bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases
Authors: Von Roemeling Christina A. , Doonan Bently P. , Klippel Kelena , Schultz Daniel , Hoang-Minh Lan , Trivedi Vrunda , Li Chenglong , Russell Rylynn A. , Kanumuri Raju S. , Sharma Abhisheak , Tun Han W. , Mitchell Duane A.
Published: April 2023

AbstractPurpose:
An ongoing challenge in cancer is the management of primary and metastatic brain malignancies. This is partly due to restrictions of the blood-brain barrier and their unique microenvironment. These challenges are most evident in cancers such as lymphoma and melanoma, which are typically responsive to treatment in systemic locations but resistant when established in the brain. We propose interleukin-1 receptor-associated kinase-4 (IRAK-4) as a potential target across these diseases and describe the activity and mechanism of oral IRAK-4 inhibitor CA-4948.
Experimental Design:
Human primary central nervous system lymphoma (PCNSL) and melanoma brain metastases (MBM) samples were analyzed for expression of IRAK-4 and downstream transcription pathways. We next determined the central nervous system (CNS) applicability of CA-4948 in naïve and tumor-bearing mice using models of PCNSL and MBM. The mechanistic effect on tumors and the tumor microenvironment was then analyzed.
Results:
Human PCNSL and MBM have high expression of IRAK-4, IRAK-1, and nuclear factor kappa B (NF-κB). This increase in inflammation results in reflexive inhibitory signaling. Similar profiles are observed in immunocompetent murine models. Treatment of tumor-bearing animals with CA-4948 results in the downregulation of mitogen-activated protein kinase (MAPK) signaling in addition to decreased NF-κB. These intracellular changes are associated with a survival advantage.
Conclusions:
IRAK-4 is an attractive target in PCNSL and MBM. The inhibition of IRAK-4 with CA-4948 downregulates the expression of important transcription factors involved in tumor growth and proliferation. CA-4948 is currently being investigated in clinical trials for relapsed and refractory lymphoma and warrants further translation into PCNSL and MBM.
Data from Five-Year Clinical Outcomes after Neoadjuvant Nivolumab in Resectable Non–Small Cell Lung Cancer
Authors: Rosner Samuel , Reuss Joshua E. , Zahurak Marianna , Zhang Jiajia , Zeng Zhen , Taube Janis , Anagnostou Valsamo , Smith Kellie N. , Riemer Joanne , Illei Peter B. , Broderick Stephen R. , Jones David R. , Topalian Suzanne L. , Pardoll Drew M. , Brahmer Julie R. , Chaft Jamie E. , Forde Patrick M.
Published: April 2023

AbstractPurpose:
Neoadjuvant anti–PD-1 therapy has shown promise for resectable non–small cell lung cancer (NSCLC). We reported the first phase I/II trial of neoadjuvant nivolumab in resectable NSCLC, finding it to be safe and feasible with encouraging major pathological responses (MPR). We now present 5-year clinical outcomes from this trial, representing to our knowledge, the longest follow-up data for neoadjuvant anti–PD-1 in any cancer type.
Patients and Methods:
Two doses of nivolumab (3 mg/kg) were administered for 4 weeks before surgery to 21 patients with Stage I–IIIA NSCLC. 5-year recurrence-free survival (RFS), overall survival (OS), and associations with MPR and PD-L1, were evaluated.
Results:
With a median follow-up of 63 months, 5-year RFS and OS rates were 60% and 80%, respectively. The presence of MPR and pre-treatment tumor PD-L1 positivity (TPS ≥1%) each trended toward favorable RFS; HR, 0.61 [95% confidence interval (CI), 0.15–2.44] and HR, 0.36 (95% CI, 0.07–1.85), respectively. At 5-year follow-up, 8 of 9 (89%) patients with MPR were alive and disease-free. There were no cancer-related deaths among patients with MPR. In contrast, 6/11 patients without MPR experienced tumor relapse, and 3 died.
Conclusions:
Five-year clinical outcomes for neoadjuvant nivolumab in resectable NSCLC compare favorably with historical outcomes. MPR and PD-L1 positivity trended toward improved RFS, though definitive conclusions are limited by cohort size.
Data from Beneficial Effects of Mifepristone Treatment in Patients with Breast Cancer Selected by the Progesterone Receptor Isoform Ratio: Results from the MIPRA Trial
Authors: Elía Andrés , Saldain Leo , Vanzulli Silvia I. , Helguero Luisa A. , Lamb Caroline A. , Fabris Victoria , Pataccini Gabriela , Martínez-Vazquez Paula , Burruchaga Javier , Caillet-Bois Ines , Spengler Eunice , Acosta Haab Gabriela , Liguori Marcos , Castets Alejandra , Lovisi Silvia , Abascal María F. , Novaro Virginia , Sánchez Jana , Muñoz Javier , Belizán José M. , Abba Martín C. , Gass Hugo , Rojas Paola , Lanari Claudia
Published: April 2023

AbstractPurpose:
Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas that express higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a presurgical window of opportunity trial to determine the therapeutic effects of mifepristone in patients with breast cancer, based on their high PRA/PRB isoform ratio (MIPRA; NCT02651844).
Patients and Methods:
Twenty patients with luminal breast carcinomas with PRA/PRB > 1.5 (determined by Western blots), and PR ≥ 50%, naïve from previous treatment, were included for mifepristone treatment (200 mg/day orally; 14 days). Core needle biopsies and surgical samples were formalin fixed for IHC studies, while others were snap-frozen to perform RNA sequencing (RNA-seq), proteomics, and/or Western blot studies. Plasma mifepristone levels were determined using mass spectrometry. The primary endpoint was the comparison of Ki67 expression pretreatment and posttreatment.
Results:
A 49.62% decrease in Ki67 staining was observed in all surgical specimens compared with baseline (P = 0.0003). Using the prespecified response parameter (30% relative reduction), we identified 14 of 20 responders. Mifepristone induced an increase in tumor-infiltrating lymphocytes; a decrease in hormone receptor and pSer118ER expression; and an increase in calregulin, p21, p15, and activated caspase 3 expression. RNA-seq and proteomic studies identified downregulated pathways related to cell proliferation and upregulated pathways related to immune bioprocesses and extracellular matrix remodeling.
Conclusions:
Our results support the use of mifepristone in patients with luminal breast cancer with high PRA/PRB ratios. The combined effects of mifepristone and estrogen receptor modulators warrant clinical evaluation to improve endocrine treatment responsiveness in these patients.

