Radioactive iodine (RAI) treatment is an effective treatment for differentiated thyroid cancer (DTC), however, many patients are refractory. Using targeted drugs to re-induce RAI sensitivity ("redifferentiation therapy") has long been sought after as the holy grail in endocrine oncology.

PURPOSE Genomic instability is a hallmark of cancer and targeting DNA damage response (DDR) is emerging as a promising therapeutic strategy in different solid tumors. The effectiveness of targeting DDR in colorectal cancer has not been extensively explored. EXPERIMENTAL DESIGN We challenged 112 cell models recapitulating the genomic landscape of metastatic colorectal cancer with ATM, ATR, CHK1, WEE1

PURPOSE The molecular complexity of acute myeloid leukemia (AML) presents a considerable challenge to implementation of clinical genetic testing for accurate risk stratification. Identification of better biomarkers therefore remains a high priority to enable improving established stratification and guiding risk-adapted therapy decisions. EXPERIMENTAL DESIGN We systematically integrated and analyzed

PURPOSE A Phase 2 trial of stereotactic radiation therapy and in situ cytotoxic virus therapy in metastatic triple-negative breast cancer (mTNBC) patients followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with ADV/HSV-tk plus valacyclovir gene therapy and SBRT in mTNBC patients. METHODS In this single-arm, open-label Phase

PURPOSE This retrospective analysis of the largest available clinico-genomic database used de-identified patient-level electronic health record-derived real-world data (RWD) combined with FoundationOne® comprehensive genomic profiling (CGP) to characterize patients with metastatic urothelial carcinoma (mUC) treated in the real-world setting, detect potential biomarkers, and develop a bladder immune

A sizable proportion of AML patients fail to achieve remission. HSCT is the only intervention with potential of long-term survival. A recent AWLP/EBMT analysis reports substantial post-transplant survival gains for patients transplanted with active disease. Decreased relapse was the largest contributor to survival, a cause for optimism in this challenging population.

Survival rates for average-risk medulloblastoma exceed 80%, however long-term sequelae are substantial. A study from Mumbai evaluated the role of omission of craniospinal irradiation. Albeit unsuccessful, this study raises the crucial question of how low therapy can be safely de-escalated with the intent of improving quality of survival.

HLA class I molecules are key in tumor recognition and T-cell mediated elimination. Loss of tumor HLA class I expression with different underlying molecular defects results in reduced antigen presentation and facilitates cancer immune evasion. It is also linked to significant changes in tumor microenvironment and tissue architecture. In this review we summarize the current advances and future perspectives

PURPOSE [131I]meta-iodobenzylguanidine ([131I]MIBG) is a targeted radiotherapeutic administered systemically to deliver beta particle radiation in neuroblastoma. However, relapses in the bone marrow are common. [211At]meta-astatobenzylguanidine [211At]MABG is an alpha particle emitter with higher biological effectiveness and short path length which effectively sterilizes microscopic residual disease

Lack of prospectively planned followup and minimal characterization of the patient population studied complicate interpretation of circulating HPV DNA as a prognostic biomarker for HPV associated oropharyngeal carcinoma patients treated with curative intent.

Tafasitamab and lenalidomide was approved for second-line treatment of diffuse large B-cell lymphoma (DLBCL) based on a single-arm phase II study. This combination was superior to routine immunochemotherapy regimens when comparing matched observational cohorts. "Synthetic" control groups may support use of novel DLBCL therapies in the absence of randomized studies.

BACKGROUND PNOC003 is a multi-center precision medicine trial for children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG). METHODS Patients (3-25 years) were enrolled based on imaging consistent with DIPG. Biopsy tissue was collected for whole exome and mRNA sequencing. After radiation therapy (RT), patients were assigned up to four FDA-approved drugs based on molecular

PURPOSE Ibrutinib has transformed the management of CLL, though its use is limited by toxicity and resistance. In this study, we utilized an "add on" approach for patients treated with ibrutinib in the front-line or R/R settings with detectable MRD. Umbralisib and ublituximab (U2) were added on to ibrutinib, patients were treated until achieving undetectable-MRD (U-MRD), and then they entered a period

