bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Intratumoral Adaptive Immunosuppression and Type 17 Immunity in Mismatch Repair Proficient Colorectal Tumors
Authors: Llosa Nicolas J. , Luber Brandon , Tam Ada J. , Smith Kellie N. , Siegel Nicholas , Awan Anas H. , Fan Hongni , Oke Teniola , Zhang JiaJia , Domingue Jada , Engle Elizabeth L. , Roberts Charles A. , Bartlett Bjarne R. , Aulakh Laveet K. , Thompson Elizabeth D. , Taube Janis M. , Durham Jennifer N. , Sears Cynthia L. , Le Dung T. , Diaz Luis A. , Pardoll Drew M. , Wang Hao , Anders Robert A. , Housseau Franck
Published: April 2023

AbstractPurpose:
Approximately 10% of patients with mismatch repair–proficient (MMRp) colorectal cancer showed clinical benefit to anti-PD-1 monotherapy (NCT01876511). We sought to identify biomarkers that delineate patients with immunoreactive colorectal cancer and to explore new combinatorial immunotherapy strategies that can impact MMRp colorectal cancer.
Experimental Design:
We compared the expression of 44 selected immune-related genes in the primary colon tumor of 19 patients with metastatic colorectal cancer (mCRC) who responded (n = 13) versus those who did not (n = 6) to anti-PD-1 therapy (NCT01876511). We define a 10 gene–based immune signature that could distinguish responder from nonresponder. Resected colon specimens (n = 14) were used to validate the association of the predicted status (responder and nonresponder) with the immune-related gene expression, the phenotype, and the function of tumor-infiltrating lymphocytes freshly isolated from the same tumors.
Results:
Although both IL17Low and IL17High immunoreactive MMRp colorectal cancers are associated with intratumor correlates of adaptive immunosuppression (CD8/IFNγ and PD-L1/IDO1 colocalization), only IL17Low MMRp tumors (3/14) have a tumor immune microenvironment (TiME) that resembles the TiME in primary colon tumors of patients with mCRC responsive to anti-PD-1 treatment.
Conclusions:
The detection of a preexisting antitumor immune response in MMRp colorectal cancer (immunoreactive MMRp colorectal cancer) is not sufficient to predict a clinical benefit to T-cell checkpoint inhibitors. Intratumoral IL17-mediated signaling may preclude responses to immunotherapy. Drugs targeting the IL17 signaling pathway are available in clinic, and their combination with T-cell checkpoint inhibitors could improve colorectal cancer immunotherapy.

See related commentary by Willis et al., p. 5185
Data from A Phase I Dose-Escalation Study of Veliparib Combined with Carboplatin and Etoposide in Patients with Extensive-Stage Small Cell Lung Cancer and Other Solid Tumors
Authors: Atrafi Florence , Groen Harry J.M. , Byers Lauren A. , Garralda Elena , Lolkema Martijn P. , Sangha Randeep S. , Viteri Santiago , Chae Young Kwang , Camidge D. Ross , Gabrail Nashat Y. , Hu Beibei , Tian Tian , Nuthalapati Silpa , Hoening Elizabeth , He Lei , Komarnitsky Philip , Calles Antonio
Published: April 2023

AbstractPurpose:
This study examined safety, pharmacokinetics, and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) and other solid tumors.
Patients and Methods:
The 3 + 3 design was used for dose escalation of oral veliparib in combination with carboplatin (AUC 5 on day 1) and etoposide (100 mg/m2 on days 1–3) in 21-day cycles. Veliparib dose was explored from 80 to 240 mg b.i.d. on 7-day, 14-day, or continuous schedules. Patients without disease progression continued on maintenance monotherapy (veliparib 400 mg b.i.d.) until disease progression or unacceptable toxicity.
Results:
Thirty-nine patients were enrolled to determine the recommended phase II dose of 240 mg veliparib for 14 days combined with carboplatin and etoposide based on long-term tolerability. Dose-limiting toxicity occurred in 1 patient (grade 2 toxic motor polyneuropathy) at veliparib 240 mg b.i.d. for 7 days. Most common adverse events related to veliparib were nausea (39%), fatigue (39%), and hematologic toxicities. Continuous dosing of veliparib 240 mg b.i.d. with carboplatin and etoposide resulted in excessive chemotherapy dose delays due to hematologic toxicity (grade 3/4 neutropenia/thrombocytopenia). Etoposide pharmacokinetics was not affected by veliparib. Confirmed responses occurred in 17 of 39 (44%) and 16 of 25 (64%) of all enrolled and ED SCLC patients, respectively. At the RP2D, confirmed responses occurred in 6 of 13 (46%) and 5 of 6 (83%) of all enrolled and ED SCLC patients, respectively.
Conclusions:
Veliparib (240 mg b.i.d. 14 days) plus carboplatin/etoposide can be safely combined. Phase II of this study is ongoing in first-line patients with ED SCLC.
Data from GATA6 Expression Distinguishes Classical and Basal-like Subtypes in Advanced Pancreatic Cancer
Authors: O’Kane Grainne M. , Grünwald Barbara T. , Jang Gun-Ho , Masoomian Mehdi , Picardo Sarah , Grant Robert C. , Denroche Robert E. , Zhang Amy , Wang Yifan , Miller Jessica K. , Lam Bernard , Krzyzanowski Paul M. , Lungu Ilinca M. , Bartlett John M.S. , Peralta Melanie , Vyas Foram , Khokha Rama , Biagi James , Chadwick Dianne , Ramotar Stephanie , Hutchinson Shawn , Dodd Anna , Wilson Julie M. , Notta Faiyaz , Zogopoulos George , Gallinger Steven , Knox Jennifer J. , Fischer Sandra E.
Published: April 2023

