bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Phase I Study of the CD47 Blocker TTI-621 in Patients with Relapsed or Refractory Hematologic Malignancies
Authors: Ansell Stephen M. , Maris Michael B. , Lesokhin Alexander M. , Chen Robert W. , Flinn Ian W. , Sawas Ahmed , Minden Mark D. , Villa Diego , Percival Mary-Elizabeth M. , Advani Anjali S. , Foran James M. , Horwitz Steven M. , Mei Matthew G. , Zain Jasmine , Savage Kerry J. , Querfeld Christiane , Akilov Oleg E. , Johnson Lisa D.S. , Catalano Tina , Petrova Penka S. , Uger Robert A. , Sievers Eric L. , Milea Anca , Roberge Kathleen , Shou Yaping , O'Connor Owen A.
Published: April 2023

AbstractPurpose:
TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 “don't eat me” signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies.
Patients and Methods:
Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR).
Results:
Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, n = 35 and nivolumab combination, n = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing.
Conclusions:
TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.
Data from Longitudinal Copy-Number Alteration Analysis in Plasma Cell-Free DNA of Neuroendocrine Neoplasms is a Novel Specific Biomarker for Diagnosis, Prognosis, and Follow-up
Authors: Boons Gitta , Vandamme Timon , Mariën Laura , Lybaert Willem , Roeyen Geert , Rondou Tim , Papadimitriou Konstantinos , Janssens Katrien , Op de Beeck Bart , Simoens Marc , Demey Wim , Dero Isabel , Van Camp Guy , Peeters Marc , Op de Beeck Ken
Published: April 2023

AbstractPurpose:
As noninvasive biomarkers are an important unmet need for neuroendocrine neoplasms (NEN), biomarker potential of genome-wide molecular profiling of plasma cell-free DNA (cfDNA) was prospectively studied in patients with NEN.
Experimental Design:
Longitudinal plasma samples were collected from patients with well-differentiated, metastatic gastroenteropancreatic and lung NEN. cfDNA was subjected to shallow whole-genome sequencing to detect genome-wide copy-number alterations (CNA) and estimate circulating tumor DNA (ctDNA) fraction, and correlated to clinicopathologic and survival data. To differentiate pancreatic NENs (PNEN) from pancreatic adenocarcinomas (PAAD) using liquid biopsies, a classification model was trained using tissue-based CNAs and validated in cfDNA.
Results:
One hundred and ninety-five cfDNA samples from 43 patients with NEN were compared with healthy control cfDNA (N = 100). Plasma samples from patients with PNEN (N = 21) were used for comparison with publicly available PNEN tissue (N = 98), PAAD tissue (N = 109), and PAAD cfDNA (N = 96). Thirty percent of the NEN cfDNA samples contained ctDNA and 44% of the patients had at least one ctDNA-positive (ctDNA+) sample. CNAs detected in cfDNA were highly specific for NENs and the classification model could distinguish PAAD and PNEN cfDNA samples with a sensitivity, specificity, and AUC of 62%, 86%, and 79%, respectively. ctDNA-positivity was associated with higher World Health Organization (WHO) grade, primary tumor location, and higher chromogranin A and neuron-specific enolase values. Overall survival was significantly worse for ctDNA+ patients and increased ctDNA fractions were associated with poorer progression-free survival.
Conclusions:
Sequential genome-wide profiling of plasma cfDNA is a novel, noninvasive biomarker with high specificity for diagnosis, prognosis, and follow-up in metastatic NENs.
Data from Impact of Duration of Neoadjuvant Aromatase Inhibitors on Molecular Expression Profiles in Estrogen Receptor–positive Breast Cancers
Authors: Bergamino Milana A. , Morani Gabriele , Parker Joel , Schuster Eugene F. , Leal Mariana F. , López-Knowles Elena , Tovey Holly , Bliss Judith M. , Robertson John F.R. , Smith Ian E. , Dowsett Mitch , Cheang Maggie C.U.
Published: April 2023

AbstractPurpose:
Aromatase inhibitor (AI) treatment is the standard of care for postmenopausal women with primary estrogen receptor–positive breast cancer. The impact of duration of neoadjuvant endocrine therapy (NET) on molecular characteristics is still unknown. We evaluated and compared changes of gene expression profiles under short-term (2-week) versus longer-term neoadjuvant AIs.
Experimental Design:
Global gene expression profiles from the PeriOperative Endocrine Therapy for Individualised Care (POETIC) trial (137 received 2 weeks of AIs and 47 received no treatment) and targeted gene expression from 80 patients with breast cancer treated with NET for more than 1 month (NeoAI) were assessed. Intrinsic subtyping, module scores covering different cancer pathways and immune-related genes were calculated for pretreated and posttreated tumors.
Results:
The differences in intrinsic subtypes after NET were comparable between the two cohorts, with most Luminal B (90.0% in the POETIC trial and 76.3% in NeoAI) and 50.0% of HER2 enriched at baseline reclassified as Luminal A or normal-like after NET. Downregulation of proliferative-related pathways was observed after 2 weeks of AIs. However, more changes in genes from cancer-signaling pathways such as MAPK and PI3K/AKT/mTOR and immune response/immune-checkpoint components that were associated with AI-resistant tumors and differential outcome were observed in the NeoAI study.
Conclusions:
Tumor transcriptional profiles undergo bigger changes in response to longer NET. Changes in HER2-enriched and Luminal B subtypes are similar between the two cohorts, thus AI-sensitive intrinsic subtype tumors associated with good survival might be identified after 2 weeks of AI. The changes of immune-checkpoint component expression in early AI resistance and its impact on survival outcome warrants careful investigation in clinical trials.
Data from Early HPV ctDNA Kinetics and Imaging Biomarkers Predict Therapeutic Response in p16+ Oropharyngeal Squamous Cell Carcinoma
Authors: Cao Yue , Haring Catherine T. , Brummel Collin , Bhambhani Chandan , Aryal Madhava , Lee Choonik , Heft Neal Molly , Bhangale Apurva , Gu Wenjin , Casper Keith , Malloy Kelly , Sun Yilun , Shuman Andrew , Prince Mark E. , Spector Matthew E. , Chinn Steven , Shah Jennifer , Schonewolf Caitlin , McHugh Jonathan B. , Mills Ryan E. , Tewari Muneesh , Worden Francis P. , Swiecicki Paul L. , Mierzwa Michelle , Brenner J. Chad
Published: April 2023

