bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Accuracy, Safety, and Reliability of Novel Phase I Trial Designs
Authors: Zhou Heng , Yuan Ying , Nie Lei
Published: April 2023

Abstract
A number of novel model-based and model-assisted designs have been proposed to find the MTD in phase I clinical trials, but their differences and relative pros and cons are not clear to many practitioners. We review three model-based designs, including the continual reassessment method (CRM), dose escalation with overdose control (EWOC), and Bayesian logistic regression model (BLRM), and three model-assisted designs, including the modified toxicity probability interval (mTPI), Bayesian optimal interval (BOIN), and keyboard (equivalently mTPI-2) designs. We conduct numerical studies to assess their accuracy, safety, and reliability and the practical implications of various empirical rules used in some designs, such as skipping a dose and imposing overdose control. Our results show that the CRM outperforms EWOC and BLRM with higher accuracy of identifying the MTD. For the CRM, skipping a dose is not recommended, as it substantially increases the chance of overdosing patients while providing limited gain for identifying the MTD. EWOC and BLRM appear excessively conservative. They are safe but have relatively poor accuracy of finding the MTD. The BOIN and keyboard (equivalently mTPI-2) designs have similar operating characteristics, outperforming the mTPI, but the BOIN is more intuitive and transparent. The BOIN yields competitive performance comparable with the CRM but is simpler to implement and free of the issue of irrational dose assignment caused by model misspecification, thereby providing an attractive approach for designing phase I trials. Clin Cancer Res; 24(18); 4357–64. ©2018 AACR.
Data from Comprehensive Liquid Profiling of Circulating Tumor DNA and Protein Biomarkers in Long-Term Follow-Up Patients with Hepatocellular Carcinoma
Authors: Cai Zhixiong , Chen Geng , Zeng Yongyi , Dong Xiuqing , Li Zhenli , Huang Yanbing , Xin Fuli , Qiu Liman , Xu Haipo , Zhang Wei , Su Xiaoping , Liu Xiaolong , Liu Jingfeng
Published: April 2023

AbstractPurpose:
Circulating tumor DNA (ctDNA) provides a novel approach for detecting tumor burden and predicting clinical outcomes of hepatocellular carcinoma (HCC). Here, we performed a thorough evaluation of HCC circulating genetic features and further fully integrated them to build a robust strategy for HCC monitoring and prognostic outcome assessment.
Experimental Design:
We performed target sequencing and low-coverage whole-genome sequencing on plasma samples collected from 34 long-term follow-up patients with HCC to capture tumor somatic SNVs and CNVs, respectively. Clinical information was also obtained to evaluate the prognostic performance of ctDNA comparing with clinically applied protein biomarkers.
Results:
All plasma samples before surgery showed somatic genetic variations resembling corresponding tumor tissues. During follow-up, SNVs and CNVs dynamically changed correlating to patients' tumor burden. We integrated the comprehensive ctDNA mutation profiles to provide a robust strategy to accurately assess patients' tumor burden with high consistence comparing with imaging results. This strategy could discover tumor occurrence in advance of imaging for an average of 4.6 months, and showed superior performance than serum biomarkers AFP, AFP-L3%, and Des-Gamma-Carboxy Prothrombin (DCP). Furthermore, our strategy could precisely detect minimal residual disease (MRD) in advance and predict patients' prognostic outcomes for both relapse-free survival (P = 0.001) and overall survival (P = 0.001); further combining ctDNA with DCP could increase the sensitivity for MRD detection.
Conclusions:
We demonstrated that plasma CNV and SNV levels dynamically correlated with patients' tumor burden in HCC. Our strategy of comprehensive mutation profile integration could accurately and better evaluate patients' prognostic risk and detect tumor occurrence in advance than traditional strategies.
Data from Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma
Authors: Pang Ying , Lu Yanxin , Caisova Veronika , Liu Yang , Bullova Petra , Huynh Thanh-Truc , Zhou Yiqiang , Yu Di , Frysak Zdenek , Hartmann Igor , Taïeb David , Pacak Karel , Yang Chunzhang
Published: April 2023

Abstract
Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways.

Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors.

Results: We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD+ metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B (SDHB)-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft.

Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations. Clin Cancer Res; 24(14); 3423–32. ©2018 AACR.
Data from Zinc Metallochaperones Reactivate Mutant p53 Using an ON/OFF Switch Mechanism: A New Paradigm in Cancer Therapeutics
Authors: Yu Xin , Kogan Samuel , Chen Ying , Tsang Ashley T. , Withers Tracy , Lin Hongxia , Gilleran John , Buckley Brian , Moore Dirk , Bertino Joseph , Chan Chang , Kimball S. David , Loh Stewart N. , Carpizo Darren R.
Published: April 2023

Abstract
Purpose: Zinc metallochaperones (ZMC) are a new class of anticancer drugs that reactivate zinc-deficient mutant p53 by raising and buffering intracellular zinc levels sufficiently to restore zinc binding. In vitro pharmacodynamics of ZMCs indicate that p53-mutant activity is ON by 4–6 hours and is OFF by 24. We sought to understand the mechanism of this regulation and to translate these findings preclinically. We further sought to innovate the formulation of ZMCs to improve efficacy.

Experimental Design: We performed in vitro mechanistic studies to determine the role of cellular zinc homeostatic mechanisms in the transient pharmacodynamics of ZMCs. We conducted preclinical pharmacokinetic, pharmacodynamic, and efficacy studies using a genetically engineered murine pancreatic cancer model (KPC) to translate these mechanistic findings and investigate a novel ZMC formulation.

Results: In vitro, cellular zinc homeostatic mechanisms that restore zinc to its physiologic levels function as the OFF switch in ZMC pharmacodynamics. In vivo pharmacokinetic studies indicate that ZMCs have a short half-life (< 30 minutes), which is sufficient to significantly improve survival in mice expressing a zinc-deficient allele (p53R172H) while having no effect in mice expressing a non–zinc-deficient allele (p53R270H). We synthesized a novel formulation of the drug in complex with zinc and demonstrate this significantly improves survival over ZMC1.