PURPOSE Durable clinical benefit to PD-1 blockade in NSCLC is currently limited to a small fraction of patients, underlining the need for predictive biomarkers. We recently identified a tumor-reactive tumor-infiltrating T lymphocyte (TIL) pool, termed PD-1T TILs, with predictive potential in NSCLC. Here, we examined PD-1T TILs as biomarker in NSCLC. EXPERIMENTAL DESIGN PD-1T TILs were digitally quantified

PURPOSE Liquid biopsy offers an attractive platform for non-invasive tumor diagnosis, prognostication and prediction of glioblastoma clinical outcomes. Prior studies report that 30-50% of GBM lesions characterized by EGFR amplification also harbor the EGFRvIII mutation. EXPERIMENTAL DESIGN A novel digital droplet PCR (ddPCR) assay for high GC content amplicons was developed and optimized for sensitive

PURPOSE Modified Gemcitabine and S-1 is an active regimen for patients with advanced biliary tract cancer (ABTC) in our previous study. Herein, we report the results of a single-arm phase II of Nivolumab plus modified GS (NGS) as first-line treatment in ABTC. PATIENTS AND METHODS Patients received Nivolumab 240 mg and 800 mg/m2 Gemcitabine on day 1 plus daily 80/100/120 mg of S-1 (based on body surface

PURPOSE Androgen Receptor (AR) antagonism is exacerbated by HOXB13 in Castration Resistant Prostate Cancers (CRPCs). However, it is unclear when and how does HOXB13 prime CRPCs for AR antagonism. By mass-spectrometry analysis of CRPC extract we uncovered a novel lysine 13 (K13) acetylation in HOXB13 mediated by CBP/p300. To determine whether acetylated K13-HOXB13 is a clinical biomarker of CRPC development

PURPOSE Microsatellite instability-high (MSI-H) endometrial carcinomas (ECs) are underpinned by distinct mechanisms of DNA mismatch repair deficiencies (MMR-D). We sought to characterize clinical and genetic features of MSI-H ECs harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph). DESIGN Of >1,100 EC patients that underwent clinical tumor-normal sequencing

PURPOSE In early-stage, Epidermal growth factor receptor mutation-positive (EGFR-M+) NSCLC, surgery remains the primary treatment, without personalized treatments. We aimed to identify risk factors for recurrence-free survival (RFS) to suggest personalized strategies. PATIENTS AND METHODS From January 2008 to August 2020, a total of 1,181 patients with pathological stage (pStage) IB-IIIA, non-squamous

Chimeric antigen receptor T-cell (CAR-T) therapy is an exciting development in the field of cancer immunology and has received a lot of interest in recent years. Many time-to-event (TTE) endpoints related to relapse, disease progression, and remission are analyzed in CAR-T studies to assess treatment efficacy. Definitions of these TTE endpoints are not always consistent, even for the same outcomes

GITR agonistic antibodies are expected to increase the antitumor response mainly by reducing the effect of Foxp3+ T regulatory cells. TRX-518 is a novel GITR agonist that has shown good pharmacodynamic activity by depleting T regs in preclinical models, with limited clinical activity demonstrated in patients with advanced solid tumors.

PURPOSE Biliary tract cancers (BTCs) are aggressive malignancies refractory to chemotherapy and immunotherapy. MEK inhibitor (MEKi)-based regimens may have utility in this disease when combined with PD-L1 blockade. We hypothesize that dual MEK/PD-L1 inhibition alters circulating soluble and cellular immune mediators to improve clinical outcomes in patients with advanced BTC. EXPERIMENTAL DESIGN We

PURPOSE Identification of inherited germline variants can guide personalized cancer screening, prevention, and treatment. Pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes are frequent among patients with locally advanced or metastatic urothelial carcinoma, but their prevalence and significance in patients with non-muscle invasive bladder cancer (NMIBC), the most