See related commentary by Ronchi and Brisken, p. 833
Data from A Pilot Study of Intralesional Injection of Triamcinolone Acetonide for Desmoid Tumors: Two-Year Outcomes
Authors: Wilke Benjamin K. , Garner Hillary W. , Bestic Joseph M. , Chase Lori A. , Heckman Michael G. , Schoch Jennifer J. , Attia Steven
Published: April 2023

AbstractPurpose:
The purpose of this pilot study was to examine the clinical efficacy and safety of serial triamcinolone injections for the treatment of desmoid tumors.
Patients and Methods:
Nine patients were enrolled into this prospective study and underwent three serial ultrasound-guided triamcinolone injections (120 mg) at 6-week intervals. MRI was compared at baseline and every 6 months, out to 24 months. Safety and tolerability were assessed by clinical evaluation and questionnaires, including the 12-item short form survey (SF-12), visual analog scale (VAS), and desmoid patient-reported outcome (PRO) tool.
Results:
At 24 months, 8 (88.9%) patients demonstrated a reduction in the volume of their tumor while 1 (11.1%) enlarged. Median tumor volume change was −26.9% (−81.1% to 34.6%; P = 0.055) All 9 tumors remained stable based on World Health Organization criteria, whereas 2 (22.2%) demonstrated partial response based on RECIST. There was a significant decrease in the tumor:muscle postcontrast mean signal intensity ratio at 6 months (P = 0.008) and 24 months (P = 0.004). There was a similar decrease in the tumor:muscle T2 mean signal intensity ratio at 24 months (P = 0.02). We found no difference in the SF-12 and VAS scores, but there were significant improvements in the desmoid PRO.
Conclusions:
Treatment of desmoid tumors with serial triamcinolone injections appears safe and well tolerated by patients, with a 22% partial response based on RECIST. Further research is needed to confirm our results and determine factors predictive of response.
Data from Exposure-Response Analyses of Tremelimumab Monotherapy or in Combination with Durvalumab in Patients with Unresectable Hepatocellular Carcinoma
Authors: Song Xuyang , Kelley Robin Kate , Khan Anis A. , Standifer Nathan , Zhou Diansong , Lim KyoungSoo , Krishna Rajesh , Liu Lu , Wang Kun , McCoon Patricia , Negro Alejandra , He Philip , Gibbs Megan , Kurland John F. , Abou-Alfa Ghassan K.
Published: April 2023

AbstractPurpose:
A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab [Single Tremelimumab Regular Interval Durvalumab (STRIDE)] has demonstrated a favorable benefit-risk profile in the phase I/II Study 22 (NCT02519348) and phase III HIMALAYA study (NCT03298451). This study evaluated the pharmacokinetics, exposure–response, and exposure–pharmacodynamics relationships of tremelimumab in patients with unresectable hepatocellular carcinoma (uHCC).
Patients and Methods:
A previous tremelimumab population pharmacokinetic model was validated using data from parts 2 and 3 of Study 22. Exposure–response analyses explored relationships of tremelimumab exposure with efficacy and safety. Pharmacokinetics and pharmacodynamics relationships were evaluated using linear and nonlinear regression models.
Results:
The observed pharmacokinetics of tremelimumab in uHCC were consistent with predictions; no significant covariates were identified. Tremelimumab exposure was not significantly associated with adverse events, objective response rate, or progression-free survival. Overall survival (OS) was longer for patients with tremelimumab exposure, minimum serum drug concentration (Cmin1) ≥ median versus Cmin1 < median (18.99 months vs. 10.97 months), but this exposure-survival analysis might be confounded with baseline characteristics of albumin level and neutrophil to lymphocyte ratio, which had a significant impact on OS (P = 0.0004 and 0.0001, respectively). The predicted Cmin1 of tremelimumab in STRIDE regimen (12.9 μg/mL) was greater than the estimated concentration of tremelimumab eliciting half-maximal increases (EC50 = 5.24 μg/mL) in CD8+Ki67+ T-cell counts.
Conclusions:
Our findings support novel insights into tremelimumab pharmacokinetics and exposure–response relationships in HCC and support the clinical utility of the STRIDE regimen in patients with uHCC.
Data from Safety and Efficacy of MEDI0457 plus Durvalumab in Patients with Human Papillomavirus–Associated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
Authors: Aggarwal Charu , Saba Nabil F. , Algazi Alain , Sukari Ammar , Seiwert Tanguy Y. , Haigentz Missak , Porosnicu Mercedes , Bonomi Marcelo , Boyer Jean , Esser Mark T. , Cheng Lily I. , Agrawal Sonia , Jennings Emily C. , Durham Nicholas M. , Fraser Karl , Lissa Delphine , Gong Maozhen , Ceaicovscaia Natalia , Gascó Hernández Amaya , Kumar Rakesh
Published: April 2023