Conclusions: Cellular zinc homeostatic mechanisms function as an OFF switch in ZMC pharmacodynamics, indicating that a brief period of p53-mutant reactivation is sufficient for on-target efficacy. ZMCs synthesized in complex with zinc are an improved formulation. Clin Cancer Res; 24(18); 4505–17. ©2018 AACR.
Data from Tryptophan Metabolism Contributes to Radiation-Induced Immune Checkpoint Reactivation in Glioblastoma
Authors: Kesarwani Pravin , Prabhu Antony , Kant Shiva , Kumar Praveen , Graham Stewart F. , Buelow Katie L. , Wilson George D. , Miller C. Ryan , Chinnaiyan Prakash
Published: April 2023

Abstract
Purpose: Immune checkpoint inhibitors designed to revert tumor-induced immunosuppression have emerged as potent anticancer therapies. Tryptophan metabolism represents an immune checkpoint, and targeting this pathway's rate-limiting enzyme IDO1 is actively being investigated clinically. Here, we studied the intermediary metabolism of tryptophan metabolism in glioblastoma and evaluated the activity of the IDO1 inhibitor GDC-0919, both alone and in combination with radiation (RT).

Experimental Design: LC/GC-MS and expression profiling was performed for metabolomic and genomic analyses of patient-derived glioma. Immunocompetent mice were injected orthotopically with genetically engineered murine glioma cells and treated with GDC-0919 alone or combined with RT. Flow cytometry was performed on isolated tumors to determine immune consequences of individual treatments.

Results: Integrated cross-platform analyses coupling global metabolomic and gene expression profiling identified aberrant tryptophan metabolism as a metabolic node specific to the mesenchymal and classical subtypes of glioblastoma. GDC-0919 demonstrated potent inhibition of this node and effectively crossed the blood–brain barrier. Although GDC-0919 as a single agent did not demonstrate antitumor activity, it had a strong potential for enhancing RT response in glioblastoma, which was further augmented with a hypofractionated regimen. RT response in glioblastoma involves immune stimulation, reflected by increases in activated and cytotoxic T cells, which was balanced by immune checkpoint reactivation, reflected by an increase in IDO1 expression and regulatory T cells (Treg). GDC-0919 mitigated RT-induced Tregs and enhanced T-cell activation.

Conclusions: Tryptophan metabolism represents a metabolic node in glioblastoma, and combining RT with IDO1 inhibition enhances therapeutic response by mitigating RT-induced immunosuppression. Clin Cancer Res; 24(15); 3632–43. ©2018 AACR.
Data from Nivolumab in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: Efficacy and Safety in CheckMate 141 by Prior Cetuximab Use
Authors: Ferris Robert L. , Licitra Lisa , Fayette Jerome , Even Caroline , Blumenschein George , Harrington Kevin J. , Guigay Joel , Vokes Everett E. , Saba Nabil F. , Haddad Robert , Ramkumar Shanmugasundaram , Russell Jeffery , Brossart Peter , Tahara Makoto , Colevas A. Dimitrios , Concha-Benavente Fernando , Lynch Mark , Li Li , Gillison Maura L.
Published: April 2023

AbstractPurpose:
Cetuximab, which modulates immune responses, may affect the efficacy of subsequent immunotherapy. Here, we assessed outcomes with nivolumab, by prior cetuximab exposure, in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) who had experienced progression within 6 months of platinum-containing chemotherapy.
Patients and Methods:
In the randomized, open-label, phase III CheckMate 141 trial, patients were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks or investigator's choice (IC) of single-agent chemotherapy, with stratification by prior cetuximab exposure. The primary endpoint was overall survival (OS); additional endpoints were progression-free survival, objective response rate, and safety.
Results:
In patients with prior cetuximab exposure, the median OS was 7.1 months with nivolumab versus 5.1 months with IC (HR, 0.84; 95% CI, 0.62–1.15); OS benefit with nivolumab was maintained across most demographic subgroups. In patients without prior cetuximab exposure, the median OS was 8.2 months with nivolumab versus 4.9 months with IC (HR, 0.52; 95% CI, 0.35–0.77); OS benefit with nivolumab was maintained across patient baseline subgroups including tumor programmed death ligand 1 (PD-L1) expression (<1% or ≥1%). Grade 3–4 treatment-related adverse event rates favored nivolumab versus IC in both subgroups.
Conclusions:
Nivolumab appeared to improve efficacy versus IC regardless of prior cetuximab use, supporting its use in patients with R/M SCCHN with or without prior cetuximab exposure. The reduction in risk of death with nivolumab compared with IC was greater in patients without prior cetuximab exposure versus with prior cetuximab exposure.
Data from Surufatinib in Advanced Well-Differentiated Neuroendocrine Tumors: A Multicenter, Single-Arm, Open-Label, Phase Ib/II Trial
Authors: Xu Jianming , Li Jie , Bai Chunmei , Xu Nong , Zhou Zhiwei , Li Zhiping , Zhou Caicun , Jia Ru , Lu Ming , Cheng Yuejuan , Mao Chenyu , Wang Wei , Cheng Ke , Su Chunxia , Hua Ye , Qi Chuan , Li Jing , Li Ke , Sun Qiaoling , Ren Yongxin , Su Weiguo
Published: April 2023