AbstractPurpose:
In locally advanced p16+ oropharyngeal squamous cell carcinoma (OPSCC), (i) to investigate kinetics of human papillomavirus (HPV) circulating tumor DNA (ctDNA) and association with tumor progression after chemoradiation, and (ii) to compare the predictive value of ctDNA to imaging biomarkers of MRI and FDG-PET.
Experimental Design:
Serial blood samples were collected from patients with AJCC8 stage III OPSCC (n = 34) enrolled on a randomized trial: pretreatment; during chemoradiation at weeks 2, 4, and 7; and posttreatment. All patients also had dynamic-contrast-enhanced and diffusion-weighted MRI, as well as FDG-PET scans pre-chemoradiation and week 2 during chemoradiation. ctDNA values were analyzed for prediction of freedom from progression (FFP), and correlations with aggressive tumor subvolumes with low blood volume (TVLBV) and low apparent diffusion coefficient (TVLADC), and metabolic tumor volume (MTV) using Cox proportional hazards model and Spearman rank correlation.
Results:
Low pretreatment ctDNA and an early increase in ctDNA at week 2 compared with baseline were significantly associated with superior FFP (P < 0.02 and P < 0.05, respectively). At week 4 or 7, neither ctDNA counts nor clearance were significantly predictive of progression (P = 0.8). Pretreatment ctDNA values were significantly correlated with nodal TVLBV, TVLADC, and MTV pre-chemoradiation (P < 0.03), while the ctDNA values at week 2 were correlated with these imaging metrics in primary tumor. Multivariate analysis showed that ctDNA and the imaging metrics performed comparably to predict FFP.
Conclusions:
Early ctDNA kinetics during definitive chemoradiation may predict therapy response in stage III OPSCC.
Data from Improved T-cell Immunity Following Neoadjuvant Chemotherapy in Ovarian Cancer
Authors: Liu Min , Tayob Nabihah , Penter Livius , Sellars MacLean , Tarren Anna , Chea Vipheaviny , Carulli Isabel , Huang Teddy , Li Shuqiang , Cheng Su-Chun , Le Phuong , Frackiewicz Laura , Fasse Julia , Qi Courtney , Liu Joyce F. , Stover Elizabeth H. , Curtis Jennifer , Livak Kenneth J. , Neuberg Donna , Zhang Guanglan , Matulonis Ursula A. , Wu Catherine J. , Keskin Derin B. , Konstantinopoulos Panagiotis A.
Published: April 2023

AbstractPurpose:
Although local tissue-based immune responses are critical for elucidating direct tumor–immune cell interactions, peripheral immune responses are increasingly recognized as occupying an important role in anticancer immunity. We evaluated serial blood samples from patients with advanced epithelial ovarian cancer (EOC) undergoing standard-of-care neoadjuvant carboplatin and paclitaxel chemotherapy (including dexamethasone for prophylaxis of paclitaxel-associated hypersensitivity reactions) to characterize the evolution of the peripheral immune cell function and composition across the course of therapy.
Experimental Design:
Serial blood samples from 10 patients with advanced high-grade serous ovarian cancer treated with neoadjuvant chemotherapy (NACT) were collected before the initiation of chemotherapy, after the third and sixth cycles, and approximately 2 months after completion of chemotherapy. T-cell function was evaluated using ex vivo IFNγ ELISpot assays, and the dynamics of T-cell repertoire and immune cell composition were assessed using bulk and single-cell RNA sequencing (RNAseq).
Results:
T cells exhibited an improved response to viral antigens after NACT, which paralleled the decrease in CA125 levels. Single-cell analysis revealed increased numbers of memory T-cell receptor (TCR) clonotypes and increased central memory CD8+ and regulatory T cells throughout chemotherapy. Finally, administration of NACT was associated with increased monocyte frequency and expression of HLA class II and antigen presentation genes; single-cell RNAseq analyses showed that although driven largely by classical monocytes, increased class II gene expression was a feature observed across monocyte subpopulations after chemotherapy.
Conclusions:
NACT may alleviate tumor-associated immunosuppression by reducing tumor burden and may enhance antigen processing and presentation. These findings have implications for the successful combinatorial applications of immune checkpoint blockade and therapeutic vaccine approaches in EOC.
Data from A Novel Mouse Model of Radiation-Induced Cardiac Injury Reveals Biological and Radiological Biomarkers of Cardiac Dysfunction with Potential Clinical Relevance
Authors: Dreyfuss Alexandra D. , Goia Denisa , Shoniyozov Khayrullo , Shewale Swapnil V. , Velalopoulou Anastasia , Mazzoni Susan , Avgousti Harris , Metzler Scott D. , Bravo Paco E. , Feigenberg Steven J. , Ky Bonnie , Verginadis Ioannis I. , Koumenis Constantinos
Published: April 2023