AbstractPurpose:
Tumoral programmed cell death ligand-1 (PD-L1) expression is common in human papillomavirus (HPV)–associated head and neck squamous cell carcinoma (HNSCC). We assessed whether a DNA vaccine targeting HPV-16/18 E6/E7 with IL12 adjuvant (MEDI0457) combined with the PD-L1 inhibitor durvalumab could enhance HPV-specific T-cell response and improve outcomes in recurrent/metastatic HPV-16/18–associated HNSCC.
Patients and Methods:
In this phase Ib/IIa study, immunotherapy-naïve patients with ≥1 previous platinum-containing regimen (neoadjuvant/adjuvant therapy or for recurrent/metastatic disease) received MEDI0457 7 mg intramuscularly with electroporation on weeks 1, 3, 7, and 12, then every 8 weeks, plus durvalumab 1,500 mg intravenously on weeks 4, 8, and 12, then every 4 weeks, until confirmed progression and/or unacceptable toxicity. Coprimary objectives were safety and objective response rate (ORR; H0: ORR ≤ 15%); secondary objectives included 16-week disease control rate (DCR-16), overall survival (OS), and progression-free survival (PFS).
Results:
Of 35 treated patients, 29 were response evaluable (confirmed HPV-associated disease; received both agents). ORR was 27.6% [95% confidence interval (CI), 12.7–47.2; four complete responses, four partial responses]; responses were independent of PD-L1 tumor-cell expression (≥25% vs. <25%). DCR-16 was 44.8% (95% CI, 26.5–64.3). Median PFS was 3.5 months (95% CI, 1.9–9.0); median OS was 29.2 months (15.2–not calculable). Twenty-eight (80.0%) patients had treatment-related adverse events [grade 3: 5 (14.3%); no grade 4/5], resulting in discontinuation in 2 (5.7%) patients. HPV-16/18–specific T cells increased on treatment; 4 of 8 evaluable patients had a >2-fold increase in tumor-infiltrating CD8+ T cells.
Conclusions:
MEDI0457 plus durvalumab was well tolerated. While the primary efficacy endpoint was not reached, clinical benefit was encouraging.
Data from ENPP1 Immunobiology as a Therapeutic Target
Authors: Ruiz-Fernández de Córdoba Borja , Martínez-Monge Rafael , Lecanda Fernando
Published: April 2023

Abstract
ENPP1 (ecto-nucleotide pyrophosphatase/phosphodiesterase) participates in the hydrolysis of different purine nucleotides in an array of physiologic processes. However, ENPP1 is frequently overexpressed in local relapses and tumor metastases, which are associated with poor prognosis and survival in a range of solid tumors. ENPP1 promotes an immunosuppressive tumor microenvironment (TME) by tilting the balance of ATP/adenosine (Ado) in conjunction with other components (CD38, CD39/ENTPD1, and CD73/NT5E). Moreover, ENPP1 intersects with the stimulator of interferon genes (STING), impairing its robust immune response through the hydrolysis of the effector 2′,3′-cyclic GMP–AMP. Thus, ENPP1 blockade emerges as a unique target eliciting immune remodeling and leveraging the STING pathway. Several ENPP1 inhibitors have shown an immunostimulatory effect, and their combination with other therapeutic modalities, such as immune-checkpoint blockade, STING activation, DNA damage response (DDR) inhibitors, and radiotherapy (RT), represents a promising avenue to boost antitumor–immune responses and to improve current clinical outcomes in several tumors. This comprehensive review summarizes the current state of the art and opens new perspectives for novel treatment strategies.
Data from Human Effectors of Acute and Chronic GVHD Overexpress CD83 and Predict Mortality
Authors: Holtan Shernan G. , Savid-Frontera Constanza , Walton Kelly , Eaton Anne A. , Demorest Connor , Hoeschen Andrea , Zhang Ling , Reid Kayla , Kurian Tony , Sayegh Zena , Julia Estefania , Maakaron Joseph , Bachanova Veronika , Jurdi Najla El , MacMillan Margaret L. , Weisdorf Daniel J. , Felices Martin , Miller Jeffrey S. , Blazar Bruce R. , Davila Marco L. , Betts Brian C.
Published: April 2023

AbstractPurpose:
Acute and chronic GVHD remain major causes of transplant-related morbidity and mortality (TRM) after allogeneic hematopoietic cell transplantation (alloHCT). We have shown CD83 chimeric antigen receptor (CAR) T cells prevent GVHD and kill myeloid leukemia cell lines. In this pilot study, we investigate CD83 expression on GVHD effector cells, correlate these discoveries with clinical outcomes, and evaluate critical therapeutic implications for transplant recipients.
Experimental Design:
CD83 expression was evaluated among circulating CD4+ T cells, B-cell subsets, T follicular helper (Tfh) cells, and monocytes from patients with/without acute or chronic GVHD (n = 48 for each group), respectively. CD83 expression was correlated with survival, TRM, and relapse after alloHCT. Differential effects of GVHD therapies on CD83 expression was determined.
Results:
CD83 overexpression on CD4+ T cells correlates with reduced survival and increased TRM. Increased CD83+ B cells and Tfh cells, but not monocytes, are associated with poor posttransplant survival. CD83 CAR T eliminate autoreactive CD83+ B cells isolated from patients with chronic GVHD, without B-cell aplasia as observed with CD19 CAR T. We demonstrate robust CD83 antigen density on human acute myeloid leukemia (AML), and confirm potent antileukemic activity of CD83 CAR T in vivo, without observed myeloablation.
Conclusions:
CD83 is a promising diagnostic marker of GVHD and warrants further investigation as a therapeutic target of both GVHD and AML relapse after alloHCT.
Data from Multi-Maintenance Olaparib Therapy in Relapsed, Germline BRCA1/2-Mutant High-Grade Serous Ovarian Cancer (MOLTO): A Phase II Trial
Authors: Morgan Robert D. , Clamp Andrew R. , White Daniel J. , Price Marcus , Burghel George J. , Ryder W. David J. , Mahmood Reem D. , Murphy Alexander D. , Hasan Jurjees , Mitchell Claire L. , Salih Zena , Wheeler Chelsey , Buckley Emma , Truelove Joanna , King Georgia , Ainaoui Yasmina , Bhaskar Sanjeev S. , Shaw Joseph , Evans D. Gareth R. , Kilerci Bedirhan , Pearce Simon P. , Brady Gerard , Dive Caroline , O'Connor James P.B. , Wallace Andrew J. , Rothwell Dominic G. , Edmondson Richard J. , Jayson Gordon C.
Published: April 2023

