bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Pilot Clinical Trial of Perioperative Durvalumab and Tremelimumab in the Treatment of Resectable Colorectal Cancer Liver Metastases
Authors: Kanikarla Marie Preeti , Haymaker Cara , Parra Edwin Roger , Kim Young Uk , Lazcano Rossana , Gite Swati , Lorenzini Daniele , Wistuba Ignacio I. , Tidwell Rebecca S. Slack , Song Xiaofei , Foo Wai Chin , Maru Dipen M. , Chun Yun Shin , Futreal Andy , Kee Bryan , Menter David , Solis Luisa , Tzeng Ching-Wei , Parseghian Christine , Raghav Kanwal , Morris Van , Chang Chia-Chi , Jenq Robert , Tam Alda , Bernatchez Chantale , Kopetz Scott , Vauthey Jean-Nicolas , Overman Michael J.
Published: April 2023

AbstractPurpose:
Despite the prognostic importance of immune infiltrate in colorectal cancer, immunotherapy has demonstrated limited clinical activity in refractory metastatic proficient mismatch-repair (pMMR) colorectal cancer. This study explores combining anti–CTLA-4 and an anti–PD-L1 therapy in the preoperative management of resectable colorectal cancer liver metastases with the intent to improve immune responses in this disease setting.
Patients and Methods:
Patients with resectable colorectal cancer liver-only metastases received one dose of tremelimumab and durvalumab preoperatively followed by single-agent durvalumab postoperatively. Primary objectives were to determine feasibility and safety.
Results:
A total of 24 patients were enrolled between November 2016 and November 2019. Twenty-three patients received treatment [21 pMMR and 2 deficient mismatch-repair (dMMR)] and subsequently 17 (74%; 95% CI: 53%–88%) underwent surgical resection. Grade 3/4 treatment-related immune toxicity and postoperative grade 3/4 toxicity were seen in 5/23 (22%; 95% CI: 10%–44%) and 2/17 (12%; 95% CI: 2%–38%) patients. The median relapse-free survival (RFS) was 9.7 (95% CI: 8.1–17.8) months, and overall survival was 24.5 (95% CI: 16.5–28.4) months. Four patients demonstrated complete pathologic response, two dMMR patients and two POLE mutation patients. Pre- and post-tumor tissue analysis by flow cytometry, immunofluorescence, and RNA sequencing revealed similar levels of T-cell infiltration, but did demonstrate evidence of CD8+ and CD4+ activation posttreatment. An increase in B-cell transcriptome signature and B-cell density was present in posttreatment samples from patients with prolonged RFS.
Conclusions:
This study demonstrates the safety of neoadjuvant combination tremelimumab and durvalumab prior to colorectal cancer liver resection. Evidence for T- and B-cell activation following this therapy was seen in pMMR metastatic colorectal cancer.
Data from Discovery of a Novel CIP2A Variant (NOCIVA) with Clinical Relevance in Predicting TKI Resistance in Myeloid Leukemias
Authors: Mäkelä Eleonora , Pavic Karolina , Varila Taru , Salmenniemi Urpu , Löyttyniemi Eliisa , Nagelli Srikar G. , Ammunét Tea , Kähäri Veli-Matti , Clark Richard E. , Elo Laura L. , Bachanaboyina Venkata Kumari , Lucas Claire M. , Itälä-Remes Maija , Westermarck Jukka
Published: April 2023