AbstractPurpose:
Radiation-induced cardiotoxicity is a significant concern in thoracic oncology patients. However, the basis for this disease pathology is not well characterized. We developed a novel mouse model of radiation-induced cardiotoxicity to investigate pathophysiologic mechanisms and identify clinically targetable biomarkers of cardiac injury.
Experimental Design:
Single radiation doses of 20, 40, or 60 Gy were delivered to the cardiac apex of female C57BL/6 mice ages 9–11 weeks, with or without adjacent lung tissue, using conformal radiotherapy. Cardiac tissue was harvested up to 24 weeks post-radiotherapy for histologic analysis. Echocardiography and Technetium-99m sestamibi single photon emission computed tomography (SPECT) at 8 and 16 weeks post-radiotherapy were implemented to evaluate myocardial function and perfusion. Mouse cardiac tissue and mouse and human plasma were harvested for biochemical studies.
Results:
Histopathologically, radiotherapy resulted in perivascular fibrosis 8 and 24 (P < 0.05) weeks post-radiotherapy. Apical perfusion deficits on SPECT and systolic and diastolic dysfunction on echocardiography 8 and 16 weeks post-radiotherapy were also observed (P < 0.05). Irradiated cardiac tissue and plasma showed significant increases in placental growth factor (PlGF), IL6, and TNFα compared with nonradiated matched controls, with greater increases in cardiac cytokine levels when radiotherapy involved lung. Human plasma showed increased PlGF (P = 0.021) and TNFα (P = 0.036) levels after thoracic radiotherapy. PlGF levels demonstrated a strong correlation (r = 0.89, P = 0.0001) with mean heart dose.
Conclusions:
We developed and characterized a pathophysiologically relevant mouse model of radiation-induced cardiotoxicity involving in situ irradiation of the cardiac apex. The model can be used to integrate radiomic and biochemical markers of cardiotoxicity to inform early therapeutic intervention and human translational studies.
Data from Three-Year Follow-Up and Response–Survival Relationship of Nivolumab in Previously Treated Patients with Advanced Esophageal Squamous Cell Carcinoma (ATTRACTION-3)
Authors: Okada Morihito , Kato Ken , Cho Byoung Chul , Takahashi Masanobu , Lin Chen-Yuan , Chin Keisho , Kadowaki Shigenori , Ahn Myung-Ju , Hamamoto Yasuo , Doki Yuichiro , Yen Chueh-Chuan , Kubota Yutaro , Kim Sung-Bae , Hsu Chih-Hung , Holtved Eva , Xynos Ioannis , Matsumura Yasuhiro , Takazawa Akira , Kitagawa Yuko
Published: April 2023

AbstractPurpose:
Limited long-term data are available on immune checkpoint inhibitor use in patients with advanced esophageal squamous cell carcinoma (ESCC). We report 3-year follow-up data from our study of nivolumab versus chemotherapy (paclitaxel or docetaxel) in patients with previously treated ESCC.
Patients and Methods:
ATTRACTION-3 was a randomized, multicenter, open-label, phase III trial. Overall survival (OS), time from randomization to death from any cause, was the primary endpoint. An exploratory subanalysis assessed OS according to the best overall response (BOR) with and without landmark at 4 months.
Results:
Of the enrolled patients, 210 received nivolumab and 209 received chemotherapy. With a minimum follow-up of 36.0 months, OS was longer in the nivolumab versus the chemotherapy group (median, 10.9 vs. 8.5 months; HR, 0.79; P = 0.0264), with 3-year OS rates of 15.3% and 8.7%, respectively. The median OS was longer with nivolumab versus chemotherapy irrespective of the BOR (complete response/partial response: 19.9 vs. 15.4 months; stable disease: 17.4 vs. 8.8 months; and progressive disease: 7.6 vs. 4.2 months). Grade 3 or higher treatment-related adverse events were reported in 40 patients (19.1%) in the nivolumab group and 133 patients (63.9%) in the chemotherapy group.
Conclusions:
Nivolumab as second-line therapy demonstrated clinically meaningful long-term improvement in OS compared with chemotherapy in previously treated patients with advanced ESCC. The OS was consistently improved in the nivolumab group compared with the chemotherapy group regardless of BOR. Nivolumab was well tolerated over the 3-year follow-up.

See related commentary by Yoon et al., p. 3173
Data from Radioimmunotherapy Targeting Delta-like Ligand 3 in Small Cell Lung Cancer Exhibits Antitumor Efficacy with Low Toxicity
Authors: Tully Kathryn M. , Tendler Salomon , Carter Lukas M. , Sharma Sai Kiran , Samuels Zachary V. , Mandleywala Komal , Korsen Joshua A. , Delos Reyes Avelyn Mae , Piersigilli Alessandra , Travis William D. , Sen Triparna , Pillarsetty Nagavarakishore , Poirier John T. , Rudin Charles M. , Lewis Jason S.
Published: April 2023

AbstractPurpose:
Small cell lung cancer (SCLC) is an exceptionally lethal form of lung cancer with limited treatment options. Delta-like ligand 3 (DLL3) is an attractive therapeutic target as surface expression is almost exclusive to tumor cells.
Experimental Design:
We radiolabeled the anti-DLL3 mAb SC16 with the therapeutic radioisotope, Lutetium-177. [177Lu]Lu-DTPA-CHX-A”-SC16 binds to DLL3 on SCLC cells and delivers targeted radiotherapy while minimizing radiation to healthy tissue.
Results:
[177Lu]Lu-DTPA-CHX-A”-SC16 demonstrated high tumor uptake with DLL3-target specificity in tumor xenografts. Dosimetry analyses of biodistribution studies suggested that the blood and liver were most at risk for toxicity from treatment with high doses of [177Lu]Lu-DTPA-CHX-A”-SC16. In the radioresistant NCI-H82 model, survival studies showed that 500 μCi and 750 μCi doses of [177Lu]Lu-DTPA-CHX-A”-SC16 led to prolonged survival over controls, and 3 of the 8 mice that received high doses of [177Lu]Lu-DTPA-CHX-A”-SC16 had pathologically confirmed complete responses (CR). In the patient-derived xenograft model Lu149, all doses of [177Lu]Lu-DTPA-CHX-A”-SC16 markedly prolonged survival. At the 250 μCi and 500 μCi doses, 5 of 10 and 7 of 9 mice demonstrated pathologically confirmed CRs, respectively. Four of 10 mice that received 750 μCi of [177Lu]Lu-DTPA-CHX-A”-SC16 demonstrated petechiae severe enough to warrant euthanasia, but the remaining 6 mice demonstrated pathologically confirmed CRs. IHC on residual tissues from partial responses confirmed retained DLL3 expression. Hematologic toxicity was dose-dependent and transient, with full recovery within 4 weeks. Hepatotoxicity was not observed.
Conclusions:
Together, the compelling antitumor efficacy, pathologic CRs, and mild and transient toxicity profile demonstrate strong potential for clinical translation of [177Lu]Lu-DTPA-CHX-A”-SC16.
Data from Single‐Cell Immune Mapping of Melanoma Sentinel Lymph Nodes Reveals an Actionable Immunotolerant Microenvironment
Authors: Yaddanapudi Kavitha , Stamp Bryce F. , Subrahmanyam Priyanka B. , Smolenkov Andrei , Waigel Sabine J. , Gosain Rahul , Egger Michael E. , Martin Robert C.G. , Buscaglia Robert , Maecker Holden T. , McMasters Kelly M. , Chesney Jason A.
Published: April 2023