AbstractPurpose:
A single maintenance course of a PARP inhibitor (PARPi) improves progression-free survival (PFS) in germline BRCA1/2-mutant high-grade serous ovarian cancer (gBRCAm-HGSOC). The feasibility of a second maintenance course of PARPi was unknown.
Patients and Methods:
Phase II trial with two entry points (EP1, EP2). Patients were recruited prior to rechallenge platinum. Patients with relapsed, gBRCAm-HGSOC were enrolled at EP1 if they were PARPi-naïve. Patients enrolled at EP2 had received their first course of olaparib prior to trial entry. EP1 patients were retreated with olaparib after RECIST complete/partial response (CR/PR) to platinum. EP2 patients were retreated with olaparib ± cediranib after RECIST CR/PR/stable disease to platinum and according to the platinum-free interval. Co-primary outcomes were the proportion of patients who received a second course of olaparib and the proportion who received olaparib retreatment for ≥6 months. Functional homologous recombination deficiency (HRD), somatic copy-number alteration (SCNA), and BRCAm reversions were investigated in tumor and liquid biopsies.
Results:
Twenty-seven patients were treated (EP1 = 17, EP2 = 10), and 19 were evaluable. Twelve patients (63%) received a second course of olaparib and 4 received olaparib retreatment for ≥6 months. Common grade ≥2 adverse events during olaparib retreatment were anemia, nausea, and fatigue. No cases of MDS/AML occurred. Mean duration of olaparib treatment and retreatment differed (12.1 months vs. 4.4 months; P < 0.001). Functional HRD and SCNA did not predict PFS. A BRCA2 reversion mutation was detected in a post-olaparib liquid biopsy.
Conclusions:
A second course of olaparib can be safely administered to women with gBRCAm-HGSOC but is only modestly efficacious.

See related commentary by Gonzalez-Ochoa and Oza, p. 2563
Data from A Phase II Window of Opportunity Study of Neoadjuvant PD-L1 versus PD-L1 plus CTLA-4 Blockade for Patients with Malignant Pleural Mesothelioma
Authors: Lee Hyun-Sung , Jang Hee-Jin , Ramineni Maheshwari , Wang Daniel Y. , Ramos Daniela , Choi Jong Min , Splawn Taylor , Espinoza Monica , Almarez Michelle , Hosey Leandria , Jo Eunji , Hilsenbeck Susan , Amos Christopher I. , Ripley R. Taylor , Burt Bryan M.
Published: April 2023

AbstractPurpose:
We report the results of a phase II, randomized, window-of-opportunity trial of neoadjuvant durvalumab versus durvalumab plus tremelimumab followed by surgery in patients with resectable malignant pleural mesothelioma (MPM; NCT02592551).
Patients and Methods:
The primary objective was alteration of the intratumoral CD8/regulatory T cell (Treg) ratio after combination immune checkpoint blockade (ICB) therapy. Secondary and exploratory objectives included other changes in the tumor microenvironment, survival, safety, tumor pathologic response (PR), and systemic immune responses.
Results:
Nine patients received monotherapy and 11 received combination therapy. Seventeen of the 20 patients (85%) receiving ICB underwent planned thoracotomy. Both ICB regimens induced CD8 T-cell infiltration into MPM tumors but did not alter CD8/Treg ratios. At 34.1 months follow-up, patients receiving combination ICB had longer median overall survival (not reached) compared with those receiving monotherapy (14.0 months). Grade ≥3 immunotoxicity occurred in 8% of patients in the monotherapy group and 27% of patients in the combination group. Tumor PR occurred in 6 of 17 patients receiving ICB and thoracotomy (35.3%), among which major PR (>90% tumor regression) occurred in 2 (11.8%). Single-cell profiling of tumor, blood, and bone marrow revealed that combination ICB remodeled the immune contexture of MPM tumors; mobilized CD57+ effector memory T cells from the bone marrow to the circulation; and increased the formation of tertiary lymphoid structures in MPM tumors that were rich in CD57+ T cells.
Conclusions:
These data indicate that neoadjuvant durvalumab plus tremelimumab orchestrates de novo systemic immune responses that extend to the tumor microenvironment and correlate with favorable clinical outcomes.
Data from Molecular Subtypes of Head and Neck Cancer in Patients of African Ancestry
Authors: Mezghani Nadia , Yao Alexandria , Vasilyeva Daria , Kaplan Nicole , Shackelford Austin , Yoon Angela , Phillipone Elizabeth , Dubey Sunil , Schwartz Gary K. , Taylor Alison M. , Momen-Heravi Fatemeh
Published: April 2023

AbstractPurpose:
The purpose of this study was to better understand the complex molecular biomarkers and signatures of head and neck cancer (HNC) among Black patients and identify possible molecular changes associated with HNC disparities.
Experimental Design:
Molecular subtypes and genomic changes in HNC samples from patients of African and European ancestry in The Cancer Genome Atlas, Memorial Sloan Kettering Cancer Center, Broad Institute, MD Anderson Cancer Center, and John Hopkins University were identified. Molecular features (genomic, proteomic, transcriptomic) associated with race and genomic alterations associated with clinical outcomes were determined. An independent cohort of HNC tumor specimens was used to validate the primary findings using IHC.
Results:
Black patients were found to have a younger age at diagnosis, more aggressive tumor types, higher rates of metastasis, and worse survival compared with White patients. Black patients had fewer human papillomavirus–positive tumor types and higher frequencies of laryngeal subtype tumors. Higher frequencies of TP53, MYO18B, KMT2D, and UNC13C mutations and a lower frequency of PIK3CA mutations were observed in Black patients. Tumors of Black patients showed significant enrichment of c-MYC and RET-tyrosine signaling and amplifications. A significant increase in tumor expression of c-MYC in Black patients was observed and was associated with poor survival outcomes in the independent cohort.
Conclusions:
Novel genomic modifications and molecular signatures may be related to environmental, social, and behavioral factors associated with racial disparities in HNC. Unique tumor mutations and biological pathways have potential clinical utility in providing more targeted and individualized screening, diagnostic, and treatment modalities to improve health outcomes.
Data from Elucidating the Genetic Landscape of Oral Leukoplakia to Predict Malignant Transformation
Authors: Wils Leon J. , Poell Jos B. , Brink Arjen , Evren Ilkay , Brouns Elisabeth R. , de Visscher Jan G.A.M. , Bloemena Elisabeth , Brakenhoff Ruud H.
Published: April 2023