AbstractPurpose:
To determine the impact of basal-like and classical subtypes in advanced pancreatic ductal adenocarcinoma (PDAC) and to explore GATA6 expression as a surrogate biomarker.
Experimental Design:
Within the COMPASS trial, patients proceeding to chemotherapy for advanced PDAC undergo tumor biopsy for RNA-sequencing (RNA-seq). Overall response rate (ORR) and overall survival (OS) were stratified by subtypes and according to chemotherapy received. Correlation of GATA6 with the subtypes using gene expression profiling, in situ hybridization (ISH) was explored.
Results:
Between December 2015 and May 2019, 195 patients (95%) had enough tissue for RNA-seq; 39 (20%) were classified as basal-like and 156 (80%) as classical. RECIST response data were available for 157 patients; 29 basal-like and 128 classical where the ORR was 10% versus 33%, respectively (P = 0.02). In patients with basal-like tumors treated with modified FOLFIRINOX (n = 22), the progression rate was 60% compared with 15% in classical PDAC (P = 0.0002). Median OS in the intention-to-treat population (n = 195) was 9.3 months for classical versus 5.9 months for basal-like PDAC (HR, 0.47; 95% confidence interval, 0.32–0.69; P = 0.0001). GATA6 expression by RNA-seq highly correlated with the classifier (P < 0.001) and ISH predicted the subtypes with sensitivity of 89% and specificity of 83%. In a multivariate analysis, GATA6 expression was prognostic (P = 0.02). In exploratory analyses, basal-like tumors, could be identified by keratin 5, were more hypoxic and enriched for a T-cell–inflamed gene expression signature.
Conclusions:
The basal-like subtype is chemoresistant and can be distinguished from classical PDAC by GATA6 expression.

See related commentary by Collisson, p. 4715
Data from The Impact of Molecular Subtype on Efficacy of Chemotherapy and Checkpoint Inhibition in Advanced Gastric Cancer
Authors: Kubota Yohei , Kawazoe Akihito , Sasaki Akinori , Mishima Saori , Sawada Kentaro , Nakamura Yoshiaki , Kotani Daisuke , Kuboki Yasutoshi , Taniguchi Hiroya , Kojima Takashi , Doi Toshihiko , Yoshino Takayuki , Ishii Genichiro , Kuwata Takeshi , Shitara Kohei
Published: April 2023

AbstractPurpose:
We evaluated the association between molecular subtypes of advanced gastric cancer (AGC) and the efficacy of standard chemotherapy or immune checkpoint inhibitors.
Experimental Design:
Patients with AGC who received systemic chemotherapy from October 2015 to July 2018 with available molecular features were analyzed. We investigated the efficacy of standard first- (fluoropyrimidine + platinum ± trastuzumab) and second-line (taxanes ± ramucirumab) chemotherapy, and subsequent anti–PD-1 therapy in patients with four molecular subtypes: MMR-D (mismatch repair deficient), EBV+, HER2+, and all negative.
Results:
410 patients were analyzed: MMR-D 5.9%, EBV+ 4.1%, HER2+ 13.7%, and all negative 76.3%. In 285 patients who received standard first-line chemotherapy, the median progression-free survival (PFS) times were 4.2, 6.0, 7.5, and 7.6 months and the objective response rates (ORR) were 31%, 62%, 60%, and 49% in MMR-D, EBV+, HER2+, and all-negative subtypes, respectively. Multivariate analysis showed shorter PFS in MMR-D versus all-negative patients [HR, 1.97; 95% CIs, 1.09–3.53; P = 0.022]. In second-line setting, there were no significant differences in efficacy. In 110 patients who received anti–PD-1 therapy, median PFS times were 13.0, 3.7, 1.6, and 1.9 months and the ORRs were 58%, 33%, 7%, and 13%, respectively. Twelve patients with MMR-D received subsequent anti–PD-1 therapy and showed longer PFS compared with that in 10 (83%) patients who received earlier-line chemotherapy.
Conclusions:
MMR-D might result in shorter PFS with first-line chemotherapy for AGC. Subsequent anti–PD-1 therapy achieved higher ORR and longer PFS than prior chemotherapy in most patients with MMR-D, supporting the earlier use of immune checkpoint inhibitors.
Data from The Influence of Immune Heterogeneity on the Effectiveness of Immune Checkpoint Inhibitors in Multifocal Hepatocellular Carcinomas
Authors: Huang Manling , He Minghui , Guo Yu , Li Heping , Shen Shunli , Xie Yubin , Li Xiaoxing , Xiao Han , Fang Lujing , Li Dongming , Peng Baogang , Liang Lijian , Yu Jun , Kuang Ming , Xu Lixia , Peng Sui
Published: April 2023

AbstractPurpose:
Immune checkpoint inhibitor therapy is emerging as the promising option for patients with advanced hepatocellular carcinoma. We aimed to investigate the heterogeneity of different tumor nodules of the same patient with multifocal hepatocellular carcinomas in response to immunotherapy and its molecular mechanisms.
Experimental Design:
We attained 45 surgical tumor samples including 33 small and 12 large nodules from 12 patients with multifocal hepatocellular carcinoma and evaluated genomic and immune heterogeneity among tumors through whole-genome sequencing and RNA sequencing. IHC was performed to validate the expression of immune markers. The responses to anti–programmed cell death protein-1 (PD-1) therapy in patients with multifocal hepatocellular carcinoma were evaluated.
Results:
The small and large tumors within the same patient presented with similar genomic characteristics, indicating their same genomic origin. We further found the small tumors had higher immune cell infiltration including more CD8+ T cells, M1 macrophages, and monocytes as compared with large tumors. Besides, the expression of interferon signature predictive of response to anti–PD-1 therapy was significantly upregulated in the small tumors. Moreover, the immune pathways were more vigorous along with less active proliferation pathways in the small tumors. In keeping with this, we found that small nodules were more sensitive to anti–PD-1 therapy than large nodules in patients with multifocal hepatocellular carcinoma.
Conclusions:
The small tumors in patients with multifocal hepatocellular carcinoma had higher immune cell infiltration and upregulation of immune pathways as compared with the large tumors, which can partially explain the different responses of small and large tumors in the same case to anti–PD-1 therapy.
Data from Angiogenic and Immune-Related Biomarkers and Outcomes Following Axitinib/Pembrolizumab Treatment in Patients with Advanced Renal Cell Carcinoma
Authors: Martini Jean-François , Plimack Elizabeth R. , Choueiri Toni K. , McDermott David F. , Puzanov Igor , Fishman Mayer N. , Cho Daniel C. , Vaishampayan Ulka , Rosbrook Bradley , Fernandez Kathrine C. , Tarazi Jamal C. , George Saby , Atkins Michael B.
Published: April 2023

