bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Treatment of prostate cancer with CD46 targeted 225Ac alpha particle radioimmunotherapy
Authors: Bidkar Anil P. , Wang Sinan , Bobba Kondapa Naidu. , Chan Emily , Bidlingmaier Scott , Egusa Emily A. , Peter Robin , Ali Umama , Meher Niranjan , Wadhwa Anju , Dhrona Suchi , Dasari Chandrashekhar , Beckford-Vera Denis , Su Yang , Tang Ryan , Zhang Li , He Jiang , Wilson David M. , Aggarwal Rahul , VanBrocklin Henry F. , Seo Youngho , Chou Jonathan , Liu Bin , Flavell Robert R.
Published: September 2024

Abstract
Purpose: Radiopharmaceutical therapy is changing the standard of care in prostate cancer (PCa) and other malignancies. We previously reported high CD46 expression in PCa and developed an antibody-drug conjugate and immunoPET agent based on the YS5 antibody, which targets a tumor-selective CD46 epitope. Here, we present the preparation, preclinical efficacy, and toxicity evaluation of [225Ac]DOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody. Experimental Design: [225Ac]DOTA-YS5 was developed, and its therapeutic efficiency was tested on cell derived (22Rv1, DU145), and patient derived (LTL-545, LTL484) PCa xenograft models. Biodistribution studies were carried out on 22Rv1 tumor xenograft models to confirm the targeting efficacy. Toxicity analysis of the [225Ac]DOTA-YS5 was carried out on nu/nu mice to study short-term (acute) and long-term (chronic) toxicity. Results: Biodistribution study shows that [225Ac]DOTA-YS5 agent delivers high levels of radiation to the tumor tissue (11.64±1.37 %ID/g, 28.58±10.88 %ID/g, 29.35±7.76%ID/g, and 31.78±5.89 %ID/g at 24 h, 96 h, 168 h, and 408 h, respectively), compared to the healthy organs. [225Ac]DOTA-YS5 suppressed tumor size and prolonged survival in cell line and patient derived xenograft models. Toxicity analysis revealed that the 0.5 µCi activity levels showed toxicity to the kidneys, likely due to redistribution of daughter isotope 213Bi. Conclusions: [225Ac]DOTA-YS5 suppressed the growth of cell-derived and patient-derived xenografts, including PSMA-positive and deficient models. Overall, this preclinical study confirms that [225Ac]DOTA-YS5 is a highly effective treatment and suggests feasibility for clinical translation of CD46 targeted radioligand therapy in PCa.
Data from Multi-center phase I trial of Ivosidenib as Maintenance Treatment following Allogeneic Hematopoietic Cell Transplantation for IDH1-Mutated Acute Myeloid Leukemia
Authors: Fathi Amir T. , Kim Haesook T. , Soiffer Robert J. , Levis Mark J. , Li Shuli , Kim Annette S. , DeFilipp Zachariah , El-Jawahri Areej , McAfee Steve L. , Brunner Andrew M. , Amrein Philip C. , Mims Alice S. , Knight Laura W. , Kelley Devon , Bottoms AJ S. , Perry Lindsey H. , Wahl Jonathan L. , Brock Jennifer , Breton Elayne , Marchione Dylan M. , Ho Vincent T. , Chen Yi-Bin
Published: September 2024

Abstract
Purpose: IDH1 (isocitrate dehydrogenase 1) mutations occur in 5-10% of patients with acute myeloid leukemia (AML). Ivosidenib is an IDH1 inhibitor, approved for use in patients with IDH1-mutated AML. Patients and Methods: We conducted a multi-center, phase I trial of maintenance ivosidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH1-mutated AML. Ivosidenib was initiated between days 30 and 90 following HCT and continued for up to twelve 28-day cycles. The first dose level was 500mg daily, with level reduction to 250mg daily, if needed, in a 3x3 de-escalation design. Ten additional patients would then receive the maximum tolerated (MTD) or recommended phase 2 dose (RP2D). The primary endpoint was establishing the MTD or RP2D of ivosidenib. Results: Eighteen patients were enrolled, of whom 16 initiated post-HCT ivosidenib. One dose limiting toxicity, grade(g) 3 QTc prolongation, was observed. The RP2D was established at 500mg daily. Attributable g≥3 adverse events were uncommon, with the most common being QTc prolongation in 2 patients. Eight patients discontinued maintenance, with only one due to adverse event. Six-month cumulative incidence (CI) of gII-IV aGVHD was 6.3%, and two-year CI of all cGVHD was 63%. Two-year CI of relapse and non-relapse mortality (NRM) were 19% and 0%, respectively. Two-year progression-free (PFS) was 81%, and two-year overall survival (OS) was 88%. Conclusions: Ivosidenib is safe and well-tolerated as maintenance therapy following HCT. Cumulative incidence of relapse and NRM, as well as estimations of PFS and OS, were promising in this phase 1 study.
Data from Granulocyte colony stimulating factor is a novel mediator of T cell suppression and an immunotherapeutic target for women with colon cancer
Authors: Ray Anita L. , Saunders Apryl S. , Nofchissey Robert A. , Reidy Megan A. , Kamal Maria , Lerner Megan R. , Fung Kar-Ming , Lang Mark L. , Hanson Joshua A. , Guo Shaoxuan , Urdaneta-Perez Maria G. , Lewis Samara E. , Cloyde Michael , Morris Katherine T.
Published: September 2024