PURPOSE We report efficacy and safety of 90Y-FAPI-46-RLT in patients with advanced sarcoma, pancreatic cancer (PDAC) and other cancer entities. EXPERIMENTAL DESIGN Up to four cycles of RLT were offered to patients with (a) progressive metastatic malignancy, (b) exhaustion of approved therapies, and (c) high fibroblast activation protein (FAP) expression, defined as SUVmax≥10 in more than 50% of tumor

PURPOSE Placental growth factor (PlGF) and its receptor neuropilin 1 (NRP-1) are elevated in malignant embryonal tumors and mediate tumor progression by promoting cell proliferation, survival, and metastasis. TB-403 is a blocking monoclonal antibody against PlGF that inhibits tumor growth and increases survival in orthotopic medulloblastoma (MB) models. PATIENTS AND METHODS We conducted a phase 1,

PURPOSE This study evaluated the efficacy and safety of nivolumab plus gemcitabine in patients with platinum failed NPC. PATIENTS AND METHODS This is a phase II, multicenter, open-label, single-arm study. Patients with recurrent or metastatic NPC received nivolumab 3 mg/kg and gemcitabine 1,250 mg/m2 every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free

Desmoid tumor research is changing how desmoid tumors are managed with the prospective documentation that growing desmoid tumors spontaneously regress one-third of the time. Patient partnership through the Desmoid Research Tumor Foundation and academia is leading to rapid advancement in desmoid tumor biology understanding and treatment.

Immunotherapy has made a significant impact in many solid tumors, including renal cell carcinoma (RCC). RCC has been known to be immune responsive since the cytokine era of interferon-alfa and interleukin-2, but only a small number of patients had durable clinical benefit. Since then, discoveries of key tumor drivers, as well as an understanding of the contribution of angiogenesis and the tumor microenvironment

PURPOSE A Phase 1b study (1604) was conducted to evaluate the safety and efficacy of GS-5829, an oral bromodomain and extra-terminal inhibitor, alone and in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). A Phase 1 study (1599) in solid tumors/lymphoma was also conducted. PATIENTS AND METHODS Men with confirmed mCRPC and disease progression despite abiraterone

PURPOSE To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. EXPERIMENTAL DESIGN We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly-defined subgroups were identified and

PURPOSE Half of the patients with high-risk neuroblastoma (NB) who receive GD2-targeted monoclonal antibody do not achieve long-term remissions. Recently, the antibody hu14.18 has been linked to interleukin (IL)2 (hu14.18-IL2) to enhance its efficacy and shown promising preclinical and clinical activity. We developed two new immunocytokines (ICs) by linking two other γc cytokines, IL15 and IL21, to

PURPOSE PD-L1 expression on tumor cells (TC) is associated with response to anti-PD-1-based therapies in some tumor types, but its significance in ccRCC is uncertain. We leveraged tumor heterogeneity to identify molecular correlates of TC PD-L1 expression in ccRCC and assessed their role in predicting response to anti-PD-1 monotherapy. EXPERIMENTAL DESIGN RNA-sequencing was performed on paired TC PD-L1

PURPOSE Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non-small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown. EXPERIMENTAL DESIGN SAFIR02-Lung was an open-label, randomized, phase 2 trial, involving 33 centers in France. We investigated

PURPOSE While optimal treatment in early TNBC remains unclear, de-escalated chemotherapy (CT) appears to be an option in selected patients within this aggressive subtype. Previous studies have identified several pro-immune factors as prognostic markers in TNBC, but their predictive impact regarding different chemotherapy strategies is still controversial. EXPERIMENTAL DESIGN ADAPT-TN is a randomized

PURPOSE We investigated why three patient derived xenograft (PDX) childhood BRAFV600E-mutant brain tumor models are highly sensitive to trametinib. Mechanisms of acquired resistance selected in situ, and approaches to prevent resistance were also examined, which may translate to both LGG molecular subtypes. EXPERIMENTAL DESIGN Sensitivity to trametinib (MEKi) alone or in combination with rapamycin

PURPOSE Fluorescence-guided surgery using tumor-targeted contrast agents has been developed to improve the completeness of oncologic resections. Quenched activity-based probes that fluoresce after covalently binding to tumor-specific enzymes have been proposed to improve specificity, but none have been tested in humans. Here, we report the successful clinical translation of a cathepsin activity-based