AbstractPurpose:
Combined axitinib/pembrolizumab is approved for advanced renal cell carcinoma (aRCC). This exploratory analysis examined associations between angiogenic and immune-related biomarkers and outcomes following axitinib/pembrolizumab treatment.
Patients and Methods:
Prospectively defined retrospective correlative exploratory analyses tested biospecimens from 52 treatment-naïve patients receiving axitinib and pembrolizumab (starting doses 5 mg twice daily and 2 mg/kg respectively, every 3 weeks). Tumor tissue, serum, and whole blood samples were collected at baseline, at cycle 2 day 1 (C2D1), and end of treatment (EOT) for blood-based samples. Clinical outcomes were objective response rate (ORR) and progression-free survival (PFS).
Results:
Higher baseline tumor levels of CD8 showed a trend toward longer PFS (HR 0.4; P = 0.091). Higher baseline serum levels of CXCL10 (P = 0.0197) and CEACAM1 (P = 0.085) showed a trend toward better ORR and longer PFS, respectively. Patients for whom IL6 was not detected at baseline had longer PFS versus patients for whom it was detected (HR 0.4; P = 0.028). At C2D1 and/or EOT, mainly immune-related biomarkers showed any association with better outcomes. The genes CA9 (P = 0.084), HIF1A (P = 0.064), and IFNG (P = 0.073) showed trending associations with ORR, and AKT3 (P = 0.0145), DDX58 (P = 0.0726), GZMA (P = 0.0666), LCN2 (NGAL; P = 0.0267), and PTPN11 (P = 0.0287) with PFS.
Conclusions:
With combined axitinib/pembrolizumab treatment in patients with aRCC, mostly immune-related biomarkers are associated with better treatment outcomes. This exploratory analysis has identified some candidate biomarkers to consider in future prospective testing.
Data from A Phase Ib/II Study of the BRAF Inhibitor Encorafenib Plus the MEK Inhibitor Binimetinib in Patients with BRAFV600E/K-mutant Solid Tumors
Authors: Sullivan Ryan J. , Weber Jeffrey , Patel Sapna , Dummer Reinhard , Carlino Matteo S. , Tan Daniel S.W. , Lebbé Celeste , Siena Salvatore , Elez Elena , Wollenberg Lance , Pickard Michael D. , Sandor Victor , Ascierto Paolo A.
Published: April 2023

AbstractPurpose:
This open-label, dose-finding phase Ib/II study reports the safety and activity of the first combination use with BRAF inhibitor (BRAFi) encorafenib plus MEK inhibitor (MEKi) binimetinib in patients with BRAF V600E–mutant solid tumors.
Patients and Methods:
In phase I, the recommended phase 2 doses (RP2D) were established (primary objective). In phase II, the clinical activity of the combination at the RP2D was assessed (primary objective) in patients with BRAF-mutant metastatic colorectal cancer (mCRC), BRAFi-treated BRAF-mutant melanoma, and BRAFi-naïve BRAF-mutant melanoma.
Results:
A total of 126 patients with BRAF-mutant solid tumors were enrolled (phase I: 47 patients; phase II: 79 patients). The RP2D was encorafenib 450 mg once daily plus binimetinib 45 mg twice daily and pharmacokinetic data suggest that drug exposures of each agent were similar in combination compared with single-agent studies. In the phase II cohorts, confirmed responses were seen in two of 11 (18%) evaluable patients with mCRC, 11 of 26 (42%) evaluable patients with BRAFi-pretreated melanoma, and 28 of 42 (67%) BRAFi-naïve patients with melanoma. The most common grade 3/4 adverse event in phase II was increased alanine aminotransferase.
Conclusions:
The combination of encorafenib (450 mg) plus binimetinib (45 mg) showed acceptable tolerability and encouraging activity in patients with BRAF V600–mutant tumors, which led to the dose selection for the melanoma COLUMBUS study. The safety profile of the combination was consistent with other approved BRAFi plus MEKi regimens, with several differences, including lower rates of dose-limiting pyrexia, arthralgia, and photosensitivity.
Data from Tislelizumab Plus Chemotherapy as First-line Treatment for Advanced Esophageal Squamous Cell Carcinoma and Gastric/Gastroesophageal Junction Adenocarcinoma
Authors: Xu Jianming , Bai Yuxian , Xu Nong , Li Enxiao , Wang Buhai , Wang Jin , Li Xiang , Wang Xin , Yuan Xianglin
Published: April 2023

AbstractPurpose:
This phase II study (NCT03469557) assessed safety/tolerability and antitumor activity of first-line tislelizumab, a monoclonal antibody against programmed cell death-1, plus chemotherapy in patients with locally advanced/metastatic esophageal squamous cell carcinoma (ESCC) or gastric/gastroesophageal junction (G/GEJ) adenocarcinoma.
Patients and Methods:
Patients with ESCC received tislelizumab [200 mg i.v. every 3 weeks (Q3W)] plus cisplatin (80 mg/m² i.v. Q3W for ≤6 cycles) and fluorouracil (800 mg/m²/day i.v., Days 1–5 Q3W for ≤6 cycles); patients with G/GEJ adenocarcinoma received tislelizumab (200 mg i.v. Q3W) plus oxaliplatin (130 mg/m² i.v. Q3W for up to six cycles) and oral capecitabine (1,000 mg/m² twice daily, Days 1–14 Q3W). The safety/tolerability profile of combination therapy was the primary endpoint; secondary endpoints included objective response rate (ORR), duration of response (DoR), disease control rate (DCR), and progression-free survival per RECIST v1.1. Exploratory endpoints included overall survival and potential predictive biomarkers.
Results:
As of March 31, 2019, 30 patients (n = 15 per cohort) were enrolled. Most common adverse events considered related to tislelizumab and/or chemotherapy were anemia (n = 18), decreased appetite (n = 17), nausea (n = 16), and asthenia (n = 15). One patient experienced fatal hepatic dysfunction, confounded by progressive disease and underlying hepatitis, attributed to treatment by the investigator. Confirmed ORRs and DCRs were 46.7% and 80%, respectively, for both ESCC and G/GEJ adenocarcinoma. In ESCC, median DoR was 12.8 months (95% confidence interval, 3.5–12.8); DoR was not yet mature for the G/GEJ cohort.
Conclusions:
Tislelizumab plus chemotherapy demonstrated durable responses with manageable tolerability in patients with advanced ESCC or G/GEJ adenocarcinoma.
Data from A Phase II Study of Cabozantinib and Androgen Ablation in Patients with Hormone-Naïve Metastatic Prostate Cancer
Authors: Corn Paul G. , Zhang Miao , Nogueras-Gonzalez Graciela M. , Xiao Lianchun , Zurita Amado J. , Subudhi Sumit K. , Tu Shi-Ming , Aparicio Ana M. , Coarfa Cristian , Rajapakshe Kimal , Huang Shixia , Navone Nora M. , Lin Sue-Hwa , Wang Guocan , Ramachandran Sumankalai , Titus Mark A. , Panaretakis Theocharis , Gallick Gary E. , Efstathiou Eleni , Troncoso Patricia , Logothetis Christopher
Published: April 2023

