; 95% CI, 3.97–6.45) when compared with the non-HPD progressor group (median, 7.33 months; 95% CI, 4.53–10.12; HR = 1.73, 95% CI, 1.05–2.85; P = 0.04). In a subset of 221 evaluable patients, 14 (6.3%) were categorized as HPD using TGR criteria, differences in median OS (mOS) between this group (mOS 4.2 months; 95% IC, 2.07–6.33) and non-HPD progressors (n = 44) by TGR criteria (mOS 6.27 months; 95% CI, 3.88–8.67) were not statistically significant (HR 1.4, 95% IC, 0.70–2.77; P = 0.346). Among 239 evaluable patients treated with TAs, 26 (10.9%) were classified as having HPD by RECIST and 14 using TGR criteria in a subset of patients. No differences in OS were observed between HPD and non-HPD progressors treated with TAs.
Conclusions:
HPD measured by TGR or by RECIST was observed in both cohorts of patients; however, in our series, there was an impact on survival only in the immune-checkpoint inhibitor cohort when evaluated by RECIST. We propose a new way to capture HPD using RECIST criteria that is intuitive and easy to use in daily clinical practice.
Data from CXCR3 and Cognate Ligands are Associated with Immune Cell Alteration and Aggressiveness of Pancreatic Ductal Adenocarcinoma
Authors: Cannon Andrew , Thompson Christopher M. , Maurer H. Carlo , Atri Pranita , Bhatia Rakesh , West Sean , Ghersi Dario , Olive Kenneth P. , Kumar Sushil , Batra Surinder K.
Published: April 2023

AbstractPurpose:
The cytokine milieu in pancreatic ductal adenocarcinoma (PDAC) promotes tumor progression and immune suppression, contributing to the dismal prognosis of patients with PDAC. The roles of many of these cytokines, however, have not been thoroughly investigated in PDAC.
Experimental Design:
PDAC microarray and The Cancer Genome Atlas datasets were analyzed to identify cytokines and cognate receptors overexpressed in PDAC and associated with survival. Pathway and CIBERSORT analyses were used to elucidate potential mechanisms of altered patient survival. Comparative analysis of cytokine expression in KPC (K-rasG12D; TP53R172H; Pdx-1cre) and KC (K-rasG12D; Pdx-1cre) PDAC models and multicolor immunofluorescence (IF) staining of human PDAC–resected samples were used to validate these findings.
Results:
CXCL9 and CXCL10 were among the most highly overexpressed cytokines by bioinformatics analyses, while their receptor, CXCR3, was significantly overexpressed by IHC analysis. Higher CXCR3 ligand expression was associated with shorter overall survival, while high CXCR3 expression was associated with better survival. The CXCR3 ligands, CXCL4, 9, and 10, were overexpressed in KPC compared with KC mice. Pathway analysis of CXCR3- and CXCR3 ligand–associated genes showed that CXCR3 is a marker of antitumor immunity, while its ligands may promote immunosuppression. CIBERSORT and IF studies of PDAC tissues demonstrated that high CXCR3 expression was associated with increased CD8+ T-cell and naïve B-cell signatures and loss of plasma cell signatures. CXCR3 ligand expression was associated with increased CD8+ T-cell signatures and loss of natural killer–cell signatures.
Conclusions:
CXCR3 ligands are overexpressed in PDAC and are associated with poor survival likely related to alterations in tumor immune infiltrate/activity.
Data from Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity
Authors: Bruun Jarle , Kryeziu Kushtrim , Eide Peter W. , Moosavi Seyed H. , Eilertsen Ina A. , Langerud Jonas , Røsok Bård , Totland Max Z. , Brunsell Tuva H. , Pellinen Teijo , Saarela Jani , Bergsland Christian H. , Palmer Hector G. , Brudvik Kristoffer W. , Guren Tormod , Dienstmann Rodrigo , Guren Marianne G. , Nesbakken Arild , Bjørnbeth Bjørn Atle , Sveen Anita , Lothe Ragnhild A.
Published: April 2023