Abstract
Purpose: Granulocyte colony stimulating factor (GCSF) enhances colon cancer development. This study defines the prevalence and effects of increased GCSF signaling in human colon cancers and investigates GCSF inhibition as an immunotherapeutic strategy against metastatic colon cancer. Experimental Design: Patient samples were used to evaluate GCSF and GCSF receptor (GCSFR) levels by immunohistochemistry with sera used to measure GCSF levels. PBMCs were used to assess the rate of GCSFR+ T cells and interferon γ (IFNγ) responses to chronic ex vivo GCSF. An immune competent mouse model of peritoneal metastasis (MC38 cells in C57Bl/6J) was used to determine the effects of GCSF inhibition (αGCSF) on survival and the tumor microenvironment (TME) with flow and mass cytometry. Results: GCSF and GCSFR are increased in human colon cancer samples as compared to patient-matched normal colon. High patient serum GCSF is associated with increases in markers of poor prognosis, (e.g., VEGF, IL6). Circulating T cells from patients express GCSFR at double the rate of T cells from controls. Prolonged GCSF exposure decreases T cell IFNγ production. Treatment with αGCSF shifts both the adaptive and innate compartments of the TME and increases survival (HR=0.46, p=0.0237) and tumor T cell infiltration, activity, and IFNγ response with greater effects in female mice. A negative correlation exists between serum GCSF levels and tumor infiltrating T cells in patient samples from women. Conclusions: These findings support GCSF as an immunotherapeutic target against colon cancer with greater potential benefit in women.
Data from Myosin light chain kinase inhibition potentiates the anti-tumor effects of avapritinib in PDGFRA D842V-mutant gastrointestinal stromal tumor
Authors: Rossi Ferdinand , Liu Mengyuan , Tieniber Andrew , Etherington Mark S. , Hanna Andrew , Vitiello Gerardo A. , Param Nesteene J. , Do Kevin , Wang Laura , Antonescu Cristina R. , Zeng Shan , Zhang Jennifer Q. , DeMatteo Ronald P.
Published: September 2024

Abstract
Purpose: To create an in vivo model of PDGFRA D842V-mutant gastrointestinal stromal tumor (GIST) and identify the mechanism of tumor persistence following avapritinib therapy. Experimental Design: We created a patient-derived xenograft of PDGFRA D842V-mutant GIST and tested the effects of imatinib, avapritinib, and ML-7, an inhibitor of myosin light chain kinase (MYLK). Bulk tumor RNA sequencing and oncogenic signaling were evaluated. Apoptosis, survival, and actin cytoskeleton were evaluated in GIST T1 cells and isolated PDX cells in vitro. Human GIST specimens were analyzed for MYLK expression. Results: The PDX was minimally responsive to imatinib but sensitive to avapritinib. Avapritinib therapy increased tumor expression of genes related to the actin cytoskeleton, including MYLK. ML-7 induced apoptosis and disrupted actin filaments in short-term cultures of PDX cells, and decreased survival in GIST T1 cells in combination with imatinib or avapritinib. Combined therapy with ML-7 improved the anti-tumor effects of low dose avapritinib in vivo. Furthermore, MYLK was expressed in human GIST specimens. Conclusions: MYLK upregulation is a novel mechanism of tumor persistence after tyrosine kinase inhibition. Concomitant MYLK inhibition may enable the use of a lower dose of avapritinib, which is associated with dose-dependent cognitive side effects.
Data from Somatic exonic deletions in RUNX1 constitutes a novel recurrent genomic abnormality in acute myeloid leukemia
Authors: Eriksson Anna , Engvall Marie , Mathot Lucy , Österroos Albin , Rippin Martin , Cavelier Lucia , Ladenvall Claes , Baliakas Panagiotis
Published: September 2024

Abstract
Purpose: In acute myeloid leukemia (AML), somatic mutations (commonly missense, nonsense and frameshift indels) in RUNX1 are associated with a dismal clinical outcome. Inherited RUNX1 mutations cause familial platelet disorder. As approximately 5-10% of germline RUNX1 mutations are large exonic deletions, we hypothesized that such exonic RUNX1 aberrations may also be acquired during the development of AML. Experimental Design: Sixty well-characterized AML patients were analyzed with Multiplex Ligation-dependent Probe Amplification (MLPA, n=60), micro-array (n=11) and/or whole genome sequencing (WGS, n=8). Results: In total, 25 (42% of the cohort) RUNX1-aberrant patients (defined by the presence of classical mutations and/or exonic deletions) were identified. Sixteen patients (27%) carried only exonic deletions, 5 (8%) carried classical mutations and 4 (7%) carried both exonic deletions and mutations. No significant difference was observed between patients with classical RUNX1 mutations and RUNX1 exonic deletions in median overall survival (OS, 53.1 vs 38.8 months respectively, p=0.63). When applying the European Leukemia Net (ELN) classification including the RUNX1-aberrant group, 20% of the patients initially stratified as intermediate-risk (5% of the whole cohort) were re-assigned to the high-risk group, which improved the performance of ELN classification regarding OS between intermediate and high-risk group (18.9 vs 9.6 months, p=0.09). Conclusions: Somatic RUNX1 exonic deletions constitute a novel recurrent aberration in AML. Our findings have important clinical implications regarding AML classification, risk-stratification and treatment decision. Moreover, they argue in favor of further investigating such genomic aberrations not only in RUNX1 but also in other genes implicated in cancer biology and management.
Data from An Immune-Related Gene Expression Signature Predicts Benefit from Adding Atezolizumab to FOLFOXIRI plus Bevacizumab in Metastatic Colorectal Cancer
Authors: Antoniotti Carlotta , Boccaccino Alessandra , Seitz Robert , Giordano Mirella , Catteau Aurélie , Rossini Daniele , Pietrantonio Filippo , Salvatore Lisa , McGregor Kimberly , Bergamo Francesca , Conca Veronica , Leonetti Simone , Morano Federica , Papiani Giorgio , Tamburini Emiliano , Bensi Maria , Murgioni Sabina , Ross Douglas Teller , Passardi Alessandro , Boquet Isabelle , Nielsen Tyler J. , Galon Jérôme , Varga Matthew Gordon , Schweitzer Brock L. , Cremolini Chiara
Published: September 2024