PURPOSE RB1 mutations and loss of Rb expression represent consistent but not entirely invariable hallmarks of small cell lung cancer (SCLC). The prevalence and characteristics of SCLC retaining wild-type Rb are not well-established. Furthermore, the performance of targeted next-generation sequencing (NGS) vs immunohistochemistry for Rb assessment are not well-defined. EXPERIMENTAL DESIGN 208 clinical

Vopratelimab, an anti-ICOS agonist, alone and in combination with nivolumab possesses limited toxicity and modest clinical activity in a large phase I/II trial. This treatment induced ICOS expression of CD4+ T cells, which may enable biomarkers for patient selection. Nevertheless, T cell agonists as cancer immunotherapies continues to be challenging.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging cancers to treat. For patients with advanced and metastatic disease, chemotherapy has yielded only modest incremental benefits which are not durable. Immunotherapy has revolutionized the treatment of other solid tumors by leading to cures where none existed only a decade ago, yet it has made few inroads with PDAC. A host of

PURPOSE Clinical patterns and the associated optimal management of acquired resistance to PD-(L)1 blockade are poorly understood. EXPERIMENTAL DESIGN All cases of metastatic lung cancer treated with PD-(L)1 blockade at Memorial Sloan Kettering were reviewed. In acquired resistance (complete/partial response per RECIST, followed by progression), clinical patterns were distinguished as oligo (OligoAR

PURPOSE This study aimed to assess the antitumor activity and safety of neoadjuvant chemotherapy combined with PD-1 inhibitor camrelizumab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN In this single-center, single-arm, phase 2 trial, patients with resectable stage III-IVB HNSCC received chemotherapy [albumin-bound paclitaxel 260 mg/m2 (or docetaxel

PURPOSE SORAMIC is a randomized controlled trial in advanced HCC patients undergoing sorafenib+/- selective internal radiation therapy (SIRT). We investigated the value of extracellular vesicle (EV)-based proteomics for treatment response prediction. EXPERIMENTAL DESIGN The analysis population comprised 25 patients receiving SIRT+sorafenib and 20 patients receiving sorafenib-alone. Patients were classified

Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) proteins transformed the management of advanced cancers. Many tumor-intrinsic factors modulate immunological and clinical responses to such therapies, but ample evidence also implicates the gut microbiome in responses. The gut microbiome, comprising the bacteria, archaea,

PURPOSE The identification of variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes by hereditary cancer testing poses great challenges for the clinical management of variant carriers. The ACMG/AMP variant classification framework, which incorporates multiple sources of evidence, has the potential to establish the clinical relevance of many VUS. We sought to classify the clinical relevance

Purpose The immunological profile of early-stage breast cancer treated with neoadjuvant PARP inhibitors has not been described. The aim of this study was to delineate the changes in the tumor immune microenvironment (TiME) induced by talazoparib. Methods Patients with operable germline BRCA1/2 pathogenic variant (gBRCA1/2+) breast cancer were enrolled in a feasibility study of neoadjuvant talazoparib

A recent study reported results from a clinical trial in cats and from experiments in minipigs in which a single dose of radiation was delivered at ultrahigh dose rates (FLASH). There was acceptable acute toxicity; however, some animals suffered severe late toxicity, raising caution in the design of future trials.

On August 5, 2020, the Food and Drug Administration granted accelerated approval to belantamab mafodotin-blmf (BLENREP; GlaxoSmithKline) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. Substantial evidence of effectiveness was

Understanding metabolic dependencies and their therapeutic vulnerabilities are key to precision oncology. Malic enzyme1 (ME1) is frequently overexpressed in cancers with pro-tumorigenic effects. In contrast, consistent loss of ME1 expression in synovial sarcoma compared with other sarcomas indicates a unique ferroptosis liability for precision therapy in this form of cancer.

The novel combination of checkpoint inhibitors targeting the PD(L)1 pathway and anti-VEGFA therapy has revolutionized the treatment landscape of advanced HCC. However, biomarkers predictive of response to these therapies are still lacking, representing a major clinical challenge.