AbstractPurpose:
Oral leukoplakia is the most common oral potentially malignant disorder with an annual malignant transformation rate of 1% to 5%. Consequently, oral leukoplakia patients have a 30% to 50% lifetime risk to develop oral squamous cell carcinoma. Although risk factors for malignant transformation of oral leukoplakia have been investigated, no definitive risk stratification model has been proposed. Next-generation sequencing can elucidate the genetic landscape of oral leukoplakia, which may be used to predict the risk for malignant transformation.
Experimental Design:
We investigated a retrospective cohort of 89 oral leukoplakia patients, and analyzed their oral leukoplakia lesions for the presence of genomic copy-number alterations and mutations in genes associated with oral squamous cell carcinoma.
Results:
In 25 of 89 (28%) patients, oral squamous cell carcinoma developed during follow-up. Seventy-nine of 89 (89%) oral leukoplakias harbored at least one genetic event. Copy-number alterations were present in 61 of 89 (69%) oral leukoplakias, most commonly gains of chromosome regions 8q24 (46%) and 20p11 (20%) and loss of 13q12 (19%). Mutations were present in 59 of 89 (66%) oral leukoplakias, most commonly in TP53 (28%), FAT1 (20%), and NOTCH1 (13%). Genetic data were combined with the presence of dysplasia to generate a prediction model, identifying three groups with a distinct risk for malignant transformation.
Conclusions:
We provide an extensive description of genetic alterations in oral leukoplakia and its relation to malignant transformation. On the basis of our data we provide a model for the prediction of malignant transformation of oral leukoplakia using dysplasia and genetic markers.
Data from Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models
Authors: Rodriguez-Berriguete Gonzalo , Ranzani Marco , Prevo Remko , Puliyadi Rathi , Machado Nicole , Bolland Hannah R. , Millar Val , Ebner Daniel , Boursier Marie , Cerutti Aurora , Cicconi Alessandro , Galbiati Alessandro , Grande Diego , Grinkevich Vera , Majithiya Jayesh B. , Piscitello Desiree , Rajendra Eeson , Stockley Martin L. , Boulton Simon J. , Hammond Ester M. , Heald Robert A. , Smith Graeme C.M. , Robinson Helen M.R. , Higgins Geoff S.
Published: April 2023

AbstractPurpose:
DNA polymerase theta (Polθ) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. In this study we evaluate whether targeting Polθ with novel small-molecule inhibitors is a feasible strategy to improve the efficacy of radiotherapy.
Experimental design:
We characterized the response to Polθ inhibition in combination with ionizing radiation in different cancer cell models in vitro and in vivo.
Results:
Here, we show that ART558 and ART899, two novel and specific allosteric inhibitors of the Polθ DNA polymerase domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, noncancerous cells were not radiosensitized by Polθ inhibition. Mechanistically, we show that the radiosensitization caused by Polθ inhibition is most effective in replicating cells and is due to impaired DNA damage repair. We also show that radiosensitization is still effective under hypoxia, suggesting that these inhibitors may help overcome hypoxia-induced radioresistance. In addition, we describe for the first time ART899 and characterize it as a potent and specific Polθ inhibitor with improved metabolic stability. In vivo, the combination of Polθ inhibition using ART899 with fractionated radiation is well tolerated and results in a significant reduction in tumor growth compared with radiation alone.
Conclusions:
These results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy.
Data from Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial
Authors: Landen Charles N. , Molinero Luciana , Hamidi Habib , Sehouli Jalid , Miller Austin , Moore Kathleen N. , Taskiran Cagatay , Bookman Michael , Lindemann Kristina , Anderson Charles , Berger Regina , Myers Tashanna , Beiner Mario , Reid Thomas , Van Nieuwenhuysen Els , Green Andrew , Okamoto Aikou , Aghajanian Carol , Thaker Premal H. , Blank Stephanie V. , Khor Victor K. , Chang Ching-Wei , Lin Yvonne G. , Pignata Sandro
Published: April 2023

AbstractPurpose:
To explore whether patients with BRCA1/2-mutated or homologous recombination deficient (HRD) ovarian cancers benefitted from atezolizumab in the phase III IMagyn050 (NCT03038100) trial.
Patients and Methods:
Patients with newly diagnosed ovarian cancer were randomized to either atezolizumab or placebo with standard chemotherapy and bevacizumab. Programmed death-ligand 1 (PD-L1) status of tumor-infiltrating immune cells (IC) was determined centrally (VENTANA SP142 assay). Genomic alterations, including deleterious BRCA1/2 alterations, genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI), were evaluated using the FoundationOne assay. HRD was defined as gLOH ≥ 16%, regardless of BRCA1/2 mutation status. Potential associations between progression-free survival (PFS) and genomic biomarkers were evaluated using standard correlation analyses and log-rank of Kaplan–Meier estimates.
Results:
Among biomarker-evaluable samples, 22% (234/1,050) harbored BRCA1/2 mutations and 46% (446/980) were HRD. Median TMB was low irrespective of BRCA1/2 or HRD. Only 3% (29/1,024) had TMB ≥10 mut/Mb, and 0.3% (3/1,022) were MSI-high. PFS was better in BRCA2-mutated versus BRCA2–non-mutated tumors and in HRD versus proficient tumors. PD-L1 positivity (≥1% expression on ICs) was associated with HRD but not BRCA1/2 mutations. PFS was not improved by adding atezolizumab in BRCA2-mutated or HRD tumors; there was a trend toward enhanced PFS with atezolizumab in BRCA1-mutated tumors.
Conclusions:
Most ovarian tumors have low TMB despite BRCA1/2 mutations or HRD. Neither BRCA1/2 mutation nor HRD predicted enhanced benefit from atezolizumab. This is the first randomized double-blind trial in ovarian cancer demonstrating that genomic instability triggered by BRCA1/2 mutation or HRD is not associated with improved sensitivity to immune checkpoint inhibitors.
Data from Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA and Predictors of Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastases
Authors: Wijetunga N. Ari , Goglia Alexander G. , Weinhold Nils , Berger Michael F. , Cislo Michael , Higginson Daniel S. , Chabot Kiana , Osman Ahmed M. , Schaff Lauren , Pentsova Elena , Miller Alexandra M. , Powell Simon N. , Boire Adrienne , Yang Jonathan T.
Published: April 2023