AbstractPurpose:
AtezoTRIBE phase II randomized study demonstrated that adding atezolizumab to first-line FOLFOXIRI (5-fluorouracil, oxaliplatin, irinotecan) plus bevacizumab prolongs progression-free survival (PFS) of patients with metastatic colorectal cancer (mCRC), with a modest benefit among proficient mismatch repair (pMMR). DetermaIO is an immune-related 27-gene expression signature able to predict benefit from immune checkpoint inhibition in triple-negative breast cancer. In this analysis of AtezoTRIBE, we investigated the predictive impact of DetermaIO in mCRC.
Experimental Design:
Patients with mCRC unselected for MMR status were randomly assigned (1:2) to FOLFOXIRI plus bevacizumab (control arm) or the same regimen with atezolizumab (atezolizumab arm). qRT-PCR by DetermaIO was performed on RNA purified from pretreatment tumors of 132 (61%) of 218 enrolled patients. A binary result (IOpos vs. IOneg) adopting the preestablished DetermaIO cut-off point (0.09) was obtained, and an exploratory optimized cut-off point (IOOPT) was computed in the overall population and in pMMR subgroup (IOOPTpos vs. IOOPTneg).
Results:
DetermaIO was successfully determined in 122 (92%) cases, and 23 (27%) tumors were IOpos. IOpos tumors achieved higher PFS benefit from atezolizumab arm than IOneg (HR: 0.39 vs. 0.83; Pinteraction = 0.066). In pMMR tumors (N = 110), a similar trend was observed (HR: 0.47 vs. 0.93; Pinteraction = 0.139). In the overall population, with the computed IOOPT cut-off point (0.277), 16 (13%) tumors were IOOPTpos and they derived higher PFS benefit from atezolizumab than IOOPTneg (HR: 0.10 vs. 0.85, Pinteraction = 0.004). Similar results were found in the pMMR subgroup.
Conclusions:
DetermaIO may be useful to predict benefit of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in mCRC. The exploratory IOOPT cut-off point should be validated in independent mCRC cohorts.
Data from An immune-related gene expression signature predicts benefit from adding atezolizumab to FOLFOXIRI plus bevacizumab in metastatic colorectal cancer
Authors: Antoniotti Carlotta , Boccaccino Alessandra , Seitz Robert , Giordano Mirella , Catteau Aurélie , Rossini Daniele , Pietrantonio Filippo , Salvatore Lisa , McGregor Kimberly , Bergamo Francesca , Conca Veronica , Leonetti Simone , Morano Federica , Papiani Giorgio , Tamburini Emiliano , Bensi Maria , Murgioni Sabina , Ross Douglas Teller. , Passardi Alessandro , Boquet Isabelle , Nielsen Tyler J. , Galon Jerome , Varga Matthew Gordon. , Schweitzer Brock L. , Cremolini Chiara
Published: September 2024

Abstract
Background: AtezoTRIBE phase II randomized study demonstrated that adding atezolizumab to first-line FOLFOXIRI (5fluoruracil, oxaliplatin, irinotecan) plus bevacizumab prolongs progression-free survival (PFS) of metastatic colorectal cancer (mCRC) patients, with a modest benefit among proficient mismatch repair (pMMR). DetermaIO is an immune-related 27-gene expression signature able to predict benefit from immune-checkpoint inhibition in triple-negative breast cancer. In this analysis of AtezoTRIBE, we investigated the predictive impact of DetermaIO in mCRC. Methods: mCRC patients unselected for MMR status were randomized(1:2) to FOLFOXIRI plus bevacizumab (control arm) or the same regimen with atezolizumab (atezolizumab arm). RT-qPCR by DetermaIO was performed on RNA purified from pre-treatment tumours of 132(61%) out of 218 enrolled patients. A binary result (IOpos versus IOneg) adopting the pre-established DetermaIO cut-point (0.09) was obtained, and an exploratory optimized cut-point (IOOPT) was computed in the overall population and in pMMR subgroup (IOOPTpos versus IOOPTneg). Results: DetermaIO was successfully determined in 122 (92%) cases, and 23 (27%) tumours were IOpos. IOpos tumours achieved higher PFS benefit from atezolizumab arm than IOneg (HR:0.39 versus 0.83, P interaction=0.066). In pMMR tumours (N=110), a similar trend was observed (HR:0.47 versus 0.93, P interaction=0.139). In the overall population, with the computed IOOPT cut-point (0.277), 16 (13%) tumours were IOOPTpos and they derived higher PFS benefit from atezolizumab than IOOPTneg(HR:0.10 versus 0.85, P interaction=0.004). Similar results were found in the pMMR subgroup. Conclusions :DetermaIO may be useful to predict benefit of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in mCRC. The exploratory IOOPT cut-point should be validated in independent mCRC cohorts.
Data from Co-clinical study of [fam-] trastuzumab deruxtecan (DS8201a) in patient-derived xenograft models of uterine carcinosarcoma and its association with clinical efficacy
Authors: Yagishita Shigehiro , Nishikawa Tadaaki , Yoshida Hiroshi , Shintani Daisuke , Sato Sho , Miwa Maiko , Suzuki Mikiko , Yasuda Masanori , Ogitani Yusuke , Jikoh Takahiro , Yonemori Kan , Hasegawa Kosei , Hamada Akinobu
Published: September 2024