AbstractPurpose:
Cabozantinib, an oral inhibitor of c-MET/VEGFR2 signaling, improved progression-free survival (mPFS) but not overall survival (OS) in metastatic castrate-resistant prostate cancer. We evaluated cabozantinib plus androgen deprivation therapy (ADT) in hormone-naïve metastatic prostate cancer (HNMPCa).
Patients and Methods:
Patients received ADT plus cabozantinib starting at 60 mg daily. The primary endpoint was castrate-resistant PFS by radiographic criteria, clinical progression, or receipt of additional therapy. Secondary endpoints included OS, safety, radiographic responses, and biomarker modulation.
Results:
Sixty-two patients received treatment. With a median follow-up of 31.2 months, the mPFS was 16.1 months (95% CI, 14.6–22.7 months), and mOS was not reached. Reductions in PSA ≥ 90%, bone-specific alkaline phosphatase ≥ 50%, and urine N-telopeptides ≥ 50% occurred in 83%, 87%, and 86% of evaluable patients, respectively. Responses in bone scan and measurable disease were observed in 81% of and 90% of evaluable patients, respectively. Most common grade 3 adverse events were hypertension (19%), diarrhea (6%), and thromboembolic events (6%), and dose reductions occurred in 85% of patients. Analysis of baseline cytokine and angiogenic factors (CAFs) revealed that higher plasma concentrations of Lumican, CXCL5, CD25, and CD30 were associated with shorter PFS as was high tumor expression of pFGFR1.
Conclusions:
Cabozantinib plus ADT has promising clinical activity in HNMPCa. CAF profiles and tissue markers suggest candidate prognostic and predictive markers of cabozantinib benefit and provide insights for rational therapy combinations.
Data from TSPO-targeted PET and Optical Probes for the Detection and Localization of Premalignant and Malignant Pancreatic Lesions
Authors: Cohen Allison S. , Li Jun , Hight Matthew R. , McKinley Eliot , Fu Allie , Payne Adria , Liu Yang , Zhang Dawei , Xie Qing , Bai Mingfeng , Ayers Gregory D. , Tantawy Mohammed Noor , Smith Jarrod A. , Revetta Frank , Washington M. Kay , Shi Chanjuan , Merchant Nipun , Manning H. Charles
Published: April 2023

AbstractPurpose:
Pancreatic cancer is among the most aggressive malignancies and is rarely discovered early. However, pancreatic “incidentalomas,” particularly cysts, are frequently identified in asymptomatic patients through anatomic imaging for unrelated causes. Accurate determination of the malignant potential of cystic lesions could lead to life-saving surgery or spare patients with indolent disease undue risk. Current risk assessment of pancreatic cysts requires invasive sampling, with attendant morbidity and sampling errors. Here, we sought to identify imaging biomarkers of high-risk pancreatic cancer precursor lesions.
Experimental Design:
Translocator protein (TSPO) expression, which is associated with cholesterol metabolism, was evaluated in premalignant and pancreatic cancer lesions from human and genetically engineered mouse (GEM) tissues. In vivo imaging was performed with [18F]V-1008, a TSPO-targeted PET agent, in two GEM models. For image-guided surgery (IGS), V-1520, a TSPO ligand for near-IR optical imaging based upon the V-1008 pharmacophore, was developed and evaluated.
Results:
TSPO was highly expressed in human and murine pancreatic cancer. Notably, TSPO expression was associated with high-grade, premalignant intraductal papillary mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasia (PanIN) lesions. In GEM models, [18F]V-1008 exhibited robust uptake in early pancreatic cancer, detectable by PET. Furthermore, V-1520 localized to premalignant pancreatic lesions and advanced tumors enabling real-time IGS.
Conclusions:
We anticipate that combined TSPO PET/IGS represents a translational approach for precision pancreatic cancer care through discrimination of high-risk indeterminate lesions and actionable surgery.
Data from Functional Genetic Screening Enables Theranostic Molecular Imaging in Cancer
Authors: Perkons Nicholas R. , Johnson Omar , Pilla Gabrielle , Profka Enri , Mercadante Michael , Ackerman Daniel , Gade Terence P.F.
Published: April 2023