AbstractPurpose:
No antiangiogenic treatment is yet approved for extrapancreatic neuroendocrine tumors (NET). Surufatinib (HMPL-012, previously named sulfatinib) is a small-molecule inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptor 1 and colony-stimulating factor 1 receptor. We conducted a single-arm phase Ib/II study of surufatinib in advanced NETs.
Patients and Methods:
Patients with histologically well-differentiated, low or intermittent grade, inoperable or metastatic NETs were enrolled into a pancreatic or extrapancreatic NET cohort. Patients were treated with surufatinib 300 mg orally, once daily. The primary endpoints were safety and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (version 1.1).
Results:
Of the 81 patients enrolled, 42 had pancreatic NETs and 39 had extrapancreatic NETs. Most patients had radiologic progression within 1 year prior to enrollment (32 patients in each cohort). In the pancreatic and extrapancreatic NET cohorts, ORRs were 19% [95% confidence intervals (CI), 9–34] and 15% (95% CI, 6–31), disease control rates were 91% (95% CI, 77–97) and 92% (95% CI, 79–98), and median progression-free survival was 21.2 months (95% CI, 15.9–24.8) and 13.4 months (95% CI, 7.6–19.3), respectively. The most common grade ≥3 treatment-related adverse events were hypertension (33%), proteinuria (12%), hyperuricemia (10%), hypertriglyceridemia, and diarrhea (6% for each), and increased alanine aminotransferase (5%).
Conclusions:
Surufatinib showed encouraging antitumor activity and manageable toxicities in patients with advanced NETs. Two ongoing phase III studies, validating the efficacy of surufatinib in patients with NETs, will contribute to the clinical evidence.
Data from Reciprocal Network between Cancer Stem-Like Cells and Macrophages Facilitates the Progression and Androgen Deprivation Therapy Resistance of Prostate Cancer
Authors: Huang Hai , Wang Chao , Liu Fei , Li Hui-Zhen , Peng Guang , Gao Xu , Dong Ke-Qin , Wang Hong-Ru , Kong De-Pei , Qu Min , Dai Li-He , Wang Kai-Jian , Zhou Zhe , Yang Jun , Yang Ze-Yu , Cheng Yan-Qiong , Tian Qin-Qin , Liu Dan , Xu Chuan-Liang , Xu Dan-Feng , Cui Xin-Gang , Sun Ying-Hao
Published: April 2023

Abstract
Purpose: Cancer stem-like cells (CSC) contribute to the progression and androgen deprivation therapy (ADT) resistance of prostate cancer. As CSCs depend on their specific niche, including tumor-associated macrophages (TAM), elucidating the network between CSCs and TAMs may help to effectively inhibit the progression and ADT resistance of prostate cancer.

Experimental Design: The underlying intracellular mechanism that sustains the stem-like characteristics of CSCs in prostate cancer was assessed via RNA sequencing, co-immunoprecipitation, chromatin immunoprecipitation, and other assays. A coculture system and cytokine antibody arrays were used to examine the interaction network between CSCs and TAMs. In addition, an orthotopic prostate cancer model was established to evaluate the in vivo effects of the combined targeting of CSCs and their interaction with TAMs on ADT resistance.

Results: Autophagy-related gene 7 (ATG7) facilitated the transcription of OCT4 via β-catenin, which binds to the OCT4 promoter, promoting CSC characteristics in prostate cancer, including self-renewal, tumor initiation, and drug resistance. In addition, CSCs remodeled their specific niche by educating monocytes/macrophages toward TAMs, and the CSC-educated TAMs reciprocally promoted the stem-like properties of CSCs, progression and ADT resistance of prostate cancer via IL6/STAT3. Furthermore, the combined targeting of CSCs and their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 receptor effectively ameliorated ADT resistance in an orthotopic prostate cancer model.

Conclusions: Targeting CSCs and their niche may prove to be a more powerful strategy than targeting CSCs alone, providing a rational approach to ameliorating ADT resistance in prostate cancer. Clin Cancer Res; 24(18); 4612–26. ©2018 AACR.
Data from Machine Learning to Build and Validate a Model for Radiation Pneumonitis Prediction in Patients with Non–Small Cell Lung Cancer
Authors: Yu Hao , Wu Huanmei , Wang Weili , Jolly Shruti , Jin Jian-Yue , Hu Chen , Kong Feng-Ming (Spring)
Published: April 2023

AbstractPurpose:
Radiation pneumonitis is an important adverse event in patients with non–small cell lung cancer (NSCLC) receiving thoracic radiotherapy. However, the risk of radiation pneumonitis grade ≥ 2 (RP2) has not been well predicted. This study hypothesized that inflammatory cytokines or the dynamic changes during radiotherapy can improve predictive accuracy for RP2.
Experimental Design:
Levels of 30 inflammatory cytokines and clinical information in patients with stages I–III NSCLC treated with radiotherapy were from our prospective studies. Statistical analysis was used to select predictive cytokine candidates and clinical covariates for adjustment. Machine learning algorithm was used to develop the generalized linear model for predicting risk RP2.
Results:
A total of 131 patients were eligible and 17 (13.0%) developed RP2. IL8 and CCL2 had significantly (Bonferroni) lower expression levels in patients with RP2 than without RP2. But none of the changes in cytokine levels during radiotherapy was significantly associated with RP2. The final predictive GLM model for RP2 was established, including IL8 and CCL2 at baseline level and two clinical variables. Nomogram was constructed based on the GLM model. The model's predicting ability was validated in the completely independent test set (AUC = 0.863, accuracy = 80.0%, sensitivity = 100%, specificity = 76.5%).
Conclusions:
By machine learning, this study has developed and validated a comprehensive model integrating inflammatory cytokines with clinical variables to predict RP2 before radiotherapy that provides an opportunity to guide clinicians.
Data from High-Fat Diet-Induced Inflammation Accelerates Prostate Cancer Growth via IL6 Signaling
Authors: Hayashi Takuji , Fujita Kazutoshi , Nojima Satoshi , Hayashi Yujiro , Nakano Kosuke , Ishizuya Yu , Wang Cong , Yamamoto Yoshiyuki , Kinouchi Toshiro , Matsuzaki Kyosuke , Jingushi Kentaro , Kato Taigo , Kawashima Atsunari , Nagahara Akira , Ujike Takeshi , Uemura Motohide , Pena Maria Del Carmen Rodriguez , Gordetsky Jennifer B. , Morii Eiichi , Tsujikawa Kazutake , Netto George J. , Nonomura Norio
Published: April 2023

Abstract
Purpose: High-fat diet (HFD) could induce prostate cancer progression. The aim of this study is to identify mechanisms of HFD-induced prostate cancer progression, focusing on inflammation.