Abstract
Background: Uterine carcinosarcoma (UCS), a subtype of endometrial carcinoma, is a rare and aggressive cancer with a poor prognosis. High clinical efficacy of trastuzumab deruxtecan (T-DXd) in HER2-expressing UCS was recently reported in phase 2 trial (STATICE trial). We performed a co-clinical study of T-DXd using patient-derived xenograft (PDX) models of participants in the STATICE trial. Patients and methods: Tumor specimens were resected during primary surgery or biopsied at recurrence from patients with UCS and transplanted into immunodeficient mice. Seven UCS-PDXs from six patients were established and HER2, estrogen receptor (ER), and p53 expression in PDX and the original tumor was assessed. Drug efficacy tests were performed using six of the seven PDXs. Of the six UCS-PDXs tested, two were derived from patients enrolled in the STATICE trial. Results: The histopathological characteristics of the six PDXs were well-conserved from the original tumors. HER2 expression was 1+ in all PDXs, and ER and p53 expression was almost similar to that in the original tumors. Remarkable tumor shrinkage after T-DXd administration was observed in four out of the six PDXs (67%), comparable to the response rate (70%) of HER2 1+ patients in the STATICE trial. Two patients enrolled in the STATICE trial showed partial response as the best response, and the clinical effect was well-replicated with marked tumor shrinkage. Conclusion: We successfully performed a co-clinical study of T-DXd in HER2-expressing UCS, along with the STATICE trial. Our PDX models can predict clinical efficacy and serve as an effective preclinical evaluation platform.
Data from DNA-Methylome based Tumor Hypoxia Classifier Identifies HPV-negative Head & Neck Cancer Patients at Risk for Locoregional Recurrence After Primary Radiochemotherapy
Authors: Tawk Bouchra , Rein Katrin , Schwager Christian , Knoll Maximilian , Wirkner Ute , Hörner-Rieber Juliane , Liermann Jakob , Kurth Ina , Balermpas Panagiotis , Roedel Claus , Linge Annett , Loeck Steffen , Lohaus Fabian , Tinhofer Ingeborg , Krause Mechthild , Stuschke Martin , Grosu Anca-Ligia , Zips Daniel , Combs Stephanie E. , Belka Claus , Stenzinger Albrecht , Herold-Mende Christel , Baumann Michael , Schirmacher Peter , Debus Jürgen , Abdollahi Amir
Published: September 2024

Abstract
Background: Tumor hypoxia is a paradigmatic negative prognosticator of treatment resistance in Head and Neck Squamous Cell Carcinoma (HNSCC). The lack of robust and reliable hypoxia classifiers limits the adaptation of stratified therapies. We hypothesized that the tumor DNA methylation landscape might indicate epigenetic reprogramming induced by chronic intratumoral hypoxia. Methods: A DNA methylome-based tumor hypoxia classifier (Hypoxia-M) was trained in the TCGA-HNSCC cohort based on matched assignments using gene expression-based signatures of hypoxia (Hypoxia-GES). Hypoxia-M was validated in a multicenter DKTK-ROG trial consisting of Human Papilloma Virus (HPV)-negative HNSCC patients treated with primary radiochemotherapy (RCHT). Results: While hypoxia-GSEs failed to stratify patients in the DKTK-ROG, Hypoxia-M was independently prognostic for local recurrence (LR, HR=4.3, p=0.001) and overall survival (OS, HR=2.34, p=0.03) but not distant metastasis (DM) after RCHT in the both cohorts. Hypoxia-M status was inversely associated with CD8 T-cells infiltration in both cohorts. Hypoxia-M was further prognostic in the TCGA-PanCancer cohort (HR=1.83, p=0.04), underscoring the breadth of this classifier for predicting tumor hypoxia status. Conclusions: Our findings highlight an unexplored avenue for DNA Methylation-based classifiers as biomarkers of tumoral hypoxia for identifying high-risk features in patients with HNSCC tumors. Trial registration: Retrospective observational study from the German Cancer Consortium (DKTK-ROG), not interventional.
Data from Clinical importance of the lncRNA NEAT1 in cancer patients treated with immune checkpoint inhibitors.
Authors: Toker Joseph , Iorgulescu J. Bryan. , Ling Alexander L. , Villa Genaro R. , Gadet Josephina A.M.A. , Parida Laxmi , Getz Gad , Wu Catherine J. , Reardon David A. , Chiocca E. Antonio , Mineo Marco
Published: September 2024

Abstract
Purpose: Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint are powerful tools to improve the survival of cancer patients. Understanding the molecular basis of clinical response to these treatments is critical to identify patients who can benefit from this immunotherapy. In this study, we investigated long non-coding RNA (lncRNA) expression in cancer patients treated with anti-PD-1/PD-L1 immunotherapy. Experimental design: LncRNA expression profile was analyzed in one cohort of melanoma patients and two independent cohorts of patients with glioblastoma (GBM) undergoing anti-PD-1/PD-L1 immunotherapy. Single-cell RNA-sequencing analyses were performed to evaluate lncRNA expression in tumor cells and tumor-infiltrating immune cells. Results:We identified the lncRNA NEAT1 as commonly upregulated between melanoma patients with complete therapeutic response and GBM patients with longer survival following anti-PD-1/PD-L1 treatment. Gene set enrichment analyses revealed that NEAT1 expression was strongly associated with the interferon-gamma pathways, along with downregulation of cell-cycle-related genes. Single-cell RNA-sequencing analyses revealed NEAT1 expression across multiple cell types within the GBM microenvironment, including tumor cells, macrophages, and T cells. High NEAT1 expression levels in tumor cells correlated with increased infiltrating macrophages and microglia. In these tumor-infiltrating myeloid cells, we found that NEAT1 expression was linked to enrichment in TNF alpha/NFKB signaling pathway genes. Silencing NEAT1 suppressed M1 macrophage polarization and reduced the expression of TNF alpha and other inflammatory cytokines. Conclusions: These findings suggest an association between NEAT1 expression and patient response to anti-PD-1/PD-L1 therapy in melanoma and GBM and have important implications for the role of lncRNAs in the tumor microenvironment.
Data from Adjuvant Nivolumab Versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results From CheckMate 238
Authors: Larkin James , Del Vecchio Michele , Mandala Mario , Gogas Helen , Arance Ana M. , Dalle Stephane , Cowey Charles Lance. , Schenker Michael , Grob Jean-Jacques , Chiarion-Sileni Vanna , Marquez-Rodas Ivan , Butler Marcus O. , Di Giacomo Anna Maria , Middleton Mark R. , Lutzky Jose , de la Cruz-Merino Luis , Arenberger Petr , Atkinson Victoria , Hill Andrew G. , Fecher Leslie A. , Millward Michael , Nathan Paul D. , Khushalani Nikhil I. , Queirolo Paola , Ritchings Corey , Lobo Maurice , Askelson Margarita , Tang Hao , Dolfi Sonia , Ascierto Paolo A. , Weber Jeffrey
Published: September 2024