AbstractPurpose:
Improving our understanding of the immunologic response to cancer cells within the sentinel lymph nodes (SLN) of primary tumors is expected to identify new approaches to stimulate clinically meaningful cancer immunity.
Experimental Design:
We used mass cytometry by time-of-flight (CyTOF), flow cytometry, and T-cell receptor immunosequencing to conduct simultaneous single-cell analyses of immune cells in the SLNs of patients with melanoma.
Results:
We found increased effector-memory αβ T cells, TCR clonality, and γδ T cells selectively in the melanoma-bearing SLNs relative to non–melanoma-bearing SLNs, consistent with possible activation of an antitumor immune response. However, we also observed a markedly immunotolerant environment in the melanoma-bearing SLNs indicated by reduced and impaired NK cells and increased levels of CD8+CD57+PD-1+ cells, which are known to display low melanoma killing capabilities. Other changes observed in melanoma-bearing SLNs when compared with non–melanoma-bearing SLNs include (i) reduced CD8+CD69+ T cell/T regulatory cell ratio, (ii) high PD-1 expression on CD4+ and CD8+ T cells, and (iii) high CTLA-4 expression on γδ T cells.
Conclusions:
Our data suggest that these immunologic changes compromise antimelanoma immunity and contribute to a high relapse rate. We propose the development of clinical trials to test the neo-adjuvant administration of anti–PD-1 antibodies prior to SLN resection in patients with stage III melanoma.

See related commentary by Lund, p. 1996
Data from A High-Content Screen for C/EBPα Expression Identifies Novel Therapeutic Agents in Dedifferentiated Liposarcoma
Authors: Angeles Christina V. , Velez Ana , Rios Jordan , Laxa Bernadette , Shum David , Ruiz Penelope D. , Shen Yawei , Ostrovnaya Irina , Gularte-Mérida Rodrigo , Nacev Benjamin A. , Dickson Mark A. , Djaballah Hakim , Okada Tomoyo , Singer Samuel
Published: April 2023

AbstractPurpose:
Dedifferentiated liposarcoma (DDLS), one of the most common and aggressive sarcomas, infrequently responds to chemotherapy. DDLS survival and growth depend on underexpression of C/EBPα, a tumor suppressor and transcriptional regulator controlling adipogenesis. We sought to screen and prioritize candidate drugs that increase C/EBPα expression and may therefore serve as differentiation-based therapies for DDLS.
Experimental Design:
We screened known bioactive compounds for the ability to restore C/EBPα expression and inhibit proliferation selectively in two DDLS cell lines but not in normal adipose-derived stem cells (ASC). Selected hits' activity was validated, and the mechanism of the most potent, SN-38, was investigated. The in vivo efficacy of irinotecan, the prodrug of SN-38, was evaluated in DDLS xenograft models.
Results:
Of 3,119 compounds, screen criteria were met by 19. Validation experiments confirmed the DDLS selectivity of deguelin, emetine, and SN-38 and showed that they induce apoptosis in DDLS cells. SN-38 had the lowest IC50 (approximately 10 nmol/L), and its pro-apoptotic effects were countered by knockdown of CEBPA but not of TP53. Irinotecan significantly inhibited tumor growth at well-tolerated doses, induced nuclear expression of C/EBPα, and inhibited HIF1α expression in DDLS patient-derived and cancer cell line xenograft models. In contrast, doxorubicin, the most common treatment for nonresectable DDLS, reduced tumor growth by 30% to 50% at a dose that caused weight loss.
Conclusions:
This high-content screen revealed potential treatments for DDLS. These include irinotecan, which induces apoptosis of DDLS cells in a C/EBPα-dependent, p53-independent manner, and should be clinically evaluated in patients with advanced DDLS.
Data from Metabolomic Biomarkers in Blood Samples Identify Cancers in a Mixed Population of Patients with Nonspecific Symptoms
Authors: Larkin James R. , Anthony Susan , Johanssen Vanessa A. , Yeo Tianrong , Sealey Megan , Yates Abi G. , Smith Claire Friedemann , Claridge Timothy D.W. , Nicholson Brian D. , Moreland Julie-Ann , Gleeson Fergus , Sibson Nicola R. , Anthony Daniel C. , Probert Fay
Published: April 2023