Experimental Design: We administered HFD and celecoxib to autochthonous immunocompetent Pb-Cre+;Pten(fl/fl) model mice for prostate cancer. Tumor growth was evaluated by tumor weight and Ki67 stain, and local immune cells were assessed by flow cytometry at 22 weeks of age. Cytokines which correlated with tumor growth were identified, and the changes of tumor growth and local immune cells after inhibition of the cytokine signals were evaluated in the mice. IHC analyses using prostatectomy specimens of obese patients were performed.

Results: HFD accelerated tumor growth and increased the myeloid-derived suppressor cells (MDSCs) fraction and M2/M1 macrophage ratio in the model mice. Celecoxib-suppressed tumor growth, and decreased both local MDSCs and M2/M1 macrophage ratio in HFD-fed mice. HFD-induced tumor growth was associated with IL6 secreted by prostatic macrophages, as were phosphorylated STAT3 (pSTAT3)-positive tumor cells. Anti-IL6 receptor antibody administration suppressed tumor growth, and decreased local MDSCs and pSTAT3-positive cell fractions in HFD-fed mice. The tumor-infiltrating CD11b-positive cell count was significantly higher in prostatectomy specimens of obese than those of nonobese patients with prostate cancer.

Conclusions: HFD increased MDSCs and accelerated prostate cancer tumor growth via IL6/pSTAT3 signaling in the mice. This mechanism could exist in obese patients with prostate cancer. IL6-mediated inflammation could be a therapeutic target for prostate cancer. Clin Cancer Res; 24(17); 4309–18. ©2018 AACR.
Data from An Integrative Approach to Inform Optimal Administration of OX40 Agonist Antibodies in Patients with Advanced Solid Tumors
Authors: Wang Rui , Gao Chan , Raymond Megan , Dito Gennaro , Kabbabe Dominic , Shao Xiao , Hilt Ed , Sun Yongliang , Pak Irene , Gutierrez Martin , Melero Ignacio , Spreafico Anna , Carvajal Richard D. , Ong Michael , Olszanski Anthony J. , Milburn Christina , Thudium Kent , Yang Zheng , Feng Yan , Fracasso Paula M. , Korman Alan J. , Aanur Praveen , Huang Shih-Min A. , Quigley Michael
Published: April 2023

AbstractPurpose:
The success of checkpoint blockade has led to a significant increase in the development of a broad range of immunomodulatory molecules for the treatment of cancer, including agonists against T-cell costimulatory receptors, such as OX40. Unlike checkpoint blockade, where complete and sustained receptor saturation may be required for maximal activity, the optimal dosing regimen and receptor occupancy for agonist agents is less well understood and requires further study.
Experimental Design:
We integrated both preclinical and clinical biomarker data sets centered on dose, exposure, receptor occupancy, receptor engagement, and downstream pharmacodynamic changes to model the optimal dose and schedule for the OX40 agonist antibody BMS-986178 alone and in combination with checkpoint blockade.
Results:
Administration of the ligand-blocking anti-mouse surrogate antibody OX40.23 or BMS-986178 as monotherapy or in combination with checkpoint blockade led to increased peripheral CD4+ and CD8+ T-cell activation in tumor-bearing mice and patients with solid tumors, respectively. OX40 receptor occupancy between 20% and 50% both in vitro and in vivo was associated with maximal enhancement of T-cell effector function by anti-OX40 treatment, whereas a receptor occupancy > 40% led to a profound loss in OX40 receptor expression, with clear implications for availability for repeat dosing.
Conclusions:
Our results highlight the value of an integrated translational approach applied during early clinical development to aggregate preclinical and clinical data in an effort to define the optimal dose and schedule for T-cell agonists in the clinic.
Data from Modulation of Target Antigen Density Improves CAR T-cell Functionality and Persistence
Authors: Ramakrishna Sneha , Highfill Steven L. , Walsh Zachary , Nguyen Sang M. , Lei Haiyan , Shern Jack F. , Qin Haiying , Kraft Ira L. , Stetler-Stevenson Maryalice , Yuan Constance M. , Hwang Jennifer D. , Feng Yang , Zhu Zhongyu , Dimitrov Dimiter , Shah Nirali N. , Fry Terry J.
Published: April 2023

AbstractPurpose:
Chimeric antigen receptor T-cell (CART) therapy targeting CD22 induces remission in 70% of patients with relapsed/refractory acute lymphoblastic leukemia (ALL). However, the majority of post-CD22 CART remissions are short and associated with reduction in CD22 expression. We evaluate the implications of low antigen density on the activity of CD22 CART and propose mechanisms to overcome antigen escape.
Experimental Design:
Using ALL cell lines with variable CD22 expression, we evaluate the cytokine profile, cytotoxicity, and in vivo CART functionality in the setting of low CD22 expression. We develop a high-affinity CD22 chimeric antigen receptor (CAR) as an approach to improve CAR sensitivity. We also assess Bryostatin1, a therapeutically relevant agent, to upregulate CD22 and improve CAR functionality.
Results:
We demonstrate that low CD22 expression negatively impacts in vitro and in vivo CD22 CART functionality and impairs in vivo CART persistence. Moreover, low antigen expression on leukemic cells increases naïve phenotype of persisting CART. Increasing CAR affinity does not improve response to low-antigen leukemia. Bryostatin1 upregulates CD22 on leukemia and lymphoma cell lines for 1 week following single-dose exposure, and improves CART functionality and in vivo persistence. While Bryostatin1 attenuates IFNγ production by CART, overall in vitro and in vivo CART cytotoxicity is not adversely affected. Finally, administration of Bryostain1 with CD22 CAR results in longer duration of in vivo response.
Conclusions:
We demonstrate that target antigen modulation is a promising strategy to improve CD22 CAR efficacy and remission durability in patients with leukemia and lymphoma.