AbstractPurpose:
Molecular tumor heterogeneity may have important implications for the efficacy of targeted therapies in metastatic cancers. Inter-metastatic heterogeneity of sensitivity to anticancer agents has not been well explored in colorectal cancer.
Experimental Design:
We established a platform for ex vivo pharmacogenomic profiling of patient-derived organoids (PDO) from resected colorectal cancer liver metastases. Drug sensitivity testing (n = 40 clinically relevant agents) and gene expression profiling were performed on 39 metastases from 22 patients.
Results:
Three drug–response clusters were identified among the colorectal cancer metastases, based primarily on sensitivities to EGFR and/or MDM2 inhibition, and corresponding with RAS mutations and TP53 activity. Potentially effective therapies, including off-label use of drugs approved for other cancer types, could be nominated for eighteen patients (82%). Antimetabolites and targeted agents lacking a decisive genomic marker had stronger differential activity than most approved chemotherapies. We found limited intra-patient drug sensitivity heterogeneity between PDOs from multiple (2–5) liver metastases from each of ten patients. This was recapitulated at the gene expression level, with a highly proportional degree of transcriptomic and pharmacological variation. One PDO with a multi-drug resistance profile, including resistance to EGFR inhibition in a RAS-mutant background, showed sensitivity to MEK plus mTOR/AKT inhibition, corresponding with low-level PTEN expression.
Conclusions:
Intra-patient inter-metastatic pharmacological heterogeneity was not pronounced and ex vivo drug screening may identify novel treatment options for metastatic colorectal cancer. Variation in drug sensitivities was reflected at the transcriptomic level, suggesting potential to develop gene expression–based predictive signatures to guide experimental therapies.
Data from Genomic Determinants of Clinical Outcomes in Rhabdomyosarcoma
Authors: Casey Dana L. , Wexler Leonard H. , Pitter Kenneth L. , Samstein Robert M. , Slotkin Emily K. , Wolden Suzanne L.
Published: April 2023

AbstractPurpose:
Increased availability of next-generation sequencing has allowed for the genomic characterization of a variety of pediatric tumors, although genomic determinants of response to treatment remain largely unknown. We sought to evaluate the genomic landscape and genomic determinants of clinical outcomes in rhabdomyosarcoma (RMS).
Experimental Design:
Of 29,067 patients who underwent genomic profiling at our institution using a 468-gene oncopanel with complete records, 87 had RMS, of whom 22 were fusion positive. The 10 most common genetic alterations were associated with locoregional control (LC), disease-free survival (DFS), and overall survival (OS). Tumor mutational burden (TMB), defined as the total number of somatic nonsynonymous mutations normalized to the number of sequenced megabases, was also associated with clinical outcomes.
Results:
Median age at diagnosis was 16.4 years and median follow-up, 2.1 years. Patients with fusion-negative RMS had more genomic alterations and a higher TMB than those with fusion-positive RMS (mean number of genomic alterations, 6.0 vs. 2.9; P = 0.007 and mean TMB, 2.6 vs. 1.0; P = 0.01). Genetic alterations in TP53 were associated with worse OS (P = 0.03). High TMB (defined as the top quartile ≥ 2.8) was associated with worse LC (P = 0.05), DFS (P = 0.04), and OS (P = 0.01), with significance retained on multivariable analysis after controlling for risk group, fusion status, and receipt of chemotherapy as per pediatric protocols.
Conclusions:
High TMB was associated with worse clinical outcomes in patients with RMS. With further validation, TMB and other genomic classifiers may be combined with traditional clinicopathologic risk factors to guide risk stratification and ultimately treatment decisions.
Data from Rapid Expansion of Highly Functional Antigen-Specific T Cells from Patients with Melanoma by Nanoscale Artificial Antigen-Presenting Cells
Authors: Ichikawa Junya , Yoshida Tatsuya , Isser Ariel , Laino Andressa S. , Vassallo Melinda , Woods David , Kim Sojung , Oelke Mathias , Jones Kristi , Schneck Jonathan P. , Weber Jeffrey S.
Published: April 2023