AbstractPurpose:
Proton craniospinal irradiation (pCSI) is a promising treatment for patients with solid tumor leptomeningeal metastasis (LM). We hypothesize that genetic characteristics before and changes resulting after pCSI will reflect clinical response to pCSI. We analyzed the cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) from patients receiving pCSI for LM and explored genetic variations associated with response.
Experimental Design:
We subjected CSF from 14 patients with LM before and after pCSI to cell-free DNA sequencing using a targeted-sequencing panel. In parallel, plasma ctDNA and primary tumors were subjected to targeted sequencing. Variant allele frequency (VAF) and cancer cell fraction (CCF) were calculated; clonality of observed mutations was determined. Kaplan–Meier analysis was used to associate genomic changes with survival.
Results:
The median overall survival (OS) for the cohort was 9 months [interquartile range (IQR), 5–21 months]. We showed clonal evolution between tumor and ctDNA of the CSF and plasma with unique mutations identified by compartment. Higher CSF ctDNA mean VAF before pCSI (VAFpre) had worse OS (6 months for VAFpre ≥ 0.32 vs. 9 months for VAFpre < 0.32; P = 0.05). Similarly, increased VAF after pCSI portended worse survival (6 vs. 18 months; P = 0.008). Higher mean CCF of subclonal mutations appearing after pCSI was associated with worse OS (8 vs. 17 months; P = 0.05).
Conclusions:
In patients with solid tumor LM undergoing pCSI, we found unique genomic profiles associated with pCSI through CSF ctDNA analyses. Patients with reduced genomic diversity within the leptomeningeal compartment demonstrated improved OS after pCSI suggesting that CSF ctDNA analysis may have use in predicting pCSI response.
Data from Bolus versus Continuous Intravenous Delivery of Doxorubicin in Soft-Tissue Sarcomas: Post Hoc Analysis of a Prospective Randomized Trial (SARC021/TH CR-406)
Authors: Cranmer Lee D. , Lu Yao , Heise Rachel S. , Ballman Karla V. , Loggers Elizabeth T. , Pollack Seth M. , Wagner Michael J. , Reinke Denise K. , Schöffski Patrick , Tap William D.
Published: April 2023

AbstractPurpose:
Continuous intravenous infusion (CIV) of doxorubicin (DOX) versus bolus (BOL) may minimize dose-dependent DOX cardiomyopathy, but it is unclear whether this advantage is evident as employed in typical soft-tissue sarcoma (STS) treatment. The impact of administration mode on adverse events (AE) and efficacy were compared using data from a randomized trial of DOX-based therapy (SARC021/TH CR-406).
Experimental Design:
In this post hoc analysis, CIV versus BOL was at discretion of the treating physician. Likelihood of AEs, and objective responses were assessed by adjusted logistic regression. Progression-free (PFS) and overall survival (OS) were compared using Kaplan–Meier, log-rank test, and adjusted Cox regression.
Results:
DOX was administered by BOL to 556 and by CIV to 84 patients. Proportions experiencing hematologic, non-hematologic, or cardiac AEs did not differ by administration mode. Hematologic AEs were associated with age, performance status, and cumulative DOX. Non-hematologic AEs were associated with age, performance status, and cumulative evofosfamide. Cardiac AEs were only associated with cumulative DOX; there was no interaction between DOX dose and delivery mode. PFS and OS were similar (median PFS 6.14 months BOL vs. 6.11 months CIV, P = 0.47; median OS 18.4 months BOL vs. 21.4 months CIV, P = 0.62). PFS, OS, and objective responses were not associated with delivery mode.
Conclusions:
CIV was not associated with superior outcomes over BOL within DOX dosing limits of SARC021. Cardiac AEs were associated with increasing cumulative DOX dose. While not randomized with respect to DOX delivery mode, the results indicate that continued investigation of AE mitigation strategies is warranted.
Data from Biomarker Data from the Phase III KATHERINE Study of Adjuvant T-DM1 versus Trastuzumab for Residual Invasive Disease after Neoadjuvant Therapy for HER2-Positive Breast Cancer
Authors: Denkert Carsten , Lambertini Chiara , Fasching Peter A. , Pogue-Geile Katherine L. , Mano Max S. , Untch Michael , Wolmark Norman , Huang Chiun-Sheng , Loibl Sibylle , Mamounas Eleftherios P. , Geyer Charles E. , Lucas Peter C. , Boulet Thomas , Song Chunyan , Lewis Gail D. , Nowicka Malgorzata , de Haas Sanne , Basik Mark
Published: April 2023

AbstractPurpose:
In KATHERINE, adjuvant T-DM1 reduced risk of disease recurrence or death by 50% compared with trastuzumab in patients with residual invasive breast cancer after neoadjuvant therapy (NAT) comprised of HER2-targeted therapy and chemotherapy. This analysis aimed to identify biomarkers of response and differences in biomarker expression before and after NAT.
Materials and Methods:
Exploratory analyses investigated the relationship between invasive disease-free survival (IDFS) and HER2 protein expression/gene amplification, PIK3CA hotspot mutations, and gene expression of HER2, PD-L1, CD8, predefined immune signatures, and Prediction Analysis of Microarray 50 intrinsic molecular subtypes, classified by Absolute Intrinsic Molecular Subtyping. HER2 expression on paired pre- and post-NAT samples was examined.
Results:
T-DM1 appeared to improve IDFS versus trastuzumab across most biomarker subgroups, except the HER2 focal expression subgroup. High versus low HER2 gene expression in residual disease was associated with worse outcomes with trastuzumab [HR, 2.02; 95% confidence interval (CI), 1.32–3.11], but IDFS with T-DM1 was independent of HER2 expression level (HR, 1.01; 95% CI, 0.56–1.83). Low PD-L1 gene expression in residual disease was associated with worse outcomes with trastuzumab (HR, 0.66; 95% CI, 0.44–1.00), but not T-DM1 (HR, 1.05; 95% CI, 0.59–1.87). PIK3CA mutations were not prognostic. Increased variability in HER2 expression was observed in post-NAT versus paired pre-NAT samples.
Conclusions:
T-DM1 appears to overcome HER2 resistance. T-DM1 benefit does not appear dependent on immune activation, but these results do not rule out an influence of the tumor immune microenvironment on the degree of response.
Data from Loss of CDKN2A Cooperates with WWTR1(TAZ)–CAMTA1 Gene Fusion to Promote Tumor Progression in Epithelioid Hemangioendothelioma
Authors: Seavey Caleb N. , Hallett Andrea , Li Shuo , Che Kepeng , Pobbati Ajaybabu V. , Ma Shuang , Burtscher Ashley , Kanai Ryan , Lamar John M. , Rubin Brian P.
Published: April 2023