AbstractPurpose:
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that inhibits the tumor suppressor PP2A-B56α. However, CIP2A mRNA variants remain uncharacterized. Here, we report the discovery of a CIP2A splicing variant, novel CIP2A variant (NOCIVA).
Experimental Design:
Characterization of CIP2A variants was performed by both 3′ and 5′ rapid amplification of cDNA ends from cancer cells. The function of NOCIVA was assessed by structural and molecular biology approaches. Its clinical relevance was studied in an acute myeloid leukemia (AML) patient cohort and two independent chronic myeloid leukemia (CML) cohorts.
Results:
NOCIVA contains CIP2A exons 1 to 13 fused to 349 nucleotides from CIP2A intron 13. Intriguingly, the first 39 nucleotides of the NOCIVA-specific sequence are in the coding frame with exon 13 of CIP2A and code for a 13-amino acid peptide tail nonhomologous to any known human protein sequence. Therefore, NOCIVA translates to a unique human protein. NOCIVA retains the capacity to bind to B56α, but, whereas CIP2A is predominantly a cytoplasmic protein, NOCIVA translocates to the nucleus. Indicative of prevalent alternative splicing from CIP2A to NOCIVA in myeloid malignancies, AML and CML patient samples overexpress NOCIVA, but not CIP2A mRNA. In AML, a high NOCIVA/CIP2A mRNA expression ratio is a marker for adverse overall survival. In CML, high NOCIVA expression is associated with inferior event-free survival among imatinib-treated patients, but not among patients treated with dasatinib or nilotinib.
Conclusions:
We discovered a novel variant of the oncoprotein CIP2A and its clinical relevance in predicting tyrosine kinase inhibitor therapy resistance in myeloid leukemias.
Data from Comprehensive Molecular Characterization and Response to Therapy in Fumarate Hydratase–Deficient Renal Cell Carcinoma
Authors: Gleeson Jack P. , Nikolovski Ines , Dinatale Renzo , Zucker Mark , Knezevic Andrea , Patil Sujata , Ged Yasser , Kotecha Ritesh R. , Shapnik Natalie , Murray Samuel , Russo Paul , Coleman Jonathan , Lee Chung Han , Stadler Zsofia K. , Hakimi A. Ari , Feldman Darren R. , Motzer Robert J. , Reznik Ed , Voss Martin H. , Chen Ying-Bei , Carlo Maria I.
Published: April 2023

AbstractPurpose:
Fumarate hydratase–deficient renal cell carcinoma (FH-RCC) is a rare, aggressive form of RCC associated with hereditary leiomyomatosis and RCC syndrome. Evidence for systemic therapy efficacy is lacking.
Experimental Design:
We studied clinical and genomic characteristics of FH-RCC, including response [objective response rate (ORR)] to systemic therapies and next-generation sequencing (NGS). Patients with metastatic FH-RCC, defined by presence of pathogenic germline or somatic FH mutation plus IHC evidence of FH loss, were included.
Results:
A total of 28 of 32 included patients (median age 46; range, 20–74; M:F, 20:12) underwent germline testing; 23 (82%) harbored a pathogenic FH germline variant. Five (16%) were negative for germline FH mutations; all had biallelic somatic FH loss. Somatic NGS (31/32 patients) revealed co-occurring NF2 mutation most frequently (n = 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4; P < 0.001) but higher fraction of genome altered (18.7% vs. 10.3%; P = 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (n = 18, ORR 44%), VEGF monotherapy (n = 15, ORR 20%), checkpoint inhibitor therapy (n = 8, ORR 0%), and mTOR monotherapy (n = 4, ORR 0%). No complete responses were seen. Median overall and progression-free survival were 21.9 months [95% confidence interval (CI): 14.3–33.8] and 8.7 months (95% CI: 4.8–12.3), respectively.
Conclusions:
Although most FH-RCC tumors are due to germline FH alterations, a significant portion result from biallelic somatic FH loss. Both somatic and germline FH-RCC have similar molecular characteristics, with NF2 mutations, low tumor mutational burden, and high fraction of genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results.
Data from A Cyclin D1–Dependent Transcriptional Program Predicts Clinical Outcome in Mantle Cell Lymphoma
Authors: Demajo Santiago , Albero Robert , Clot Guillem , Castellano Giancarlo , Navarro Alba , Capdevila Cristina , Enjuanes Anna , Nadeu Ferran , Giné Eva , Pinyol Magda , Jaffe Elaine S. , Ott German , Staudt Louis M. , Rosenwald Andreas , Scott David W. , Rimsza Lisa M. , López-Guillermo Armando , Beà Sílvia , Campo Elias , Jares Pedro
Published: April 2023