Abstract
Purpose: In the phase III CheckMate 238 study, adjuvant nivolumab (NIVO) significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab (IPI) in patients with resected stage IIIB–C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings. Patients and Methods: Patients with resected stage IIIB–C/IV melanoma were stratified by stage and baseline PD-L1 expression and received NIVO 3 mg/kg every 2 weeks or IPI 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. Results: At a minimum follow-up of 62 months, RFS with NIVO remained superior to IPI (HR 0.72; 95% CI, 0.60–0.86; 5-year rates of 50% versus 39%). 5-year DMFS rates were 58% with NIVO versus 51% with IPI. Five-year OS rates were 76% with NIVO and 72% with IPI (75% data maturity: 228 of 302 planned events). Higher levels of TMB, tumor PD-L1, intratumoral CD8+ T cells and interferon-gamma–associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both NIVO and IPI, albeit with limited clinically meaningful predictive value. Conclusion: NIVO is a proven adjuvant treatment for resected melanoma at high-risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with IPI and high OS rates. Identification of additional biomarkers are needed to better predict treatment outcome.
Data from PI3K Inhibition Restores and Amplifies Response to Ruxolitinib in patients with Myelofibrosis
Authors: Moyo Tamara K. , Kishtagari Ashwin , Villaume Matthew , McMahon Brandon , Mohan Sanjay R. , Stopczynski Tess , Chen Sheau-Chiann , Fan Run , Huo Yuankai , Moon Hyeonsoo , Tang Yucheng , Bejan Cosmin A. , Childress Merrida , Anderson Ingrid , Rawling Kyle , Simons Rhea M. , Moncrief Ashley , Caza Rebekah , Dugger Laura , Collins Aunshka , Dudley Channing V. , Ferrell P. Brent , Byrne Michael , Strickland Stephen A. , Ayers Gregory D. , Landman Bennett A. , Mason Emily F. , Mesa Ruben A. , Palmer Jeanne M. , Michaelis Laura C. , Savona Michael R.
Published: September 2024

Abstract
Purpose: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (PMF), or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F mutant cell lines. Patients and Methods: In a phase I dose-escalation and expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor umbralisib in combination with ruxolitinib in MF patients who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that maximally tolerated dose at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas. Results: Thirty-seven MF patients with prior exposure to ruxolitinib were enrolled. 2 patients treated with 800mg umbralisib experienced reversible Grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved complete response (CR), and 12 patients (32%) met the IWG-MRT response criteria of clinical improvement (CI). With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up. Conclusions: Adding umbralisib to ruxolitinib in patients was well-tolerated and may re-sensitize MF patients to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors.
Data from A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E Mutated Differentiated thyroid Cancer
Authors: Leboulleux Sophie , Do Cao Christine , Zerdoud Slimane , Attard Marie , Bournaud Claire , Lacroix Ludovic , Benisvy Danielle , Taïeb David , Bardet Stephane , Terroir-Cassou-Mounat Marie , Anizan Nadege , Bouvier-Morel Emilie , Lamartina Livia , Lion Georges , Betrian Sarah , Sajous Christophe , Schiazza Aurelie , Garcia Marie-Eve , Ciappuccini Renaud , Schlumberger Martin , Al Ghuzlan Abir , Godbert Yann , Borget Isabelle
Published: September 2024

Abstract
Purpose: To evaluate the efficacy and safety of dabrafenib-trametinib-131I for the treatment of radioactive iodine refractory metastatic differentiated thyroid cancer (DTC) with a BRAFp.V600E mutation. Experimental Design: A prospective phase II trial including patients with RECIST progression within 18 months and no lesion >3 cm. Following a baseline recombinant human (rh)TSH-stimulated diagnostic whole-body scan (dc1-WBS), dabrafenib and trametinib were given for 42 days. A second rhTSH-stimulated dc WBS (dc2-WBS) was done at day 28 and 131I (5.5 GBq-150mCi after rhTSH) was administered at day 35. Primary endpoint was the 6-months RECIST objective response rate. In case of partial response (PR) at 6 or 12 months, a second treatment course could be given. Among 24 enrolled patients, 21 were evaluable at 6 months. Results: Abnormal 131I uptake was present on 5%, 65% and 95% of the dc1-WBS, dc2-WBS and post-therapy scan, respectively. At 6 months, PR was achieved in 38%, stable disease in 52% and progressive disease (PD) in 10%. Ten patients received a second treatment course: one complete response and 6 PR were observed at 6 months. The median progression free survival (PFS) was not reached. The 12 and 24-months PFS were 82% and 68%, respectively. One death due to PD occurred at 24 months. Adverse events (AEs) occurred in 96% of the patients with 10 grade 3-4 AEs in 7 patients. Conclusion: Dabrafenib-trametinib is effective in BRAFp.V600E mutated DTC patients for restoring 131I uptake with partial response observed 6 months after 131I administration in 38% of the patients.
Data from Uncoupling CD4+ TIL-mediated tumor killing from JAK-signaling in melanoma
Authors: Draghi Arianna , Presti Mario , Jensen Agnete W.P. , Chamberlain Christopher A. , Albieri Benedetta , Rasmussen Anne-Christine K. , Andersen Mads H. , Crowther Michael D. , Svane Inge Marie , Donia Marco
Published: September 2024