See related commentary by Guedan and Delgado, p. 5188
Data from Alterations in DNA Damage Repair Genes in Primary Liver Cancer
Authors: Lin Jianzhen , Shi Junping , Guo Honglin , Yang Xu , Jiang Yan , Long Junyu , Bai Yi , Wang Dongxu , Yang Xiaobo , Wan Xueshuai , Zhang Lei , Pan Jie , Hu Ke , Guan Mei , Huo Li , Sang Xinting , Wang Kai , Zhao Haitao
Published: April 2023

AbstractPurpose:
Alterations in DNA damage repair (DDR) genes produce therapeutic biomarkers. However, the characteristics and significance of DDR alterations remain undefined in primary liver cancer (PLC).
Experimental Design:
Patients diagnosed with PLC were enrolled in the trial (PTHBC, NCT02715089). Tumors and matched blood samples from participants were collected for a targeted next-generation sequencing assay containing exons of 450 cancer-related genes, including 31 DDR genes. The OncoKB knowledge database was used to identify and classify actionable alterations, and therapeutic regimens were determined after discussion by a multidisciplinary tumor board.
Results:
A total of 357 patients with PLC were enrolled, including 214 with hepatocellular carcinoma, 122 with ICC, and 21 with mixed hepatocellular-cholangiocarcinoma. A total of 92 (25.8%) patients had at least one DDR gene mutation, 15 of whom carried germline mutations. The most commonly altered DDR genes were ATM (5%) and BRCA1/2 (4.8%). The occurrence of DDR mutations was significantly correlated with a higher tumor mutation burden regardless of the PLC pathologic subtype. For DDR-mutated PLC, 26.1% (24/92) of patients possessed at least one actionable alteration, and the actionable frequency in DDR wild-type PLC was 18.9% (50/265). Eight patients with the BRCA mutation were treated by olaparib, and patients with BRCA2 germline truncation mutations showed an objective response.
Conclusions:
The landscape of DDR mutations and their association with genetic and clinicopathologic features demonstrated that patients with PLC with altered DDR genes may be rational candidates for precision oncology treatment.
Data from Individual Assignment of Adult Diffuse Gliomas into the EM/PM Molecular Subtypes Using a TaqMan Low-Density Array
Authors: Li Jiuyi , Xue Yang , Wenger Anna , Sun Yingyu , Wang Zheng , Zhang Chuanbao , Zhang Yunqiu , Fekete Boglarka , Rydenhag Bertil , Jakola Asgeir Store , Jiang Tao , Carén Helena , Fan Xiaolong
Published: April 2023

AbstractPurpose:
We aimed to develop a diagnostic platform to capture the transcriptomic resemblance of individual adult diffuse gliomas of WHO grades II to IV to neural development and the genomic signature associated with glioma progression.
Experimental Design:
Based on the EM/PM classification scheme, we designed a RT-PCR–based TaqMan low-density array (TLDA) containing 44 classifier and 4 reference genes. Samples of a training dataset (GSE48865), characterized by RNA-sequencing, were utilized to optimize the TLDA design and to develop a support vector machine (SVM)-based prediction model. Complemented with Sanger sequencing for IDH1/2, and low coverage whole genome sequencing (WGS), the TLDA and SVM prediction model were tested in a validation (31 gliomas) and a test (121 gliomas) dataset.
Results:
Independent of morphologically defined subtypes and grades, gliomas can be individually assigned into the EM and PM glioma subtypes with the respective areas under ROC curves at 0.86 and 0.85 in the validation dataset. The EM gliomas showed a medium overall survival (OS) of 15.6 months, whereas the medium OS for PM gliomas was not reached (HR = 3.55; 95% confidence interval, 1.96–6.45). The EM and PM gliomas showed distinct patterns of genomic alterations, with IDH mutation and 1p19q codeletion in the PM gliomas and gain of chromosome 7/loss of chromosome 10 in the EM gliomas. Extensive chromosomal abnormalities marked the progression of PM gliomas.
Conclusions:
The integration of EM/PM subtyping, IDH sequencing, and low coverage WGS may improve the risk stratification and selection of treatment regimens for patients with glioma.
Data from Treatment with Humanized Selective CD19CAR-T Cells Shows Efficacy in Highly Treated B-ALL Patients Who Have Relapsed after Receiving Murine-Based CD19CAR-T Therapies
Authors: Zhao Yu , Liu Zhongfeng , Wang Xuan , Wu Huantong , Zhang Jianping , Yang Junfang , Zhang Fayou , Liu Lining , Long Jiafu , Lu Peihua , Chen Zhiguo
Published: April 2023

AbstractPurpose:
CD19 chimeric antigen receptor (CAR)-T therapy has shown impactful results in treatment of B-cell malignancies. However, immune recognition of the murine scFv may render subsequent infusion(s) ineffective. Also, nonselective expansion of both CAR-transduced and nontransduced T cells during the production stage affects the yield and purity of final products. Here, we aim to develop a humanized selective (hs) CD19 CAR to solve the above problems.