AbstractPurpose:
Targeted therapies for cancer have accelerated the need for functional imaging strategies that inform therapeutic efficacy. This study assesses the potential of functional genetic screening to integrate therapeutic target identification with imaging probe selection through a proof-of-principle characterization of a therapy–probe pair using dynamic nuclear polarization (DNP)-enhanced magnetic resonance spectroscopic imaging (MRSI).
Experimental Design:
CRISPR-negative selection screens from a public dataset were used to identify the relative dependence of 625 cancer cell lines on 18,333 genes. Follow-up screening was performed in hepatocellular carcinoma with a focused CRISPR library targeting imaging-related genes. Hyperpolarized [1-13C]-pyruvate was injected before and after lactate dehydrogenase inhibitor (LDHi) administration in male Wistar rats with autochthonous hepatocellular carcinoma. MRSI evaluated intratumoral pyruvate metabolism, while T2-weighted segmentations quantified tumor growth.
Results:
Genetic screening data identified differential metabolic vulnerabilities in 17 unique cancer types that could be imaged with existing probes. Among these, hepatocellular carcinoma required lactate dehydrogenase (LDH) for growth more than the 29 other cancer types in this database. LDH inhibition led to a decrease in lactate generation (P < 0.001) and precipitated dose-dependent growth inhibition (P < 0.01 overall, P < 0.05 for dose dependence). Intratumoral alanine production after inhibition predicted the degree of growth reduction (P < 0.001).
Conclusions:
These findings demonstrate that DNP-MRSI of LDH activity using hyperpolarized [1-13C]-pyruvate is a theranostic strategy for hepatocellular carcinoma, enabling quantification of intratumoral LDHi pharmacodynamics and therapeutic efficacy prediction. This work lays the foundation for a novel theranostic platform wherein functional genetic screening informs imaging probe selection to quantify therapeutic efficacy on a cancer-by-cancer basis.
Data from Treatment of Patients with Relapsed or Refractory Mantle–Cell Lymphoma with Zanubrutinib, a Selective Inhibitor of Bruton's Tyrosine Kinase
Authors: Song Yuqin , Zhou Keshu , Zou Dehui , Zhou Jianfeng , Hu Jianda , Yang Haiyan , Zhang Huilai , Ji Jie , Xu Wei , Jin Jie , Lv Fangfang , Feng Ru , Gao Sujun , Guo Haiyi , Zhou Lei , Elstrom Rebecca , Huang Jane , Novotny William , Wei Rachel , Zhu Jun
Published: April 2023

AbstractPurpose:
Mantle-cell lymphoma (MCL) is an incurable mature B-cell neoplasm with high initial response rates followed almost invariably by relapse. Prognosis for patients following relapse is poor, and treatment choices are limited. We evaluated the efficacy and safety of zanubrutinib, an investigational selective Bruton's tyrosine kinase (BTK) inhibitor.
Patients and Methods:
Patients with relapsed/refractory MCL were enrolled in this ongoing phase II, single-arm, open-label study, and treated with oral zanubrutinib 160 mg twice daily. The primary endpoint is overall response rate (ORR) assessed by an independent review committee (per Lugano 2014 classification); secondary endpoints include duration of response (DOR), time to response, progression-free survival (PFS), and safety.
Results:
Eighty-six patients (median age, 60.5 years) were enrolled after a median of 2 prior lines of therapy, received ≥1 dose of the study drug, and were evaluable for safety and efficacy. After a median follow-up of 18.4 months, 72 (84%) patients achieved an objective response, with 59 (68.6%) achieving a complete response (CR). Median DOR and PFS were 19.5 and 22.1 months, respectively; 12-month event-free estimates for DOR and PFS are 78% and 76%, respectively. Most common grade ≥3 adverse events (AE) were neutropenia (19.8%) and lung infection/pneumonia (9.3%). Three patients experienced major bleeding events, and there were no reports of atrial fibrillation. Eight (9.3%) patients discontinued zanubrutinib for AEs.
Conclusions:
These results demonstrate high and durable ORR and CR rates in patients with relapsed/refractory MCL. Zanubrutinib was generally well tolerated; grade ≥3 BTK inhibitor-associated toxicities (hemorrhage, rash, hypertension, diarrhea, atrial fibrillation) were uncommon.
Data from A Serum Protein Classifier Identifying Patients with Advanced Non–Small Cell Lung Cancer Who Derive Clinical Benefit from Treatment with Immune Checkpoint Inhibitors
Authors: Muller Mirte , Hummelink Karlijn , Hurkmans Daan P. , Niemeijer Anna-Larissa N. , Monkhorst Kim , Roder Joanna , Oliveira Carlos , Roder Heinrich , Aerts Joachim G. , Smit Egbert F.
Published: April 2023

AbstractPurpose:
Pretreatment selection of patients with non–small cell lung cancer (NSCLC) who would derive clinical benefit from treatment with immune checkpoint inhibitors (CPIs) would fulfill an unmet clinical need by reducing unnecessary toxicities from treatment and result in substantial health care savings.
Experimental Design:
In a retrospective study, mass spectrometry (MS)-based proteomic analysis was performed on pretreatment sera derived from patients with advanced NSCLC treated with nivolumab as part of routine clinical care (n = 289). Machine learning combined spectral and clinical data to stratify patients into three groups with good (“sensitive”), intermediate, and poor (“resistant”) outcomes following treatment in the second-line setting. The test was applied to three independent patient cohorts and its biology was investigated using protein set enrichment analyses (PSEA).
Results:
A signature consisting of 274 MS features derived from a development set of 116 patients was associated with progression-free survival (PFS) and overall survival (OS) across two validation cohorts (N = 98 and N = 75). In pooled analysis, significantly better OS was demonstrated for “sensitive” relative to “not sensitive” patients treated with nivolumab; HR, 0.58 (95% confidence interval, 0.38–0–87; P = 0.009). There was no significant association with clinical factors including PD-L1 expression, available from 133 of 289 patients. The test demonstrated no significant association with PFS or OS in a historical cohort (n = 68) of second-line NSCLC patients treated with docetaxel. PSEA revealed proteomic classification to be significantly associated with complement and wound-healing cascades.
Conclusions:
This serum-derived protein signature successfully stratified outcomes in cohorts of patients with advanced NSCLC treated with second-line PD-1 CPIs and deserves further prospective study.
Data from Prospective Evaluation of Bone Metabolic Markers as Surrogate Markers of Response to Radium-223 Therapy in Metastatic Castration-resistant Prostate Cancer
Authors: Agarwal Neeraj , Nussenzveig Roberto , Hahn Andrew W. , Hoffman John M. , Morton Kathryn , Gupta Sumati , Batten Julia , Thorley Jared , Hawks Josiah , Santos Victor Sacristan , Nachaegari Gayatri , Wang Xuechen , Boucher Kenneth , Haaland Benjamin , Maughan Benjamin L.
Published: April 2023