On August 13, 2021, the United States Food and Drug Administration (FDA) approved belzutifan (WELIREG, Merck), a first-in-class hypoxia-inducible factor (HIF) inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate

PURPOSE Tumor-associated vasculature is distinguished its convolutedness, leakiness, and chaotic architecture, which facilitates the creation of a treatment resistant tumor microenvironment. Measurable differences in these attributes might help stratify patients by potential benefit of systemic therapy. In this work, we present a new category of radiomic quantitative tumor-associated vasculature (QuanTAV)

PURPOSE Chimeric antigen receptor (CAR) T cell therapy has shown great promise for treating hematologic malignancies but requires a long duration of T-cell expansion, is associated with severe toxicity, and has limited efficacy for treating solid tumors. We designed experiments to address those challenges. EXPERIMENTAL DESIGN We generated a cell membrane-anchored and tumor-targeted interleukin-12 (attIL12)

PURPOSE New therapeutic options are needed in relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). Lenalidomide based schedules can reverse rituximab refractoriness in lymphoma. EXPERIMENTAL DESIGN In the phase II R2-GDP trial, 78 patients unsuitable for autologous stem cell transplant received treatment with R2-GDP schedule: lenalidomide 10 mg d1-14, rituximab 375 mg/m2 d1, cisplatin 60

PURPOSE To evaluate the anti-cancer effects of cabozantinib, temozolomide, and their combination in uterine sarcoma cell lines and mouse xenograft models. EXPERIMENTAL DESIGN Human uterine sarcoma cell lines (SK-LMS-1, SK-UT-1, MES-SA, and SKN) were used to evaluate the anti-cancer activity of cabozantinib, temozolomide, and their combination. The optimal dose of each drug was determined by MTT assay

PURPOSE This study evaluated the central nervous system (CNS) pharmacokinetics and target engagement of lapatinib, neratinib, and tucatinib in patients with cancer, using a physiologically based pharmacokinetic (PBPK) modeling approach. EXPERIMENTAL DESIGN Drug-specific parameters for in vitro metabolism, binding to plasma proteins and brain tissues, transcellular passive permeability, and interactions

PURPOSE Dynamic changes in circulating tumor DNA (ctDNA) are under investigation as an early indicator of treatment outcome. EXPERIMENTAL DESIGN Serial plasma ctDNA (baseline, 8 weeks and at progression) was prospectively incorporated into the SWOG S1403 clinical trial of afatinib +/- cetuximab in TKI-naive, EGFR-mutation tissue-positive NSCLC. RESULTS EGFR mutations were detected in baseline ctDNA

PURPOSE Despite accumulating evidence on dual blockade of human epidermal growth factor receptor 2 (HER2) for locally advanced HER2-positive breast cancer, no robust evidence supports the addition of pyrotinib to trastuzumab in the neoadjuvant setting. The NeoATP trial aimed to evaluate the efficacy and safety of pyrotinib with neoadjuvant trastuzumab and chemotherapy. METHODS The phase II NeoATP trial

PURPOSE Current endoscopy-based screening and surveillance programs have not been proven effective at decreasing esophageal adenocarcinoma (EAC) mortality, creating an unmet need for effective molecular tests for early detection of this highly lethal cancer. We conducted a genome-wide methylation screen to identify novel methylation markers that distinguish EAC and high grade dysplasia (HGD) from normal

PURPOSE Study the biology and identify markers of severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in children post chimeric antigen receptor T-cell (CART) treatment. EXPERIMENTAL DESIGN We use comprehensive proteomic profiling to measure over 1400 serum proteins at multiple serial timepoints in a cohort of patients with B-cell acute lymphoblastic

PURPOSE Combination therapies targeting immunological checkpoints have shown promise in treating multiple tumor types. We report safety and tolerability of MEDI0562, a humanized IgG1K OX40 monoclonal antibody, in combination with durvalumab (anti-PD-L1), or tremelimumab (anti-CTLA-4), in adult patients with previously treated advanced solid tumors. EXPERIMENTAL DESIGN In this phase 1, multicenter,