Abstract
Introduction: Impaired MHCI-presentation and insensitivity to immune effector molecules are common features of immune checkpoint blockade(ICB)-resistant tumors and can be respectively associated with loss of β2 microglobulin(B2M) or impaired IFNγ-signaling. Patients with ICB-resistant tumors can respond to alternative immunotherapies, such as infusion of autologous tumor-infiltrating lymphocytes(TILs). CD4+ T cells can exert cytotoxic functions against tumor cells; however, it is unclear whether CD4+ T cell responses can be exploited to improve the clinical outcomes of patients affected by ICB-resistant tumors. Materials and methods: Here, we exploited CRISPR/Cas9 gene editing to reproduce immune-resistant tumor phenotypes via gene knockout(KO). To determine the role of cytotoxic CD4+ TILs in ICB-resistant tumors, we investigated CD4+ TIL-mediated cytotoxicity in matched pairs of TILs and autologous melanoma cell lines, used as a model of patient-specific immune-tumor interaction. Around 40% of melanomas constitutively express MHC Class II molecules; hence melanomas with or without natural constitutive MHC Class II expression(MHCIIconst+ or MHCIIconst-) were employed. Results: CD4+ TIL-mediated cytotoxicity was not affected by B2M loss but was dependent on the expression of CIITA. MHCIIconst+ melanomas were killed by tumor-specific CD4+ TILs even in the absence of IFNγ-mediated MHCII upregulation, whereas IFNγ was necessary for CD4+ TIL-mediated cytotoxicity against MHCIIconst- melanomas. Notably, while tumor-specific CD4+ TILs did not kill JAK1KO MHCIIconst- melanomas even post IFNγ stimulation, sensitivity toCD4+ TIL-mediated cytotoxicity was maintained by JAK1KO MHCIIconst+ melanomas. Conclusion: In conclusion, our data indicate that exploiting tumor-specific cytotoxic CD4+ TILs could help overcome resistance to ICB mediated by IFNγ-signaling loss in MHCIIconst+ melanomas.
Data from Investigation of poly ADP-ribose polymerase inhibitor resistance based on serially collected circulating tumor DNA in patients with BRCA-mutated ovarian cancer
Authors: Kim Yoo-Na , Shim Yeeun , Seo Jieun , Choi Zisun , Lee Yong Jae , Shin Saeam , Kim Sang Wun , Kim Sunghoon , Choi Jong Rak , Lee Jung-Yun , Lee Seung-Tae
Published: September 2024

Abstract
Purpose: Patient-specific molecular alterations leading to poly ADP-ribose polymerase inhibitor (PARPi) resistance are relatively unexplored. In this study, we analyzed serially collected circulating tumor DNA (ctDNA) from patients with BRCA1/2 mutations who received PARPis to investigate the resistance mechanisms and their significance in post-progression treatment response and survival. Experimental Design: Patients were prospectively enrolled between January 2018 and December 2021 (NCT05458973). Whole-blood samples were obtained before PARPi administration and serially every 3 months until progression. ctDNA was extracted from the samples and sequenced with a 531-gene panel; gene sets for each resistance mechanism were curated. Results: Fifty-four patients were included in this analysis. Mutation profiles of genes in pre-PARPi samples indicating a high tumor mutational burden and alterations in genes associated with replication fork stabilization and drug efflux were associated with poor progression-free survival on PARPis. BRCA hypomorphism and reversion were found in one and three patients, respectively. Among 29 patients with matched samples, mutational heterogeneity increased post-progression on PARPis, showing at least one post-specific mutation in 89.7% of the patients. These mutations indicate non-exclusive acquired resistance mechanisms—homologous recombination repair restoration (28%), replication fork stability (34%), upregulated survival pathway (41%), target loss (10%), and drug efflux (3%). We observed poor progression-free survival with subsequent chemotherapy in patients with homologous recombination repair restoration (P = 0.003) and those with the simultaneous involvement of two or more resistance mechanisms (P = 0.040). Conclusions: Analysis of serial ctDNAs highlighted multiple acquired resistance mechanisms, providing valuable insights for improving post-progression treatment and survival.
Data from RAD51 foci as a biomarker predictive of platinum chemotherapy response in ovarian cancer
Authors: Compadre Amanda J. , van Biljon Lillian N. , Valentine Mark C. , Llop-Guevara Alba , Graham Emily , Fashemi Bisiayo , Herencia-Ropero Andrea , Kotnik Emilee N. , Cooper Isaac , Harrington Shariska P. , Kuroki Lindsay M. , McCourt Carolyn K. , Hagemann Andrea R. , Thaker Premal H. , Mutch David G. , Powell Matthew A. , Sun Lulu , Mosammaparast Nima , Serra Violeta , Zhao Peinan , Lomonosova Elena , Khabele Dineo , Mullen Mary M.
Published: September 2024

Abstract
Purpose: To determine the ability of RAD51 foci to predict platinum chemotherapy response in high-grade serous ovarian cancer (HGSOC) patient-derived samples. Experimental Design: RAD51 and γH2AX nuclear foci were evaluated by immunofluorescence in HGSOC patient-derived cell lines (n=5), organoids (n=11), and formalin-fixed, paraffin-embedded tumor samples (discovery n=31, validation n=148). Samples were defined as RAD51-High if >10% of geminin-positive cells had ≥5 RAD51 foci. Associations between RAD51 scores, platinum chemotherapy response, and survival were evaluated. Results: RAD51 scores correlated with in vitro response to platinum chemotherapy in established and primary ovarian cancer cell lines (Pearson r=0.96, P=0.01). Organoids from platinum-nonresponsive tumors had significantly higher RAD51 scores than those from platinum-responsive tumors (P<0.001). In a discovery cohort, RAD51-Low tumors were more likely to have a pathologic complete response (RR 5.28, P<0.001) and to be platinum-sensitive (RR ∞, P = 0.05). The RAD51 score was predictive of chemotherapy response score (AUC 0.90, 95% CI 0.78-1.0; P<0.001). A novel automatic quantification system accurately reflected the manual assay (92%). In a validation cohort, RAD51-Low tumors were more likely to be platinum-sensitive (RR ∞, P < 0.001) than RAD51-High tumors. Moreover, RAD51-Low status predicted platinum sensitivity with 100% positive predictive value and was associated with better progression-free (HR 0.53, 95% CI 0.33-0.85, P<0.001) and overall survival (HR 0.43, 95% CI 0.25-0.75, P=0.003) than RAD51-High status. Conclusions: RAD51 foci are a robust marker of platinum chemotherapy response and survival in ovarian cancer. The utility of RAD51 foci as a predictive biomarker for HGSOC should be tested in clinical trials.
Data from Phase I study of SYNB1891, an engineered E coli Nissle strain expressing STING agonist, with and without atezolizumab in advanced malignancies
Authors: Luke Jason J. , Piha-Paul Sarina A. , Medina Theresa , Verschraegen Claire F. , Varterasian Mary , Brennan Aoife M. , Riese Richard J. , Sokolovska Anna , Strauss James F. , Hava David L. , Janku Filip
Published: September 2024