AbstractPurpose:
Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma caused by the WWTR1(TAZ)–CAMTA1 (TC) gene fusion. This fusion gene has been observed in almost all reported EHE cases and functions as a constitutively activated TAZ. Sequencing of human tumors has, however, identified additional secondary mutations in approximately 50% of EHE, most commonly the loss of tumor suppressor CDKN2A. In this study, the effect of loss of CDKN2A in EHE tumorigenesis was evaluated.
Experimental Design:
Mice bearing a conditional TC allele were paired with a conditional Cdkn2a knockout allele and an endothelial-specific Cre. Histologic characterization and single-cell RNA-seq of the resultant tumors were performed. EHE cell lines were established through ex vivo culture of tumor cells and evaluated for sensitivity to TEAD inhibition and trametinib.
Results:
Loss of Cdkn2a within EHE was associated with more aggressive disease, as displayed by earlier tumor-related morbidity/mortality and enhanced tumor cell proliferation. As no previous EHE cell lines exist, we attempted, successfully, to expand EHE tumor cells ex vivo and produced the first EHE cell lines. These cell lines are “addicted” to the TC oncoprotein, replicate the EHE transcriptional profile, and generate EHE tumors when injected into immunodeficient mice.
Conclusions:
CDKN2A loss enhances the tumorigenicity of EHE in vivo and enabled the generation of the first cell lines of this disease. These cell lines replicate key facets of the human disease phenotype. Therefore, these cell lines and allograft tumors generated after implantation serve as robust model systems for therapeutic testing of compounds directed at either EHE or other TAZ-driven cancers.
Data from Exploring the Immunogenicity of Noncanonical HLA-I Tumor Ligands Identified through Proteogenomics
Authors: Lozano-Rabella Maria , Garcia-Garijo Andrea , Palomero Jara , Yuste-Estevanez Anna , Erhard Florian , Farriol-Duran Roc , Martín-Liberal Juan , Ochoa-de-Olza Maria , Matos Ignacio , Gartner Jared J. , Ghosh Michael , Canals Francesc , Vidal August , Piulats Josep Maria , Matías-Guiu Xavier , Brana Irene , Muñoz-Couselo Eva , Garralda Elena , Schlosser Andreas , Gros Alena
Published: April 2023

AbstractPurpose:
Tumor antigens are central to antitumor immunity. Recent evidence suggests that peptides from noncanonical (nonC) aberrantly translated proteins can be presented on HLA-I by tumor cells. Here, we investigated the immunogenicity of nonC tumor HLA-I ligands (nonC-TL) to better understand their contribution to cancer immunosurveillance and their therapeutic applicability.
Experimental Design:
Peptides presented on HLA-I were identified in 9 patient-derived tumor cell lines from melanoma, gynecologic, and head and neck cancer through proteogenomics. A total of 507 candidate tumor antigens, including nonC-TL, neoantigens, cancer-germline, or melanocyte differentiation antigens, were tested for T-cell recognition of preexisting responses in patients with cancer. Donor peripheral blood lymphocytes (PBL) were in vitro sensitized against 170 selected nonC-TL to isolate antigen-specific T-cell receptors (TCR) and evaluate their therapeutic potential.
Results:
We found no recognition of the 507 nonC-TL tested by autologous ex vivo expanded tumor-reactive T-cell cultures while the same cultures demonstrated reactivity to mutated, cancer-germline, or melanocyte differentiation antigens. However, in vitro sensitization of donor PBL against 170 selected nonC-TL, led to the identification of TCRs specific to three nonC-TL, two of which mapped to the 5′ UTR regions of HOXC13 and ZKSCAN1, and one mapping to a noncoding spliced variant of C5orf22C. T cells targeting these nonC-TL recognized cancer cell lines naturally presenting their corresponding antigens. Expression of the three immunogenic nonC-TL was shared across tumor types and barely or not detected in normal cells.
Conclusions:
Our findings predict a limited contribution of nonC-TL to cancer immunosurveillance but demonstrate they may be attractive novel targets for widely applicable immunotherapies.
Data from Pilot Study of Recurrent Ewing's Sarcoma Management with Vigil/Temozolomide/Irinotecan and Assessment of Circulating Tumor (ct) DNA
Authors: Anderson Peter , Ghisoli Maurizio , Crompton Brian D. , Klega Kelly S. , Wexler Leonard H. , Slotkin Emily K. , Stanbery Laura , Manning Luisa , Wallraven Gladice , Manley Meghan , Horvath Staci , Bognar Ernest , Nemunaitis John
Published: April 2023