AbstractPurpose:
Radium-223 is approved for metastatic castration-resistant prostate cancer (mCRPC) based on improved overall survival, and delay in skeletal related events. However, it is not associated with PSA or radiographic response, which poses a challenge in real-time assessment of its efficacy. Surrogate markers of treatment outcomes may facilitate tailoring treatment duration with radium-223, by limiting the duration of therapy with radium-223 in these patients. Here, we sought to investigate the utility of bone metabolic markers (BMMs) as surrogate markers of response to radium-223 in mCRPC.
Patients and Methods:
A prospective phase II trial of radium-223 plus enzalutamide (RE) versus enzalutamide alone was designed to assess surrogacy of BMMs with respect to response to radium-223. Enzalutamide was used as a comparator in lieu of placebo due to the progressive disease. Co-primary endpoints were relative change in serum BMM N-telopeptide (NTP) levels from baseline to 6 months between the two arms and safety and feasibility of the combination.
Results:
Thirty-nine men were randomized to RE (n = 27) or enzalutamide (n = 12). Combination was safe and feasible. Primary endpoint was met. A statistically significant relative change to NTP ratios between arms (0.64, 95% confidence interval, 0.51–0.81; P = 0.00048) favored RE versus enzalutamide. Overall, BMMs decreased with the RE therapy compared with enzalutamide. Improved PSA response rate in RE versus enzalutamide (P = 0.024), correlated with decline in BMMs.
Conclusions:
BMMs declined significantly with combination therapy, and were associated with improved outcomes. Upon external validation, BMMs may emerge as surrogate markers to monitor treatment with radium-223 in real-time.
Data from Romidepsin Plus Liposomal Doxorubicin Is Safe and Effective in Patients with Relapsed or Refractory T-Cell Lymphoma: Results of a Phase I Dose-Escalation Study
Authors: Vu Khoan , Wu Chi-Heng , Yang Chen-Yen , Zhan Aaron , Cavallone Erika , Berry Wade , Heeter Pamela , Pincus Laura , Wieduwilt Matthew J. , William Basem M. , Andreadis Charalambos , Kaplan Lawrence K. , McCormick Frank , Porcu Pierluigi , Brammer Jonathan E. , Ai Weiyun Z.
Published: April 2023

AbstractPurpose:
The histone deacetylase (HDAC) inhibitor romidepsin and the anthracycline liposomal doxorubicin (LD) have modest single-agent activity in cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). We investigated the safety and efficacy of the combination of these two agents in CTCL and PTCL.
Patients and Methods:
Using CTCL cell lines and primary CTCL tumor cells, we demonstrated synergistic antitumor activity with romidepsin plus doxorubicin. We then conducted a phase I dose-escalation study of the romidepsin/LD combination in relapsed/refractory CTCL and PTCL. The primary objective was to determine the MTD of romidepsin in combination with LD at 20 mg/m2 i.v., once every 28 days.
Results:
Eleven patients with CTCL and 12 patients with PTCL were treated. The MTD of romidepsin was determined to be 12 mg/m2. Grade 3/4 hematologic toxicities included thrombocytopenia (17%), anemia (13%), and neutropenia (9%). The most frequent treatment-related nonhematologic adverse events were fatigue (48%), nausea (48%), vomiting (35%), and anorexia (30%). Among 21 evaluable patients, the overall response rate was 70% [1 complete response (CR), 6 partial responses (PR)] in CTCL and 27% (3 CR, 0 PR) in PTCL. Of the patients with CTCL, 8 of 10 had skin response, including 6 patients (60%) achieving skin involvement less than 10% of their body surface area at time of best response.
Conclusions:
Romidepsin plus LD demonstrated an acceptable safety profile and promising clinical efficacy with deep skin responses in relapsed/refractory CTCL. Thus, this combination could be considered as a bridge to skin-directed treatment or allogeneic hematopoietic cell transplantation in patients with aggressive CTCL.
Data from CD8+ T-cell–Mediated Immunoediting Influences Genomic Evolution and Immune Evasion in Murine Gliomas
Authors: Kane Joshua R. , Zhao Junfei , Tsujiuchi Takashi , Laffleur Brice , Arrieta Víctor A. , Mahajan Aayushi , Rao Ganesh , Mela Angeliki , Dmello Crismita , Chen Li , Zhang Daniel Y. , González-Buendia Edgar , Lee-Chang Catalina , Xiao Ting , Rothschild Gerson , Basu Uttiya , Horbinski Craig , Lesniak Maciej S. , Heimberger Amy B. , Rabadan Raul , Canoll Peter , Sonabend Adam M.
Published: April 2023

AbstractPurpose:
Cancer immunoediting shapes tumor progression by the selection of tumor cell variants that can evade immune recognition. Given the immune evasion and intratumor heterogeneity characteristic of gliomas, we hypothesized that CD8+ T cells mediate immunoediting in these tumors.
Experimental Design:
We developed retrovirus-induced PDGF+Pten−/− murine gliomas and evaluated glioma progression and tumor immunogenicity in the absence of CD8+ T cells by depleting this immune cell population. Furthermore, we characterized the genomic alterations present in gliomas that developed in the presence and absence of CD8+ T cells.
Results:
Upon transplantation, gliomas that developed in the absence of CD8+ T cells engrafted poorly in recipients with intact immunity but engrafted well in those with CD8+ T-cell depletion. In contrast, gliomas that developed under pressure from CD8+ T cells were able to fully engraft in both CD8+ T-cell–depleted mice and immunocompetent mice. Remarkably, gliomas developed in the absence of CD8+ T cells exhibited increased aneuploidy, MAPK pathway signaling, gene fusions, and macrophage/microglial infiltration, and showed a proinflammatory phenotype. MAPK activation correlated with macrophage/microglia recruitment in this model and in the human disease.
Conclusions:
Our studies indicate that, in these tumor models, CD8+ T cells influence glioma oncogenic pathways, tumor genotype, and immunogenicity. This suggests immunoediting of immunogenic tumor clones through their negative selection by CD8+ T cells during glioma formation.
Data from Genome Instability Profiles Predict Disease Outcome in a Cohort of 4,003 Patients with Breast Cancer
Authors: Lischka Annette , Doberstein Natalie , Freitag-Wolf Sandra , Koçak Ayla , Gemoll Timo , Heselmeyer-Haddad Kerstin , Ried Thomas , Auer Gert , Habermann Jens K.
Published: April 2023