Abstract
Purpose: SYNB1891 is a live, modified strain of the probiotic E. coli Nissle 1917 (EcN) engineered to produce cyclic dinucleotides under hypoxia leading to stimulator of interferon genes (STING)-activation in phagocytic antigen-presenting cells in tumors and activating complementary innate immune pathways. Patients and Methods: This first-in-human study (NCT04167137) enrolled participants with refractory advanced cancers to receive repeat intratumoral (IT) injections of SYNB1891 either alone or in combination atezolizumab, with the primary objective of evaluating the safety and tolerability of both regimens. Results: Twenty-four participants received monotherapy across 6 cohorts, and 8 participants received combination therapy in 2 cohorts. Five cytokine release syndrome events occurred with monotherapy, including one that met the criteria for dose-limiting toxicity at the highest dose; no other SYNB1891-related serious adverse events occurred, and no SYNB1891-related infections were observed. SYNB1891 was not detected in the blood at 6 or 24h after the first IT dose or in tumor tissue 7 days following the first dose. Treatment with SYNB1891 resulted in activation of the STING pathway and target engagement as assessed by upregulation of interferon-stimulated genes, chemokines/cytokines, and T-cell response genes in core biopsies obtained pre-dose and 7 days following the third weekly dose. In addition, a dose‑related increase in serum cytokines was observed, as well as stable disease in 4 participants refractory to prior PD-1/L1 antibodies. Conclusions: Repeat IT injection of SYNB1891 as monotherapy and in combination atezolizumab was safe and well tolerated and evidence of STING pathway target engagement was observed.
Data from Alternating 17beta-estradiol and aromatase inhibitor therapies is efficacious in post-menopausal women with advanced endocrine-resistant ER+ breast cancer
Authors: Schwartz Gary N. , Kaufman Peter A. , Giridhar Karthik V. , Marotti Jonathan D. , Chamberlin Mary D. , Arrick Bradley A. , Makari-Judson Grace , Goetz Matthew P. , Soucy Shannon M. , Kolling Fred , Demidenko Eugene , Miller Todd W.
Published: September 2024

Abstract
Purpose: Strategies to implement estrogen therapy for advanced estrogen receptor (ER)-positive breast cancer are under-developed. Preclinical data suggest that cycling treatment with 17b-estradiol followed by estrogen deprivation can control tumor growth long-term. Experimental Design: Post-menopausal women with advanced ER+/HER2- breast cancer with recurrence or progression on ≥1 anti-estrogen- or aromatase inhibitor (AI)-based therapy were eligible. Patients received 17b-estradiol (2 mg orally TID) for 8 weeks followed by AI (physician’s choice) for 16 weeks, alternating treatments on an 8-week/16-week schedule until disease progression. Patients then optionally received continuous single-agent treatment until a second instance of disease progression. Endpoints included 24-week clinical benefit and objective response per RECIST, and tumor genetic alterations. Results: Of 19 evaluable patients, clinical benefit rate was 42.1% (95% CI: 23.1-63.9%) and objective response rate was 15.8% (95% CI: 5.7-37.9%). One subject experienced a grade 3 adverse event related to 17b-estradiol. Among patients who received continuous single-agent treatment until a second instance of disease progression, clinical benefit was observed in 5/12 (41.7%) cases. Tumor ER (ESR1) mutations were found by whole-exome profiling in 4/7 (57.1%) vs. 2/9 (22.2%) patients who did vs. did not experience clinical benefit from alternating 17b-estradiol/AI therapy. The only two patients to experience objective responses to initial 17b-estradiol had tumor ESR1 mutations. Conclusions: Alternating 17b-estradiol/aromatase inhibitor therapy may be a promising treatment for endocrine-refractory ER+ breast cancer, including following progression on CDK4/6 inhibitors or everolimus. Further study is warranted to determine whether the anti-tumor activity of 17b-estradiol differs according to ESR1 mutation status.
Data from TIGIT expression delineates T cell populations with distinct functional and prognostic impact in pancreatic cancer
Authors: Heiduk Max , Klimova Anna , Reiche Charlotte , Digomann David , Beer Carolin , Aust Daniela E. , Distler Marius , Weitz Jürgen , Seifert Adrian M. , Seifert Lena
Published: September 2024