AbstractPurpose:
Early diagnosis of cancer is critical for improving patient outcomes, but cancers may be hard to diagnose if patients present with nonspecific signs and symptoms. We have previously shown that nuclear magnetic resonance (NMR) metabolomics analysis can detect cancer in animal models and distinguish between differing metastatic disease burdens. Here, we hypothesized that biomarkers within the blood metabolome could identify cancers within a mixed population of patients referred from primary care with nonspecific symptoms, the so-called “low-risk, but not no-risk” patient group, as well as distinguishing between those with and without metastatic disease.
Experimental Design:
Patients (n = 304 comprising modeling, n = 192, and test, n = 92) were recruited from 2017 to 2018 from the Oxfordshire Suspected CANcer (SCAN) pathway, a multidisciplinary diagnostic center (MDC) referral pathway for patients with nonspecific signs and symptoms. Blood was collected and analyzed by NMR metabolomics. Orthogonal partial least squares discriminatory analysis (OPLS-DA) models separated patients, based upon diagnoses received from the MDC assessment, within 62 days of initial appointment.
Results:
Area under the ROC curve for identifying patients with solid tumors in the independent test set was 0.83 [95% confidence interval (CI): 0.72–0.95]. Maximum sensitivity and specificity were 94% (95% CI: 73–99) and 82% (95% CI: 75–87), respectively. We could also identify patients with metastatic disease in the cohort of patients with cancer with sensitivity and specificity of 94% (95% CI: 72–99) and 88% (95% CI: 53–98), respectively.
Conclusions:
For a mixed group of patients referred from primary care with nonspecific signs and symptoms, NMR-based metabolomics can assist their diagnosis, and may differentiate both those with malignancies and those with and without metastatic disease.

See related commentary by Van Tine and Lyssiotis, p. 1477
Data from Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer
Authors: Fasching Peter A. , Liu Duan , Scully Steve , Ingle James N. , Lyra Paulo C. , Rack Brigitte , Hein Alexander , Ekici Arif B. , Reis Andre , Schneeweiss Andreas , Tesch Hans , Fehm Tanja N. , Heinrich Georg , Beckmann Matthias W. , Ruebner Matthias , Huebner Hanna , Lambrechts Diether , Madden Ebony , Shen Jess , Romm Jane , Doheny Kim , Jenkins Gregory D. , Carlson Erin E. , Li Liang , Fridley Brooke L. , Cunningham Julie M. , Janni Wolfgang , Monteiro Alvaro N.A. , Schaid Daniel J. , Häberle Lothar , Weinshilboum Richard M. , Wang Liewei
Published: April 2023

AbstractPurpose:
To identify molecular predictors of grade 3/4 neutropenic or leukopenic events (NLE) after chemotherapy using a genome-wide association study (GWAS).
Experimental Design:
A GWAS was performed on patients in the phase III chemotherapy study SUCCESS-A (n = 3,322). Genotyping was done using the Illumina HumanOmniExpress-12v1 array. Findings were functionally validated with cell culture models and the genotypes and gene expression of possible causative genes were correlated with clinical treatment response and prognostic outcomes.
Results:
One locus on chromosome 16 (rs4784750; NLRC5; P = 1.56E-8) and another locus on chromosome 13 (rs16972207; TNFSF13B; P = 3.42E-8) were identified at a genome-wide significance level. Functional validation revealed that expression of these two genes is altered by genotype-dependent and chemotherapy-dependent activity of two transcription factors. Genotypes also showed an association with disease-free survival in patients with an NLE.
Conclusions:
Two loci in NLRC5 and TNFSF13B are associated with NLEs. The involvement of the MHC I regulator NLRC5 implies the possible involvement of immuno-oncological pathways.
Data from Systematic Evaluation of the Immune Environment of Small Intestinal Neuroendocrine Tumors
Authors: Vesely Clare , Wong Yien Ning Sophia , Childs Alexa , Akarca Ayse U. , Dhami Pawan , Vaikkinen Heli , Conde Lucia , Herrero Javier , Ogunbiyi Olagunju , Gander Amir , Luong Tu Vinh , Thirlwell Chrissie , Caplin Martyn , Toumpanakis Christos , Peggs Karl , Quezada Sergio A. , Marafioti Teresa , Meyer Tim
Published: April 2023

AbstractPurpose:
The immune tumor microenvironment and the potential therapeutic opportunities for immunotherapy in small intestinal neuroendocrine tumors (siNET) have not been fully defined.
Experimental Design:
Herein, we studied 40 patients with primary and synchronous metastatic siNETs, and matched blood and normal tissue obtained during surgery. We interrogated the immune checkpoint landscape using multi-parametric flow cytometry. In addition, matched FFPE tissue was obtained for multi-parametric IHC to determine the relative abundance and distribution of T-cell infiltrate. Tumor mutational burden (TMB) was also assessed and correlated with immune infiltration.
Results:
Effector tumor-infiltrating lymphocytes (TIL) had a higher expression of PD-1 in the tumor microenvironment compared with the periphery. In addition, CD8+ TILs had a significantly higher co-expression of PD-1/ICOS and PD-1/CTLA-4 (cytotoxic T lymphocyte antigen-4) and higher levels of PD-1 expression compared with normal tissue. IHC revealed that the majority of cases have ≤10% intra-tumoral T cells but a higher number of peri-tumoral T cells, demonstrating an “exclusion” phenotype. Finally, we confirmed that siNETs have a low TMB compared with other tumor types in the TCGA database but did not find a correlation between TMB and CD8/Treg ratio.
Conclusions:
Taken together, these results suggest that a combination therapy approach will be required to enhance the immune response, using PD-1 as a checkpoint immunomodulator backbone in combination with other checkpoint targeting molecules (CTLA-4 or ICOS), or with drugs targeting other pathways to recruit “excluded” T cells into the tumor microenvironment to treat patients with siNETs.
Data from Multiomic Characterization of High-Grade Serous Ovarian Carcinoma Enables High-Resolution Patient Stratification
Authors: Hollis Robert L. , Meynert Alison M. , Michie Caroline O. , Rye Tzyvia , Churchman Michael , Hallas-Potts Amelia , Croy Ian , McCluggage W. Glenn , Williams Alistair R.W. , Bartos Clare , Iida Yasushi , Okamoto Aikou , Dougherty Brian , Barrett J. Carl , March Ruth , Matakidou Athena , Roxburgh Patricia , Semple Colin A. , Harkin D. Paul , Kennedy Richard , Herrington C. Simon , Gourley Charlie
Published: April 2023