AbstractPurpose:
The choice of therapy for patients with breast cancer is often based on clinicopathologic parameters, hormone receptor status, and HER2 amplification. To improve individual prognostication and tailored treatment decisions, we combined clinicopathologic prognostic data with genome instabilty profiles established by quantitative measurements of the DNA content.
Experimental Design:
We retrospectively assessed clinical data of 4,003 patients with breast cancer with a minimum postoperative follow-up period of 10 years. For the entire cohort, we established genome instability profiles. We applied statistical methods, including correlation matrices, Kaplan–Meier curves, and multivariable Cox proportional hazard models, to ascertain the potential of standard clinicopathologic data and genome instability profiles as independent predictors of disease-specific survival in distinct subgroups, defined clinically or with respect to treatment.
Results:
In Cox regression analyses, two parameters of the genome instability profiles, the S-phase fraction and the stemline scatter index, emerged as independent predictors in premenopausal women, outperforming all clinicopathologic parameters. In postmenopausal women, age and hormone receptor status were the predominant prognostic factors. However, by including S-phase fraction and 2.5c exceeding rate, we could improve disease outcome prediction in pT1 tumors irrespective of the lymph node status. In pT3-pT4 tumors, a higher S-phase fraction led to poorer prognosis. In patients who received adjuvant endocrine therapy, chemotherapy or radiotherapy, or a combination, the ploidy profiles improved prognostication.
Conclusions:
Genome instability profiles predict disease outcome in patients with breast cancer independent of clinicopathologic parameters. This applies especially to premenopausal patients. In patients receiving adjuvant therapy, the profiles improve identification of high-risk patients.
Data from Itacitinib (INCB039110), a JAK1 Inhibitor, Reduces Cytokines Associated with Cytokine Release Syndrome Induced by CAR T-cell Therapy
Authors: Huarte Eduardo , O'Connor Roddy S. , Peel Michael T. , Nunez-Cruz Selene , Leferovich John , Juvekar Ashish , Yang Yan-ou , Truong Lisa , Huang Taisheng , Naim Ahmad , Milone Michael C. , Smith Paul A.
Published: April 2023

AbstractPurpose:
T cells engineered to express a chimeric antigen receptor (CAR) are a promising cancer immunotherapy. Such targeted therapies have shown long-term relapse-free survival in patients with B-cell leukemia and lymphoma. However, cytokine release syndrome (CRS) represents a serious, potentially life-threatening side effect often associated with CAR T-cell therapy. CRS manifests as a rapid (hyper)immune reaction driven by excessive inflammatory cytokine release, including IFNγ and IL6.
Experimental Design:
Many cytokines implicated in CRS are known to signal through the JAK-STAT pathway. Here we study the effect of blocking JAK pathway signaling on CAR T-cell proliferation, antitumor activity, and cytokine levels in in vitro and in vivo models.
Results:
We report that itacitinib, a potent, selective JAK1 inhibitor, was able to significantly and dose-dependently reduce levels of multiple cytokines implicated in CRS in several in vitro and in vivo models. Importantly, we also report that at clinically relevant doses that mimic human JAK1 pharmacologic inhibition, itacitinib did not significantly inhibit proliferation or antitumor killing capacity of three different human CAR T-cell constructs (GD2, EGFR, and CD19). Finally, in an in vivo model, antitumor activity of CD19-CAR T cells adoptively transferred into CD19+ tumor-bearing immunodeficient animals was unabated by oral itacitinib treatment.
Conclusions:
Together, these data suggest that itacitinib has potential as a prophylactic agent for the prevention of CAR T cell–induced CRS, and a phase II clinical trial of itacitinib for prevention of CRS induced by CAR T-cell therapy has been initiated (NCT04071366).
Data from Copy Number Loss of 17q22 Is Associated with Enzalutamide Resistance and Poor Prognosis in Metastatic Castration-Resistant Prostate Cancer
Authors: Guan Xiangnan , Sun Duanchen , Lu Eric , Urrutia Joshua A. , Reiter Robert Evan , Rettig Matthew , Evans Christopher P. , Lara Primo , Gleave Martin , Beer Tomasz M. , Thomas George V. , Huang Jiaoti , Aggarwal Rahul R. , Quigley David A. , Foye Adam , Chen William S. , Youngren Jack , Weinstein Alana S. , Stuart Joshua M. , Feng Felix Y. , Small Eric J. , Xia Zheng , Alumkal Joshi J.
Published: April 2023

AbstractPurpose:
The purpose of this study was to measure genomic changes that emerge with enzalutamide treatment using analyses of whole-genome sequencing and RNA sequencing.
Experimental Design:
One hundred and one tumors from men with metastatic castration-resistant prostate cancer (mCRPC) who had not been treated with enzalutamide (n = 64) or who had enzalutamide-resistant mCRPC (n = 37) underwent whole genome sequencing. Ninety-nine of these tumors also underwent RNA sequencing. We analyzed the genomes and transcriptomes of these mCRPC tumors.
Results:
Copy number loss was more common than gain in enzalutamide-resistant tumors. Specially, we identified 124 protein-coding genes that were more commonly lost in enzalutamide-resistant samples. These 124 genes included eight putative tumor suppressors located at nine distinct genomic regions. We demonstrated that focal deletion of the 17q22 locus that includes RNF43 and SRSF1 was not present in any patient with enzalutamide-naïve mCRPC but was present in 16% (6/37) of patients with enzalutamide-resistant mCRPC. 17q22 loss was associated with lower RNF43 and SRSF1 expression and poor overall survival from time of biopsy [median overall survival of 19.3 months in 17q22 intact vs. 8.9 months in 17q22 loss, HR, 3.44 95% confidence interval (CI), 1.338–8.867, log-rank P = 0.006]. Finally, 17q22 loss was linked with activation of several targetable factors, including CDK1/2, Akt, and PLK1, demonstrating the potential therapeutic relevance of 17q22 loss in mCRPC.
Conclusions:
Copy number loss is common in enzalutamide-resistant tumors. Focal deletion of chromosome 17q22 defines a previously unappreciated molecular subset of enzalutamide-resistant mCRPC associated with poor clinical outcome.
Data from 5-Azacitidine Induces NOXA to Prime AML Cells for Venetoclax-Mediated Apoptosis
Authors: Jin Sha , Cojocari Dan , Purkal Julie J. , Popovic Relja , Talaty Nari N. , Xiao Yu , Solomon Larry R. , Boghaert Erwin R. , Leverson Joel D. , Phillips Darren C.
Published: April 2023