Experimental Design: A CD19 hsCAR was designed, which incorporated a short selective domain between the humanized heavy chain and light chain. The CAR was examined for its property, and then trialed in 5 highly treated B-ALL patients.
Results:
hsCAR possessed around 6-fold higher affinity to CD19 versus murine CAR (mCAR). Incubation with selective domain-specific mAbs (SmAb) selectively expanded CAR-transduced T cells, and led to a higher proportion of central memory T cells in the final products. SmAb-stimulated CD19 hsCAR-T cells exhibited superior antitumor cytotoxic functions in vitro and in vivo. Autologous (n = 2) and allogeneic donor (n = 3, with hematopoietic stem cell transplantation) hsCAR-T cells were infused into 5 patients who had relapsed after receiving mCAR-T treatments. Two patients received mCAR-T treatments twice previously but the second treatments were ineffective. In contrast, subsequent hsCAR-T treatments proved effective in all 5 patients and achieved complete molecular remission in four, including one with extramedullary disease with central nervous system involvement.
Conclusions:
hsCD19 CAR-T treatment shows efficacy in highly treated B-ALL patients who have relapsed after receiving CD19 mCAR-T therapies.
Data from Analysis of Tumor Genomic Pathway Alterations Using Broad-Panel Next-Generation Sequencing in Surgically Resected Lung Adenocarcinoma
Authors: Zhou Jian , Sanchez-Vega Francisco , Caso Raul , Tan Kay See , Brandt Whitney S. , Jones Gregory D. , Yan Shi , Adusumilli Prasad S. , Bott Matthew , Huang James , Isbell James M. , Sihag Smita , Molena Daniela , Rusch Valerie W. , Chatila Walid K. , Rekhtman Natasha , Yang Fan , Ladanyi Marc , Solit David B. , Berger Michael F. , Schultz Nikolaus , Jones David R.
Published: April 2023

AbstractPurpose:
The majority of broad-panel tumor genomic profiling has used a gene-centric approach, although much of that data is unused in clinical decision making. We hypothesized that a pathway-centric approach using next-generation sequencing (NGS), combined with conventional clinicopathologic features, may better predict disease-free survival (DFS) in early stage lung adenocarcinoma.
Experimental Design:
Utilizing our prospectively maintained database, we analyzed 492 patients with primary, untreated, completely surgically resected lung adenocarcinoma. Ten canonical pathways were analyzed using broad-panel NGS. The correlations of DFS and number (and type) of pathway (NPA) were analyzed using the Kaplan–Meier method and log-rank test. Associations between altered pathways and clinicopathologic variables, as well as identification of actionable therapeutic strategies were explored.
Results:
Median NPA for the cohort was two (range, 0–5). Smoking status, solid morphologic appearance on preoperative CT, maximal standardized uptake value, pathologic tumor size, aggressive histologic subtype, lymphovascular invasion, visceral pleural invasion, and positive lymph nodes were significantly associated with NPA (P < 0.05). Of 543 actionable genetic alterations identified, 455 (84%) were within the RTK/RAS pathway. A total of 86 tumors had actionable therapeutic genomic alterations in >1 pathway. On multivariable analysis, higher NPA was significantly associated with worse DFS (HR, 1.31; P = 0.014).
Conclusions:
NPA and specific pathway alterations are associated with clinicopathologic features in patients with surgically resected lung adenocarcinoma. Cell cycle, Hippo, TGFβ, and p53 pathway alterations are associated with poor DFS. Finally, NPA is an independent risk factor for poor DFS in our cohort.

See related commentary by Blakely, p. 7269
Data from Tissue and Plasma EGFR Mutation Analysis in the FLAURA Trial: Osimertinib versus Comparator EGFR Tyrosine Kinase Inhibitor as First-Line Treatment in Patients with EGFR-Mutated Advanced Non–Small Cell Lung Cancer
Authors: Gray Jhanelle E. , Okamoto Isamu , Sriuranpong Virote , Vansteenkiste Johan , Imamura Fumio , Lee Jong Seok , Pang Yong-Kek , Cobo Manuel , Kasahara Kazuo , Cheng Ying , Nogami Naoyuki , Cho Eun Kyung , Su Wu Chou , Zhang Guili , Huang Xiangning , Li-Sucholeiki Xiaocheng , Lentrichia Brian , Dearden Simon , Jenkins Suzanne , Saggese Matilde , Rukazenkov Yuri , Ramalingam Suresh S.
Published: April 2023

AbstractPurpose:
To assess the utility of the cobas EGFR Mutation Test, with tissue and plasma, for first-line osimertinib therapy for patients with EGFR-mutated (EGFRm; Ex19del and/or L858R) advanced or metastatic non–small cell lung cancer (NSCLC) from the FLAURA study (NCT02296125).
Experimental Design:
Tumor tissue EGFRm status was determined at screening using the central cobas tissue test or a local tissue test. Baseline circulating tumor (ct)DNA EGFRm status was retrospectively determined with the central cobas plasma test.
Results:
Of 994 patients screened, 556 were randomized (289 and 267 with central and local EGFR test results, respectively) and 438 failed screening. Of those randomized from local EGFR test results, 217 patients had available central test results; 211/217 (97%) were retrospectively confirmed EGFRm positive by central cobas tissue test. Using reference central cobas tissue test results, positive percent agreements with cobas plasma test results for Ex19del and L858R detection were 79% [95% confidence interval (CI), 74–84] and 68% (95% CI, 61–75), respectively. Progression-free survival (PFS) superiority with osimertinib over comparator EGFR-TKI remained consistent irrespective of randomization route (central/local EGFRm-positive tissue test). In both treatment arms, PFS was prolonged in plasma ctDNA EGFRm-negative (23.5 and 15.0 months) versus -positive patients (15.2 and 9.7 months).
Conclusions:
Our results support utility of cobas tissue and plasma testing to aid selection of patients with EGFRm advanced NSCLC for first-line osimertinib treatment. Lack of EGFRm detection in plasma was associated with prolonged PFS versus patients plasma EGFRm positive, potentially due to patients having lower tumor burden.
Data from Loss of Function of DOCK4 in Myelodysplastic Syndromes Stem Cells is Restored by Inhibitors of DOCK4 Signaling Networks
Authors: Sundaravel Sriram , Kuo Wen-Liang , Jeong Jong Jin , Choudhary Gaurav S. , Gordon-Mitchell Shanisha , Liu Hui , Bhagat Tushar D. , McGraw Kathy L. , Gurbuxani Sandeep , List Alan F. , Verma Amit , Wickrema Amittha
Published: April 2023

AbstractPurpose:
Myelodysplastic syndromes (MDS) with deletion of chromosome 7q/7 [-7/(del)7q MDS] is associated with worse outcomes and needs novel insights into pathogenesis. Reduced expression of signaling protein dedicator of cytokinesis 4 (DOCK4) in patients with -7/(del)7q MDS leads to a block in hematopoietic stem cell (HSC) differentiation. Identification of targetable signaling networks downstream of DOCK4 will provide means to restore hematopoietic differentiation in MDS.