AbstractPurpose:
High-grade serous ovarian carcinoma (HGSOC) is the most common ovarian cancer type; most patients experience disease recurrence that accumulates chemoresistance, leading to treatment failure. Genomic and transcriptomic features have been associated with differential outcome and treatment response. However, the relationship between events at the gene sequence, copy number, and gene-expression levels remains poorly defined.
Experimental Design:
We perform multiomic characterization of a large HGSOC cohort (n = 362) with detailed clinical annotation to interrogate the relationship between patient subgroups defined by specific molecular events.
Results:
BRCA2-mutant (BRCA2m) and EMSY-overexpressing cases demonstrated prolonged survival [multivariable hazard ratios (HR) 0.40 and 0.51] and significantly higher first- and second-line chemotherapy response rate. CCNE1-gained (CCNE1g) cases demonstrated underrepresentation of FIGO stage IV cases, with shorter survival but no significant difference in treatment response. We demonstrate marked overlap between the TCGA- and Tothill-derived subtypes. IMR/C2 cases displayed higher BRCA1/2m frequency (25.5%, 32.5%) and significantly greater immune cell infiltration, whereas PRO/C5 cases had the highest CCNE1g rate (23.9%, 22.2%) and were uniformly low in immune cell infiltration. The survival benefit for cases with aberrations in homologous recombination repair (HRR) genes was apparent across all transcriptomic subtypes (HR range, 0.48–0.68). There was significant co-occurrence of RB loss and HRR gene aberrations; RB loss was further associated with favorable survival within HRR-aberrant cases (multivariable HR, 0.50).
Conclusions:
These data paint a high-resolution picture of the molecular landscape in HGSOC, better defining patients who may benefit most from specific molecular therapeutics and highlighting those for whom novel treatment strategies are needed to improve outcomes.
Data from Safety and Tolerability of MEDI0562, an OX40 Agonist mAb, in Combination with Durvalumab or Tremelimumab in Adult Patients with Advanced Solid Tumors
Authors: Goldman Jonathan W. , Piha-Paul Sarina A. , Curti Brendan , Pedersen Katrina S. , Bauer Todd M. , Groenland Stefanie L. , Carvajal Richard D. , Chhaya Vaishali , Kirby Gray , McGlinchey Kelly , Hammond Scott A. , Streicher Katie , Townsley Danielle M. , Chae Young Kwang , Voortman Jens , Marabelle Aurelien , Powderly John
Published: April 2023

AbstractPurpose:
Combination therapies targeting immunologic checkpoints have shown promise in treating multiple tumor types. We report safety and tolerability of MEDI0562, a humanized IgG1K OX40 mAb, in combination with durvalumab (anti-PD-L1), or tremelimumab (anti-CTLA-4), in adult patients with previously treated advanced solid tumors.
Patients and Methods:
In this phase I, multicenter, open-label study, patients received escalating doses of MEDI0562 (2.25, 7.5, or 22.5 mg) every 2 weeks in combination with durvalumab (1,500 mg) or tremelimumab (75 or 225 mg) every 4 weeks, intravenously, until unacceptable toxicity or progressive disease. Tumor assessments were performed every 8 weeks. The primary objective was to evaluate safety and tolerability.
Results:
Among the 27 and 31 patients who received MEDI0562 + durvalumab or MEDI0562 + tremelimumab, 74.1% and 67.7% reported a treatment-related adverse event (AE), and 22.2% and 19.4% experienced a treatment-emergent AE that led to discontinuation, respectively. The MTD of MEDI0562 + durvalumab was 7.5 mg MEDI0562 + 1,500 mg durvalumab; the maximum administered dose of MEDI0562 + tremelimumab was 22.5 mg MEDI0562 + 225 mg tremelimumab. Three patients in the MEDI0562 + durvalumab arm had a partial response. The mean percentage of Ki67+CD4+ and Ki67+CD8+ memory T cells increased by >100% following the first dose of MEDI0562 + durvalumab or tremelimumab in all dose cohorts. A decrease in OX40+FOXP3 regulatory T cells was observed in a subset of patients with available paired biopsies.
Conclusions:
Following dose escalation, moderate toxicity was observed in both treatment arms, with no clear efficacy signals demonstrated.
Data from Exploratory Study of NPC-0501 Trial: Optimal Cisplatin Dose of Concurrent and Induction/Adjuvant Chemotherapy for Locoregionally Advanced Nasopharyngeal Carcinoma
Authors: Ng Wai-Tong , Choi Cheuk-Wai , But Barton , Ngan Roger K.C. , Tung Stewart , Cheng Ashley C. , Kwong Dora L.W. , Lu Tai-Xiang , Chan Anthony T.C. , Yiu Harry , Lee Sarah , Wong Frank , Yuen Kam-Tong , Chappell Richard J. , Lee Anne W.M.
Published: April 2023