AbstractPurpose:
Patients with acute myeloid leukemia (AML) frequently do not respond to conventional therapies. Leukemic cell survival and treatment resistance have been attributed to the overexpression of B-cell lymphoma 2 (BCL-2) and aberrant DNA hypermethylation. In a phase Ib study in elderly patients with AML, combining the BCL-2 selective inhibitor venetoclax with hypomethylating agents 5-azacitidine (5-Aza) or decitabine resulted in 67% overall response rate; however, the underlying mechanism for this activity is unknown.
Experimental Design:
We studied the consequences of combining two therapeutic agents, venetoclax and 5-Aza, in AML preclinical models and primary patient samples. We measured expression changes in the integrated stress response (ISR) and the BCL-2 family by Western blot and qPCR. Subsequently, we engineered PMAIP1 (NOXA)- and BBC3 (PUMA)-deficient AML cell lines using CRISPR-Cas9 methods to understand their respective roles in driving the venetoclax/5-Aza combinatorial activity.
Results:
In this study, we demonstrate that venetoclax and 5-Aza act synergistically to kill AML cells in vitro and display combinatorial antitumor activity in vivo. We uncover a novel nonepigenetic mechanism for 5-Aza–induced apoptosis in AML cells through transcriptional induction of the proapoptotic BH3-only protein NOXA. This induction occurred within hours of treatment and was mediated by the ISR pathway. NOXA was detected in complex with antiapoptotic proteins, suggesting that 5-Aza may be “priming” the AML cells for venetoclax-induced apoptosis. PMAIP1 knockout confirmed its major role in driving venetoclax and 5-Aza synergy.
Conclusions:
These data provide a novel nonepigenetic mechanism of action for 5-Aza and its combinatorial activity with venetoclax through the ISR-mediated induction of PMAIP1.
Data from FDA Approval Summary: Tagraxofusp-erzs For Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm
Authors: Jen Emily Y. , Gao Xin , Li Liang , Zhuang Luning , Simpson Natalie E. , Aryal Baikuntha , Wang Rong , Przepiorka Donna , Shen Yuan Li , Leong Ruby , Liu Chao , Sheth Christopher M. , Bowen Steven , Goldberg Kirsten B. , Farrell Ann T. , Blumenthal Gideon M. , Pazdur Richard
Published: April 2023

Abstract
Tagraxofusp-erzs (Elzonris, Stemline) is a cytotoxin that targets CD123-expressing cells. On December 21, 2018, FDA approved tagraxofusp-erzs for the treatment of blastic plasmacytoid dendritic cell neoplasms (BPDCN) in adult and pediatric patients 2 years and older. Approval was based on the response rate in a single-arm trial, Study STML-401-0114; the pivotal cohort included 13 patients with treatment-naïve BPDCN who received tagraxofusp-erzs monotherapy. The complete response or clinical complete response (CR/CRc) rate in the pivotal cohort was 54% (95% CI: 25%–81%), and the median duration of CR/CRc was not reached with a median follow-up of 11.5 months (range: 0.2–12.7). In a separate exploratory cohort, a CR/CRc was achieved by 2 (13%) patients with R/R BPDCN. Safety was assessed in 94 patients with myeloid neoplasms treated with tagraxofusp-erzs at the approved dose and schedule. The major toxicity was capillary leak syndrome (CLS), which occurred in 55% of patients and was fatal in 2%. Hepatotoxicity and hypersensitivity reactions were reported in 88% and 46% of patients, respectively. Other common (≥30%) adverse reactions were nausea, fatigue, peripheral edema, pyrexia, and weight increase. A high proportion of patients (85%) developed neutralizing antidrug antibodies. Tagraxofusp-erzs is the first FDA-approved treatment for BPDCN.
Data from A Randomized Placebo Controlled Phase II Trial Evaluating Exemestane with or without Enzalutamide in Patients with Hormone Receptor–Positive Breast Cancer
Authors: Krop Ian , Abramson Vandana , Colleoni Marco , Traina Tiffany , Holmes Frankie , Garcia-Estevez Laura , Hart Lowell , Awada Ahmad , Zamagni Claudio , Morris Patrick G. , Schwartzberg Lee , Chan Stephen , Gucalp Ayca , Biganzoli Laura , Steinberg Joyce , Sica Lorenzo , Trudeau Maureen , Markova Denka , Tarazi Jamal , Zhu Zhou , O'Brien Thomas , Kelly Catherine M. , Winer Eric , Yardley Denise A.
Published: April 2023

AbstractPurpose:
To determine whether the androgen receptor (AR) inhibitor, enzalutamide, improves effectiveness of endocrine therapy (ET) in hormone receptor–positive (HR+) breast cancer.
Patients and Methods:
In this phase II trial, patients with HR+/HER2 normal advanced/metastatic breast cancer were randomized 1:1 to exemestane 25 mg with placebo or exemestane 50 mg with enzalutamide 160 mg daily (NCT02007512). Two parallel cohorts enrolled patients with 0 (cohort 1) or 1 (cohort 2) prior ET for advanced disease. Progression-free survival (PFS) was the primary endpoint in the intent-to-treat (ITT) population of each cohort. Biomarkers were evaluated in an exploratory analysis.
Results:
Overall, 247 patients were randomized (cohort 1, n = 127 and cohort 2, n = 120). PFS was not improved in either cohort of the ITT population [HR, 0.82 (95% confidence interval (CI), 0.54–1.26); P = 0.3631 for cohort 1 and HR, 1.02 (95% CI, 0.66–1.59); P = 0.9212 for cohort 2]. In cohort 1, high levels of AR mRNA were associated with greater benefit of enzalutamide (Pinteraction = 0.0048). This effect was particularly apparent in patients with both high levels of AR mRNA and low levels of ESR1 mRNA [HR, 0.24 (95% CI, 0.10–0.60); P = 0.0011]. The most common any grade adverse events in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2.
Conclusions:
Enzalutamide with exemestane was well tolerated. While PFS was not improved by the addition of enzalutamide to exemestane in an unselected population, ET-naïve patients with high AR mRNA levels, particularly in combination with low ESR1 mRNA levels, may benefit from enzalutamide with exemestane.