Experimental Design: We utilized phosphoproteomics approaches to identify signaling proteins perturbed as a result of reduced expression of DOCK4 in human HSCs and tested their functional significance in primary model systems.
Results:
We demonstrate that reduced levels of DOCK4 lead to increased global tyrosine phosphorylation of proteins in primary human HSCs. LYN kinase and phosphatases INPP5D (SHIP1) and PTPN6 (SHP1) displayed greatest levels of tyrosine phosphorylation when DOCK4 expression levels were reduced using DOCK4-specific siRNA. Our data also found that increased phosphorylation of SHIP1 and SHP1 phosphatases were due to LYN kinase targeting these phosphatases as substrates. Increased migration and impediment of HSC differentiation were consequences of these signaling alterations. Pharmacologic inhibition of SHP1 reversed these functional aberrations in HSCs expressing low DOCK4 levels. In addition, differentiation block seen in DOCK4 haplo-insufficient [-7/(del)7q] MDS was rescued by inhibition of SHP1 phosphatase.
Conclusions:
LYN kinase and phosphatases SHP1 and SHIP1 are perturbed when DOCK4 expression levels are low. Inhibition of SHP1 promotes erythroid differentiation in healthy HSCs and in -7/(del)7q MDS samples with low DOCK4 expression. Inhibitors of LYN, SHP1 and SHIP1 also abrogated increased migratory properties in HSCs expressing reduced levels of DOCK4.
Data from Microbiota- and Radiotherapy-Induced Gastrointestinal Side-Effects (MARS) Study: A Large Pilot Study of the Microbiome in Acute and Late-Radiation Enteropathy
Authors: Reis Ferreira Miguel , Andreyev H. Jervoise N. , Mohammed Kabir , Truelove Lesley , Gowan Sharon M. , Li Jia , Gulliford Sarah L. , Marchesi Julian R. , Dearnaley David P.
Published: April 2023

AbstractPurpose:
Radiotherapy is important in managing pelvic cancers. However, radiation enteropathy may occur and can be dose limiting. The gut microbiota may contribute to the pathogenesis of radiation enteropathy. We hypothesized that the microbiome differs between patients with and without radiation enteropathy.

Experimental Design: Three cohorts of patients (n = 134) were recruited. The early cohort (n = 32) was followed sequentially up to 12 months post-radiotherapy to assess early radiation enteropathy. Linear mixed models were used to assess microbiota dynamics. The late cohort (n = 87) was assessed cross-sectionally to assess late radiation enteropathy. The colonoscopy cohort compared the intestinal mucosa microenvironment in patients with radiation enteropathy (cases, n = 9) with healthy controls (controls, n = 6). Fecal samples were obtained from all cohorts. In the colonoscopy cohort, intestinal mucosa samples were taken. Metataxonomics (16S rRNA gene) and imputed metataxonomics (Piphillin) were used to characterize the microbiome. Clinician- and patient-reported outcomes were used for clinical characterization.
Results:
In the acute cohort, we observed a trend for higher preradiotherapy diversity in patients with no self-reported symptoms (P = 0.09). Dynamically, diversity decreased less over time in patients with rising radiation enteropathy (P = 0.05). A consistent association between low bacterial diversity and late radiation enteropathy was also observed, albeit nonsignificantly. Higher counts of Clostridium IV, Roseburia, and Phascolarctobacterium significantly associated with radiation enteropathy. Homeostatic intestinal mucosa cytokines related to microbiota regulation and intestinal wall maintenance were significantly reduced in radiation enteropathy [IL7 (P = 0.05), IL12/IL23p40 (P = 0.03), IL15 (P = 0.05), and IL16 (P = 0.009)]. IL15 inversely correlated with counts of Roseburia and Propionibacterium.
Conclusions:
The microbiota presents opportunities to predict, prevent, or treat radiation enteropathy. We report the largest clinical study to date into associations of the microbiota with acute and late radiation enteropathy. An altered microbiota associates with early and late radiation enteropathy, with clinical implications for risk assessment, prevention, and treatment of radiation-induced side-effects.

See related commentary by Lam et al., p. 6280
Data from Impact of a Pre-Operative Exercise Intervention on Breast Cancer Proliferation and Gene Expression: Results from the Pre-Operative Health and Body (PreHAB) Study
Authors: Ligibel Jennifer A. , Dillon Deborah , Giobbie-Hurder Anita , McTiernan Anne , Frank Elizabeth , Cornwell MacIntosh , Pun Matthew , Campbell Nancy , Dowling Ryan J.O. , Chang Martin C. , Tolaney Sara , Chagpar Anees B. , Yung Rachel L. , Freedman Rachel A. , Dominici Laura S. , Golshan Mehra , Rhei Esther , Taneja Krishan , Huang Ying , Brown Myles , Winer Eric P. , Jeselsohn Rinath , Irwin Melinda L.
Published: April 2023