AbstractPurpose:
The current recommendation for patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is cisplatin-based induction chemotherapy (IC) or adjuvant chemotherapy (AC) plus concurrent chemoradiotherapy (CRT). However, data on the optimal platinum doses for each phase of combined regimens are lacking.
Experimental Design:
742 patients with NPC in the NPC-0501 trial treated with CRT plus IC/AC and irradiated with intensity-modulated radiotherapy (IMRT) were analyzed. The optimal platinum dose to achieve the best overall survival (OS) in the concurrent and induction/adjuvant phases was studied.
Results:
Evaluation of the whole series shows the optimal platinum dose was 160 mg/m2 in the concurrent and 260 mg/m2 in the induction/adjuvant phase. Repeating the analyses on 591 patients treated with cisplatin throughout (no replacement by carboplatin) confirmed the same results. The cohort with optimal platinum doses in both phases had better OS than the cohort suboptimal in both phases (stage III: 90% vs. 75%; stage IVA–B: 80% vs. 56%, at 5-year). Multivariable analyses confirmed optimal platinum doses in both phases versus suboptimal dose in each phase are significant independent factors for OS, with HR of 0.61 [95% confidence interval (CI), 0.41–0.91] and 0.67 (95% CI, 0.48–0.94), respectively. Treatment sequence was statistically insignificant after adjusting for platinum doses.
Conclusions:
Both concurrent and IC/AC are needed for locoregionally advanced NPC, even for patients irradiated by IMRT; the concurrent platinum dosage could be set at ≥160 mg/m2 when coupled with adequate induction/adjuvant dosage at ≥260 mg/m2 (or at least ≥240 mg/m2). To achieve these optimal dosages, IC-CRT at conventional fractionation is favored.
Data from A Phase Ib/II Study of the CDK4/6 Inhibitor Ribociclib in Combination with Docetaxel plus Prednisone in Metastatic Castration-Resistant Prostate Cancer
Authors: de Kouchkovsky Ivan , Rao Arpit , Carneiro Benedito A. , Zhang Li , Lewis Catriona , Phone Audrey , Small Eric J. , Friedlander Terence , Fong Lawrence , Paris Pamela L. , Ryan Charles J. , Szmulewitz Russell Z. , Aggarwal Rahul
Published: April 2023

AbstractPurpose:
Ribociclib, a CDK4/6 inhibitor, demonstrates preclinical antitumor activity in combination with taxanes. We evaluated the safety and efficacy of ribociclib plus docetaxel in a phase Ib/II study in metastatic castration-resistant prostate cancer (mCRPC).
Patients and Methods:
Patients had chemotherapy-naïve mCRPC with progression on ≥ 1 androgen receptor signaling inhibitor (ARSI). The phase II primary endpoint was 6-month radiographic progression-free survival (rPFS) rate, with an alternative hypothesis of 55% versus 35% historical control. Circulating tumor cells (CTC) were collected at baseline and genomically profiled.
Result:
Forty-three patients were enrolled (N = 30 in phase II). Two dose-limiting toxicities were observed (grade 4 neutropenia and febrile neutropenia). The recommended phase II dose (RP2D) and schedule was docetaxel 60 mg/m2 every 21 days plus ribociclib 400 mg/day on days 1–4 and 8–15 with filgrastim on days 5–7. At the RP2D, neutropenia was the most common grade ≥ 3 adverse event (37%); however, no cases of febrile neutropenia were observed. The primary endpoint was met; the 6-month rPFS rate was 65.8% [95% confidence interval (CI): 50.6%–85.5%; P = 0.005] and median rPFS was 8.1 months (95% CI, 6.0–10.0 months). Thirty-two percent of evaluable patients achieved a PSA50 response. Nonamplified MYC in baseline CTCs was associated with longer rPFS (P = 0.052).
Conclusions:
The combination of intermittent ribociclib plus every-3-weeks docetaxel demonstrated acceptable toxicity and encouraging efficacy in ARSI-pretreated mCRPC. Genomic profiling of CTCs may enrich for those most likely to derive benefit. Further evaluation in a randomized clinical trial is warranted.
Data from Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non–Small Cell Lung Cancer
Authors: Sabari Joshua K. , Velcheti Vamsidhar , Shimizu Kazuhide , Strickland Matthew R. , Heist Rebecca S. , Singh Mohini , Nayyar Naema , Giobbie-Hurder Anita , Digumarthy Subba R. , Gainor Justin F. , Rajan Anant P. , Nieblas-Bedolla Edwin , Burns Aaron C. , Hallin Jill , Olson Peter , Christensen James G. , Kurz Sylvia C. , Brastianos Priscilla K. , Wakimoto Hiroaki
Published: April 2023

AbstractPurpose:
Patients with KRAS-mutant non–small cell lung cancer (NSCLC) with brain metastases (BM) have a poor prognosis. Adagrasib (MRTX849), a potent oral small-molecule KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib has been optimized for favorable pharmacokinetic properties, including long half-life (∼24 hours), extensive tissue distribution, dose-dependent pharmacokinetics, and central nervous system penetration; however, BM-specific antitumor activity of KRASG12C inhibitors remains to be fully characterized.
Experimental Design:
A retrospective database query identified patients with KRAS-mutant NSCLC to understand their propensity to develop BM. Preclinical studies assessed physiochemical and pharmacokinetic properties of adagrasib. Mice bearing intracranial KRASG12C-mutant NSCLC xenografts (LU99-Luc/H23-Luc/LU65-Luc) were treated with clinically relevant adagrasib doses, and levels of adagrasib in plasma, cerebrospinal fluid (CSF), and brain were determined along with antitumor activity. Preliminary clinical data were collected from 2 patients with NSCLC with untreated BM who had received adagrasib 600 mg twice daily in the phase Ib cohort of the KRYSTAL-1 trial; CSF was collected, adagrasib concentrations measured, and antitumor activity in BM evaluated.
Results:
Patients with KRAS-mutant NSCLC demonstrated high propensity to develop BM (≥40%). Adagrasib penetrated into CSF and demonstrated tumor regression and extended survival in multiple preclinical BM models. In 2 patients with NSCLC and untreated BM, CSF concentrations of adagrasib measured above the target cellular IC50. Both patients demonstrated corresponding BM regression, supporting potential clinical activity of adagrasib in the brain.
Conclusions:
These data support further development of adagrasib in patients with KRASG12C-mutant NSCLC with untreated BM.