Abstract
Purpose: Immunotherapy has led to a fundamental shift in the treatment of several cancers. However, its efficacy in pancreatic ductal adenocarcinoma (PDAC) is limited. Understanding the expression of inhibitory immune checkpoint receptors (ICR) by intratumoral T cells may help to unravel their involvement in insufficient T cell-mediated antitumor immunity. Experimental Design: Using multicolor flow cytometry, we analyzed circulating and intratumoral T cells from blood (n = 144) and matched tumor samples (n = 107) of PDAC patients. We determined the expression of PD-1 and TIGIT by CD8+ T cells, conventional CD4+ T cells (Tconv) and regulatory T cells (Treg) and their association with T cell differentiation, tumor reactivity, and cytokine expression. A comprehensive follow-up was used to determine their prognostic value. Results: Intratumoral T cells were characterized by increased PD-1 and TIGIT expression. Both markers delineated distinct T cell subpopulations. PD-1+TIGIT- T cells highly expressed proinflammatory cytokines and markers of tumor reactivity (CD39, CD103), whereas TIGIT expression was linked to antiinflammatory and exhausted phenotypes. In addition, the enhanced presence of intratumoral PD-1+TIGIT- Tconv was associated with improved clinical outcomes, while high ICR expression on blood T cells was a significant hazard for overall survival. Conclusions: Our results uncover the association between ICR expression and T cell functionality. PD-1 and TIGIT characterized intratumoral T cells with highly divergent phenotypes linked to clinical outcomes, further underscoring the relvance of TIGT for immunotherapeutic approaches in PDAC. The prognostic value of ICR expression in patient blood may be a valuable tool for patient stratification.
Data from Type 2 diabetes mellitus and efficacy outcomes from imune checkpoint blockade in patients with cancer
Authors: Cortellini Alessio , D'Alessio Antonio , Cleary Siobhan , Buti Sebastiano , Bersanelli Melissa , Bordi Paola , Tonini Giuseppe , Vincenzi Bruno , Tucci Marco , Russo Alessandro , Pantano Francesco , Russano Marco , Stucci Luigia Stefania , Sergi Maria Chiara , Falconi Martina , Zarzana Maria Antonietta. , Santini Daniele , Spagnolo Francesco , Tanda Enrica T. , Rastelli Francesca , Giorgi Francesca Chiara. , Pergolesi Federica , Giusti Raffaele , Filetti Marco , Lo Bianco Francesca , Marchetti Paolo , Botticelli Andrea , Gelibter Alain , Siringo Marco , Ferrari Marco , Marconcini Riccardo , Vitale Maria Giuseppa. , Nicolardi Linda , Chiari Rita , Ghidini Michele , Nigro Olga , Grossi Francesco , De Tursi Michele , Di Marino Pietro , Queirolo Paola , Bracarda Sergio , Macrini Serena , Inno Alessandro , Zoratto Federica , Veltri Enzo , Spoto Chiara , Vitale Maria Grazia. , Cannita Katia , Gennari Alessandra , Morganstein Daniel L. , Mallardo Domenico , Nibid Lorenzo , Sabarese Giovanna , Brunetti Leonardo , Perrone Giuseppe , Ascierto Paolo A. , Ficorella Corrado , Pinato David J.
Published: September 2024

Abstract
Purpose: No evidence exists as to whether type 2 diabetes (T2DM) impairs clinical outcome from Immune Checkpoint Inhibitors (ICI) in patients with solid tumors. Experimental Design: In a large cohort of ICI recipients treated at 21 institutions from June 2014 to June 2020, we studied whether patients on glucose lowering medications (GLM) for T2DM had shorter OS and PFS. We used targeted transcriptomics in a subset of patients to explore differences in the tumor microenvironment of patients with/without diabetes. Results: A total of 1395 patients were included. Primary tumors included NSCLC (54.7%), melanoma (24.7%), renal cell (15.0%) and other carcinomas (5.6%). Following multivariable analysis, patients on GLM (n=226, 16.2%) displayed an increased risk of death (HR 1.29, 95%CI:1.07-1.56) and disease progression/death (HR 1.21, 95%CI:1.03-1.43) independent of number of GLM received. We matched 92 metformin exposed with 363 controls and 78 patients on other oral GLM or insulin with 299 control patients. Exposure to metformin, but not other GLM was associated with an increased risk of death (HR 1.53, 95%CI:1.16-2.03) and disease progression/death (HR 1.34, 95%CI:1.04-1.72). T2DM patients with higher pre-treatment glycaemia had higher neutrophil-to-lymphocyte ratio (p=0.04), while exploratory tumoral transcriptomic profiling in a subset of patients (n=22) revealed differential regulation of innate and adaptive immune pathways in T2DM patients. Conclusions: In this study patients on GLM experienced worse outcomes from immunotherapy, independent of baseline features. Prospective studies are warranted to clarify the relative impact of metformin over a pre-existing diagnosis of T2DM in influencing poorer outcomes in this population.
Data from Efficacy of Nivolumab in Pediatric Cancers with High Mutation Burden and Mismatch Repair Deficiency
Authors: Das Anirban , Tabori Uri , Sambira Nahum Lauren C. , Collins Natalie B. , Deyell Rebecca , Dvir Rina , Faure-Conter Cecile , Hassall Timothy E. , Minturn Jane E. , Edwards Melissa , Brookes Elissa , Bianchi Vanessa , Levine Adrian , Stone Simone C. , Sudhaman Sumedha , Sanchez Ramirez Santiago , Ercan Ayse B. , Stengs Lucie , Chung Jill , Negm Logine , Getz Gad , Maruvka Yosef E. , Ertl-Wagner Birgit , Ohashi Pamela S. , Pugh Trevor , Hawkins Cynthia , Bouffet Eric , Morgenstern Daniel A.
Published: September 2024

AbstractPurpose:
Checkpoint inhibitors have limited efficacy for children with unselected solid and brain tumors. We report the first prospective pediatric trial (NCT02992964) using nivolumab exclusively for refractory nonhematologic cancers harboring tumor mutation burden (TMB) ≥5 mutations/megabase (mut/Mb) and/or mismatch repair deficiency (MMRD).
Patients and Methods:
Twenty patients were screened, and 10 were ultimately included in the response cohort of whom nine had TMB >10 mut/Mb (three initially eligible based on MMRD) and one patient had TMB between 5 and 10 mut/Mb.
Results:
Delayed immune responses contributed to best overall response of 50%, improving on initial objective responses (20%) and leading to 2-year overall survival (OS) of 50% [95% confidence interval (CI), 27–93]. Four children, including three with refractory malignant gliomas are in complete remission at a median follow-up of 37 months (range, 32.4–60), culminating in 2-year OS of 43% (95% CI, 18.2–100). Biomarker analyses confirmed benefit in children with germline MMRD, microsatellite instability, higher activated and lower regulatory circulating T cells. Stochastic mutation accumulation driven by underlying germline MMRD impacted the tumor microenvironment, contributing to delayed responses. No benefit was observed in the single patient with an MMR-proficient tumor and TMB 7.4 mut/Mb.
Conclusions:
Nivolumab resulted in durable responses and prolonged survival for the first time in a pediatric trial of refractory hypermutated cancers including malignant gliomas. Novel biomarkers identified here need to be translated rapidly to clinical care to identify children who can benefit from checkpoint inhibitors, including upfront management of cancer.

See related commentary by Mardis, p. 4701