AbstractPurpose:
Exercise after breast cancer diagnosis is associated with lower cancer-specific mortality, but the biological mechanisms through which exercise impacts breast cancer are not fully understood. The Pre-Operative Health and Body (PreHAB) Study was a randomized window-of-opportunity trial designed to test the impact of exercise on Ki-67, gene expression, and other biomarkers in women with breast cancer.
Experimental Design:
Inactive women with newly diagnosed breast cancer were randomized to an exercise intervention or mind–body control group, and participated in the study between enrollment and surgery (mean 29.3 days). Tumor and serum were collected at baseline and surgery.
Results:
Forty-nine women were randomized (27 exercise, 22 control). At baseline, mean age was 52.6, body mass index was 30.2 kg/m2, and exercise was 49 minutes/week. Exercise participants significantly increased exercise versus controls (203 vs. 23 minutes/week, P < 0.0001). There were no differences in changes of expression of Ki-67, insulin receptor, and cleaved caspase-3 in exercise participants versus controls. KEGG pathway analysis demonstrated significant upregulation of 18 unique pathways between the baseline biopsy and surgical excision in exercise participants and none in control participants (q < 0.1). Top-ranked pathways included several implicated in immunity and inflammation. Exploratory analysis of tumor immune infiltrates demonstrated a trend toward a decrease in FOXP3+ cells in exercise versus control participants over the intervention period (P = 0.08).
Conclusions:
A window-of-opportunity exercise intervention did not impact proliferation but led to alterations in gene expression in breast tumors, suggesting that exercise may have a direct effect on breast cancer.

See related commentary by Koelwyn and Jones, p. 5179
Data from A Phase II Trial of Hu14.18K322A in Combination with Induction Chemotherapy in Children with Newly Diagnosed High-Risk Neuroblastoma
Authors: Furman Wayne L. , Federico Sara M. , McCarville Mary Beth , Shulkin Barry L. , Davidoff Andrew M. , Krasin Matthew J. , Sahr Natasha , Sykes April , Wu Jianrong , Brennan Rachel C. , Bishop Michael William , Helmig Sara , Stewart Elizabeth , Navid Fariba , Triplett Brandon , Santana Victor M. , Bahrami Armita , Anthony Gwendolyn , Yu Alice L. , Hank Jacquelyn , Gillies Stephen D. , Sondel Paul M. , Leung Wing H. , Pappo Alberto S.
Published: April 2023

AbstractPurpose:
We sought to evaluate whether combining a humanized antidisialoganglioside mAb (hu14.18K322A) with induction chemotherapy improves early responses and outcomes in children with newly diagnosed high-risk neuroblastoma.
Patients and Methods:
We conducted a prospective nonrandomized, single-arm, two-stage, phase II clinical trial. Six courses of induction chemotherapy were coadministered with hu14.18K322A and followed with granulocyte–macrophage colony-stimulating factor (GM-CSF) and low-dose IL2. Consolidation was performed with a busulfan/melphalan preparative regimen. An additional course of hu14.18K322A was administered with parent-derived natural killer cells, when available, during consolidation. Hu14.18K322A, GM-CSF, IL2, and isotretinoin were then administered. Secondary outcomes included reduced tumor volume and semiquantitative 123I-metaiodobenzylguanidine scoring [i.e., Curie scores (CS)] at the end of induction.
Results:
Forty-two patients received hu14.18K322A and induction chemotherapy. This regimen was well tolerated, with continuous-infusion narcotics adjusted to patient tolerance. Partial responses (PR) or better after the first two chemoimmunotherapy courses occurred in 32 patients [76.2%; 95% confidence interval (CI), 60.6–88.0]. This was accompanied by primary tumor volume reductions (median, –76%; range, –100% to 5%). Of 35 patients with stage IV disease who completed induction, 31 had end-of-induction CSs of 2 or less. No patients experienced progression during induction. Two-year event-free survival (EFS) was 85.7% (95% CI, 70.9–93.3).
Conclusions:
Adding hu14.18K322A to induction chemotherapy produced early PR or better in most patients, reduced tumor volumes, improved CSs at the end of induction, and yielded an encouraging 2-year EFS. These results, if validated in a larger study, may change the standard of care for children with high-risk neuroblastoma.
Data from Tumor-associated Macrophages as Prognostic and Predictive Biomarkers for Postoperative Adjuvant Chemotherapy in Patients with Stage II Colon Cancer
Authors: Feng Qingyang , Chang Wenju , Mao Yihao , He Guodong , Zheng Peng , Tang Wentao , Wei Ye , Ren Li , Zhu Dexiang , Ji Meiling , Tu Yongjiu , Qin Xinyu , Xu Jianmin
Published: April 2023

AbstractPurpose:
For stage II colon cancer, the efficacy of postoperative adjuvant chemotherapy remains controversial. It is well known that tumor-associated macrophages (TAMs) are important in tumor progression. In this study, TAMs were investigated as prognostic and predictive biomarkers for the efficacy of adjuvant chemotherapy for stage II colon cancer after radical resection.
Experimental Design:
This study enrolled two independent cohorts of consecutive patients from one medical center with pathologic stage II colon cancer after radical resections. Macrophages were detected using IHC staining of CD68 and CD206. Infiltration densities of CD68+ TAMs, CD206+ TAMs, and ratio of CD206+ TAMs/CD68+ TAMs (CD206/CD68 ratio) were calculated as prognostic and predictive biomarkers.
Results:
The primary and validation cohorts consisted of 521 and 314 patients, respectively. In both cohorts, high CD206/CD68 ratio was significantly associated with poor disease-free survival (DFS) and overall survival (OS). As an independent risk factor, CD206/CD68 ratio also had significantly better prognostic efficacy than CD68+ TAM density, CD206+ TAM density, and traditional clinicopathologic high-risk factors. Moreover, adjuvant chemotherapy significantly improved DFS and OS for patients with high CD206/CD68 ratio but not for those with low CD206/CD68 ratio. The interaction analyses were also significant for DFS. In subgroup analysis, CD206/CD68 ratio was still a significant predictor for adjuvant chemotherapy for patients in traditional high-risk group of recurrence (significant interaction for DFS).
Conclusions:
For stage II colon cancer, CD206/CD68 ratio is a better prognostic and predictive biomarker for postoperative adjuvant chemotherapy. Together with clinicopathologic high-risk factors, it will aid in precision treatment.