See related commentary by Kommalapati and Mansfield, p. 3179
Data from Single-Cell RNA Sequencing Unveils the Clonal and Transcriptional Landscape of Cutaneous T-Cell Lymphomas
Authors: Gaydosik Alyxzandria M. , Stonesifer Connor J. , Khaleel Alexandra E. , Geskin Larisa J. , Fuschiotti Patrizia
Published: April 2023

AbstractPurpose:
Clonal malignant T lymphocytes constitute only a fraction of T cells in mycosis fungoides skin tumors and in the leukemic blood of Sézary syndrome, the classic types of cutaneous T-cell lymphomas. However, lack of markers specific for malignant lymphocytes prevents distinguishing them from benign T cells, thus delaying diagnosis and the development of targeted treatments. Here we applied single-cell methods to assess the transcriptional profiles of both malignant T-cell clones and reactive T lymphocytes directly in mycosis fungoides/Sézary syndrome patient samples.
Experimental Design:
Single-cell RNA sequencing was used to profile the T-cell immune repertoire simultaneously with gene expression in CD3+ lymphocytes from mycosis fungoides and healthy skin biopsies as well as from Sézary syndrome and control blood samples. Transcriptional data were validated in additional advanced-stage mycosis fungoides/Sézary syndrome skin and blood samples by immunofluorescence microscopy.
Results:
Several nonoverlapping clonotypes are expanded in the skin and blood of individual advanced-stage mycosis fungoides/Sézary syndrome patient samples, including a dominant malignant clone as well as additional minor malignant and reactive clones. While we detected upregulation of patient-specific as well as mycosis fungoides– and Sézary syndrome–specific oncogenic pathways within individual malignant clones, we also detected upregulation of several common pathways that included genes associated with cancer cell metabolism, cell-cycle regulation, de novo nucleotide biosynthesis, and invasion.
Conclusions:
Our analysis unveils new insights into mycosis fungoides/Sézary syndrome pathogenesis by providing an unprecedented report of the transcriptional profile of malignant T-cell clones in the skin and blood of individual patients and offers novel prospective targets for personalized therapy.
Data from Cetuximab Responses in Patients with HNSCC Correlate to Clonal Expansion Feature of Peripheral and Tumor-Infiltrating T Cells with Top T-Cell Receptor Clonotypes
Authors: Ge Huaibin , Ferris Robert L. , Wang Jing H.
Published: April 2023

AbstractPurpose:
Cetuximab is a standard-of-care treatment for head and neck squamous cell carcinoma (HNSCC). Well-defined correlative markers of therapeutic responses are still lacking. Characterizing dynamic changes of T-cell receptor (TCR) repertoire in peripheral blood and tumor tissue may facilitate developing markers for cetuximab response in HNSCCs.
Experimental Design:
We analyzed high-throughput TCRβ sequencing data generated with ImmunoSEQ platform using peripheral blood mononuclear cells (PBMC) and tumor-infiltrating lymphocytes (TIL) from patients with HNSCC before and after cetuximab treatment (pre-/post-PBMC vs. pre-/post-TIL). Multiple analytic approaches were employed to normalize sequencing data.
Results:
Normalized TCR richness was significantly lower in post-TIL than pre-TIL, suggesting that cetuximab reduced TCR diversity and promoted TCR expansion in TIL samples, regardless of response status. The magnitude of clonal expansion (defined as expansion rate) in top 20 TCR clonotypes was significantly higher in responder PBMC with or without normalization, and in responder TIL upon normalization, than nonresponder ones. Notably, the expanded top 20 or top 50 TCR clonotypes overlapped between PBMC and TIL samples, which occurred significantly more frequently in responders than nonresponders.
Conclusions:
Patients with cetuximab-treated HNSCC harbor dynamic changes of TCR repertoires correlative to therapeutic responses. The expansion rate of top TCR clonotypes in peripheral blood may serve as a minimally invasive, readily accessible, and feasible marker for predicting cetuximab responses in HNSCCs and beyond, and the expansion rate of top TCR clonotypes in TILs and their overlapping probability between PBMC and TIL may serve as additional predictive markers. Our study also highlights the importance of data normalization for TCR repertoire analysis.
Data from A Phase I/II Trial of Nivolumab plus Ipilimumab in Children and Young Adults with Relapsed/Refractory Solid Tumors: A Children's Oncology Group Study ADVL1412
Authors: Davis Kara L. , Fox Elizabeth , Isikwei Emasenyie , Reid Joel M. , Liu Xiaowei , Minard Charles G. , Voss Stephan , Berg Stacey L. , Weigel Brenda J. , Mackall Crystal L.
Published: April 2023

AbstractPurpose:
In many cancers, nivolumab in combination with ipilimumab improves response rates compared with either agent alone, but the combination has not been evaluated in childhood cancer. We conducted a phase I/II trial of nivolumab plus ipilimumab in children and young adults with recurrent/refractory solid tumors.
Patients and Methods:
ADVL1412, Part C assessed safety of nivolumab plus ipilimumab at two dose levels (DL): DL1 1 mg/kg of each drug and DL2 3 mg/kg nivolumab plus 1 mg/kg ipilimumab. Part D evaluated response at the recommended phase II dose (RP2D) in Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Part E tested DL3 (1 mg/kg nivolumab plus 3 mg/kg ipilimumab) in Ewing sarcoma and rhabdomyosarcoma. Tumor response was measured using RECIST v1.1. Pharmacokinetics and PD-L1 expression on archival tissues were assessed.
Results:
Fifty-five eligible patients enrolled. Based on safety, tolerability, and similar drug exposure to the same doses administered in adults, DL2 was defined as the pediatric RP2D. Among 41 patients treated at the RP2D, 2 patients experienced dose-limiting toxicities during cycle 1, and 4 patients experienced toxicities beyond that period. Two patients had clinically significant sustained partial responses (1 rhabdomyosarcoma, 1 Ewing sarcoma) and 4 had stable disease. Among 8 patients treated at DL3, 3 dose-limiting toxicities (DLT) occurred, all immune-related adverse events; no objective responses were observed.
Conclusions:
The RP2D of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) is well tolerated in children and young adults with solid tumors and shows some clinical activity. Increased dose of ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) was associated with increased toxicity without clinical benefit.