AbstractPurpose:
Treatment options for recurrent or refractory Ewing's sarcoma (ES) are limited. Vigil is a novel autologous tumor cell therapy expressing bi-shRNA furin/GMCSF plasmid, which previously demonstrated monotherapy activity in advanced ES. Herein we report safety and evidence of benefit to Vigil for ES as potential treatment.
Patients and Methods:
In this pilot trial, eligible patients with recurrent or refractory ES who failed initial standard-of-care therapy received treatment with temozolomide (TEM) 100 mg/m2/day oral and irinotecan (IRI) 50 mg/m2/day oral, Days 1 to 5, in combination with Vigil (1 × 106–107 cells/mL/day intradermal, Day 15), every 21 days (Vigil/TEM/IRI). Objective response rate (ORR) by RECIST v1.1, progression-free survival (PFS), and overall survival (OS) were assessed. Circulating tumor (ct) DNA analysis was done by patient-specific droplet digital PCR on baseline and serially collected on-treatment samples.
Results:
Eight of 10 enrolled patients were evaluable for safety and efficacy (mean age 24.6; 12.6–46.1 years old); 2 did not receive Vigil. Seven of 8 patients previously received TEM/IRI. No Vigil-related adverse events were reported. Common ≥Grade 3 chemotherapy-related toxicity included neutropenia (50%) and thrombocytopenia (38%). We observed two partial response patients by RECIST; both showed histologic complete response without additional cancer therapy. Median PFS was 8.2 months (95% confidence interval, 4.3–NA). Five patients showed stable disease or better for ≥6 months. Patient-specific EWS/FLI1 ctDNA was detectable in all 8 evaluable patients at baseline. Changes in ctDNA levels corresponded to changes in disease burden.
Conclusions:
Results demonstrated safety of combination Vigil/TEM/IRI.
Data from Pilot Study of Recurrent Ewing's Sarcoma Management with Vigil/Temozolomide/Irinotecan and Assessment of Circulating Tumor (ct) DNA
Authors: Anderson Peter , Ghisoli Maurizio , Crompton Brian D. , Klega Kelly S. , Wexler Leonard H. , Slotkin Emily K. , Stanbery Laura , Manning Luisa , Wallraven Gladice , Manley Meghan , Horvath Staci , Bognar Ernest , Nemunaitis John
Published: April 2023

AbstractBackground:
Treatment options for recurrent or refractory Ewing's sarcoma (ES) are limited. Vigil is a novel autologous tumor cell therapy expressing bi-shRNA furin/GMCSF plasmid, which previously demonstrated monotherapy activity in advanced ES. Herein we report safety and evidence of benefit to Vigil for ES as potential treatment.
Patients and Methods:
In this pilot trial, eligible patients with recurrent or refractory ES who failed initial standard-of-care therapy received treatment with temozolomide (TEM) 100 mg/m2/day oral and irinotecan (IRI) 50 mg/m2/day oral, Days 1 to 5, in combination with Vigil (1 × 106–107 cells/mL/day intradermal, Day 15), every 21 days (Vigil/TEM/IRI). Objective response rate (ORR) by RECIST v1.1, progression-free survival (PFS), and overall survival (OS) were assessed. Circulating tumor (ct) DNA analysis was done by patient-specific droplet digital PCR on baseline and serially collected on-treatment samples.
Results:
Eight of 10 enrolled patients were evaluable for safety and efficacy (mean age 24.6; 12.6–46.1 years old); 2 did not receive Vigil. Seven of 8 patients previously received TEM/IRI. No Vigil-related adverse events were reported. Common ≥Grade 3 chemotherapy-related toxicity included neutropenia (50%) and thrombocytopenia (38%). We observed two partial response patients by RECIST; both showed histologic complete response without additional cancer therapy. Median PFS was 8.2 months (95% confidence interval, 4.3–NA). Five patients showed stable disease or better for ≥6 months. Patient-specific EWS/FLI1 ctDNA was detectable in all 8 evaluable patients at baseline. Changes in ctDNA levels corresponded to changes in disease burden.
Conclusions:
Results demonstrated safety of combination Vigil/TEM/IRI.
Data from Intratumoral CD16+ Macrophages Are Associated with Clinical Outcomes of Patients with Metastatic Melanoma Treated with Combination Anti-PD-1 and Anti-CTLA-4 Therapy
Authors: Lee Hansol , Ferguson Angela L. , Quek Camelia , Vergara Ismael A. , Pires daSilva Ines , Allen Ruth , Gide Tuba Nur , Conway Jordan W. , Koufariotis Lambros T. , Hayward Nicholas K. , Waddell Nicola , Carlino Matteo S. , Menzies Alexander M. , Saw Robyn P.M. , Shklovskaya Elena , Rizos Helen , Lo Serigne , Scolyer Richard A. , Long Georgina V. , Palendira Umaimainthan , Wilmott James S.
Published: April 2023

AbstractPurpose:
This study characterizes intratumoral macrophage populations within baseline melanoma biopsies from patients with advanced melanoma who received either anti-PD-1 monotherapy or a combination with anti-CTLA-4. Particularly, FcγRIIIa (CD16)-expressing macrophage densities were investigated for associations with response and progression-free survival.
Experimental Design:
Patients with advanced melanoma who received either anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 were retrospectively identified. Macrophage populations were analyzed within baseline melanoma biopsies via multiplex IHC in relation to treatment outcomes.
Results:
Patients who responded to combination immune checkpoint inhibitor contained higher CD16+ macrophage densities than those who did not respond (196 vs. 7 cells/mm2; P = 0.0041). There was no diffidence in CD16+ macrophage densities in the PD-1 monotherapy-treated patients based on response (118 vs. 89 cells/mm2; P = 0.29). A significantly longer 3-year progression-free survival was observed in combination-treated patients with high intratumoral densities of CD16+ macrophages compared with those with low densities (87% vs. 42%, P = 0.0056, n = 40). No association was observed in anti-PD-1 monotherapy-treated patients (50% vs. 47%, P = 0.4636, n = 50). Melanoma biopsies with high densities of CD16+ macrophages contained upregulated gene expression of critical T-cell recruiting chemokines (CXCL9, CXCL10, and CXCL11).
Conclusions:
Our data demonstrate that tumor microenvironments enriched with CD16+ macrophages are favorable for response to combination anti-PD-1 and anti-CTLA-4 therapy but not anti-PD-1 monotherapy. These data provides a potential biomarker of response for combination immunotherapies in patients with metastatic melanoma.

See related commentary by Smithy and Luke, p. 2345