AbstractPurpose:
Generation of antigen-specific T cells from patients with cancer employs large numbers of peripheral blood cells and/or tumor-infiltrating cells to generate antigen-presenting and effector cells commonly requiring multiple rounds of restimulation ex vivo. We used a novel paramagnetic, nanoparticle-based artificial antigen-presenting cell (nano-aAPC) that combines anti-CD28 costimulatory and human MHC class I molecules that are loaded with antigenic peptides to rapidly expand tumor antigen–specific T cells from patients with melanoma.
Experimental Design:
Nano-aAPC–expressing HLA-A*0201 molecules and costimulatory anti-CD28 antibody and HLA-A*0201 molecules loaded with MART-1 or gp100 class I–restricted peptides were used to stimulate CD8 T cells purified from the peripheral blood of treatment-naïve or PD-1 antibody–treated patients with stage IV melanoma. Expanded cells were restimulated with fresh peptide-pulsed nano-aAPC at day 7. Phenotype analysis and functional assays including cytokine release, cytolysis, and measurement of avidity were conducted.
Results:
MART-1–specific CD8 T cells rapidly expanded up to 1,000-fold by day 14 after exposure to peptide-pulsed nano-aAPC. Expanded T cells had a predominantly stem cell memory CD45RA+/CD62L+/CD95+ phenotype; expressed ICOS, PD-1, Tim3, and LAG3; and lacked CD28. Cells from patients with melanoma were polyfunctional; highly avid; expressed IL2, IFNγ, and TNFα; and exhibited cytolytic activity against tumor cell lines. They expanded 2- to 3-fold after exposure to PD-1 antibody in vivo, and expressed a highly diverse T-cell receptor V beta repertoire.
Conclusions:
Peptide-pulsed nano-aAPC rapidly expanded polyfunctional antigen-specific CD8 T cells with high avidity, potent lytic function, and a stem cell memory phenotype from patients with melanoma.
Data from CUE-101, a Novel E7-pHLA-IL2-Fc Fusion Protein, Enhances Tumor Antigen-Specific T-Cell Activation for the Treatment of HPV16-Driven Malignancies
Authors: Quayle Steven N. , Girgis Natasha , Thapa Dharma R. , Merazga Zohra , Kemp Melissa M. , Histed Alex , Zhao Fan , Moreta Miguel , Ruthardt Paige , Hulot Sandrine , Nelson Alyssa , Kraemer Lauren D. , Beal Dominic R. , Witt Luke , Ryabin Jessica , Soriano Jonathan , Haydock Mark , Spaulding Emily , Ross John F. , Kiener Peter A. , Almo Steven , Chaparro Rodolfo , Seidel Ronald , Suri Anish , Cemerski Saso , Pienta Kenneth J. , Simcox Mary Ellen
Published: April 2023

AbstractPurpose:
To assess the potential for CUE-101, a novel therapeutic fusion protein, to selectively activate and expand HPV16 E711-20-specific CD8+ T cells as an off-the shelf therapy for the treatment of HPV16-driven tumors, including head and neck squamous cell carcinoma (HNSCC), cervical, and anal cancers.
Experimental Design:
CUE-101 is an Fc fusion protein composed of a human leukocyte antigen (HLA) complex, an HPV16 E7 peptide epitope, reduced affinity human IL2 molecules, and an effector attenuated human IgG1 Fc domain. Human E7-specific T cells and human peripheral blood mononuclear cells (PBMC) were tested to demonstrate cellular activity and specificity of CUE-101, whereas in vivo activity of CUE-101 was assessed in HLA-A2 transgenic mice. Antitumor efficacy with a murine surrogate (mCUE-101) was tested in the TC-1 syngeneic tumor model.
Results:
CUE-101 demonstrates selective binding, activation, and expansion of HPV16 E711-20-specific CD8+ T cells from PBMCs relative to nontarget cells. Intravenous administration of CUE-101 induced selective expansion of HPV16 E711-20-specific CD8+ T cells in HLA-A2 (AAD) transgenic mice, and anticancer efficacy and immunologic memory was demonstrated in TC-1 tumor-bearing mice treated with mCUE-101. Combination therapy with anti-PD-1 checkpoint blockade further enhanced the observed efficacy.
Conclusions:
Consistent with its design, CUE-101 demonstrates selective expansion of an HPV16 E711-20-specific population of cytotoxic CD8+ T cells, a favorable safety profile, and in vitro and in vivo evidence supporting its potential for clinical efficacy in an ongoing phase I trial (NCT03978689).