AbstractPurpose:
Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression. Cyclin D1 is a major cell-cycle regulator and also regulates transcription, but the impact of cyclin D1–mediated transcriptional dysregulation on MCL pathogenesis remains poorly understood. The aim of this study was to define a cyclin D1–dependent gene expression program and analyze its prognostic value.
Experimental Design:
We integrated genome-wide expression analysis of cyclin D1–silenced and overexpressing cells with cyclin D1 chromatin-binding profiles to identify a cyclin D1–dependent transcriptional program in MCL cells. We analyzed this gene program in two MCL series of peripheral blood samples (n = 53) and lymphoid tissues (n = 106) to determine its biological and clinical relevance. We then obtained a simplified signature of this program and evaluated a third series of peripheral blood MCL samples (n = 81) by NanoString gene expression profiling to validate our findings.
Results:
We identified a cyclin D1–dependent transcriptional program composed of 295 genes that were mainly involved in cell-cycle control. The cyclin D1–dependent gene program was overexpressed in MCL tumors directly proportional to cyclin D1 levels. High expression of this program conferred an adverse prognosis with significant shorter overall survival of the patients. These observations were validated in an independent cohort of patients using a simplified 37-gene cyclin D1 signature. The cyclin D1–dependent transcriptional program was also present in multiple myeloma and breast tumors with cyclin D1 overexpression.
Conclusions:
We identified a cyclin D1–dependent transcriptional program that is overexpressed in MCL and predicts clinical outcome.
Data from SOX11 Inhibitors Are Cytotoxic in Mantle Cell Lymphoma
Authors: Jatiani Shashidhar S. , Christie Stephanie , Leshchenko Violetta V. , Jain Rinku , Kapoor Abhijeet , Bisignano Paola , Lee Clement , Kaniskan H. Ümit , Edwards Donna , Meng Fanye , Laganà Alessandro , Youssef Youssef , Wiestner Adrian , Alinari Lapo , Jin Jian , Filizola Marta , Aggarwal Aneel K. , Parekh Samir
Published: April 2023

AbstractPurpose:
Mantle cell lymphoma (MCL) is a fatal subtype of non–Hodgkin lymphoma. SOX11 transcription factor is overexpressed in the majority of nodal MCL. We have previously reported that B cell–specific overexpression of SOX11 promotes MCL pathogenesis via critically increasing BCR signaling in vivo. SOX11 is an attractive target for MCL therapy; however, no small-molecule inhibitor of SOX11 has been identified to date. Although transcription factors are generally considered undruggable, the ability of SOX11 to bind to the minor groove of DNA led us to hypothesize that there may exist cavities at the protein–DNA interface that are amenable to targeting by small molecules.
Experimental Design:
Using a combination of in silico predictions and experimental validations, we report here the discovery of three structurally related compounds (SOX11i) that bind SOX11, perturb its interaction with DNA, and effect SOX11-specific anti-MCL cytotoxicity.
Results:
We find mechanistic validation of on-target activity of these SOX11i in the inhibition of BCR signaling and the transcriptional modulation of SOX11 target genes, specifically, in SOX11-expressing MCL cells. One of the three SOX11i exhibits relatively superior in vitro activity and displays cytotoxic synergy with ibrutinib in SOX11-expressing MCL cells. Importantly, this SOX11i induces cytotoxicity specifically in SOX11-positive ibrutinib-resistant MCL patient samples and inhibits Bruton tyrosine kinase phosphorylation in a xenograft mouse model derived from one of these subjects.
Conclusions:
Taken together, our results provide a foundation for therapeutically targeting SOX11 in MCL by a novel class of small molecules.
Data from Phase I Study of MK-4166, an Anti-human Glucocorticoid-Induced TNF Receptor Antibody, Alone or with Pembrolizumab in Advanced Solid Tumors
Authors: Papadopoulos Kyriakos P. , Autio Karen , Golan Talia , Dobrenkov Konstantin , Chartash Elliot , Chen Qiusheng , Wnek Richard , Long Georgina V.
Published: April 2023

AbstractPurpose:
In this first-in-human phase I study (NCT02132754), we explored MK-4166 [humanized IgG1 agonist mAb targeting glucocorticoid-induced TNF receptor (GITR)] with and without pembrolizumab in advanced solid tumors.
Patients and Methods:
MK-4166 was tested alone (0.0015–900 mg i.v. every 3 weeks for four doses) or with pembrolizumab (200 mg i.v. every 3 weeks for ≤35 doses) in patients with metastatic solid tumors (dose escalation/confirmation) and advanced melanoma (expansion). Primary objectives were to evaluate the safety and tolerability and establish the MTD of MK-4166. Exploratory endpoints were objective response rate (ORR) and T cell–inflamed gene expression profile (GEP) analysis using RNA from baseline tumor samples.
Results:
A total of 113 patients were enrolled [monotherapy, n = 48; combination therapy, n = 65 (20 in the expansion)]. Forty-six patients (40.7%) had grade ≥3 adverse events, 9 (8.0%) of which were treatment related. No treatment-related deaths were observed. One dose-limiting toxicity event with monotherapy (bladder perforation in patient with neobladder) was considered related to study drug. MTD was not reached. MK-4166 pharmacodynamics showed decreased GITR availability on circulating T cells with increasing doses. One objective response (ORR, 2.2%) was achieved with combination therapy in the dose escalation/confirmation (n = 45). In the expansion, 8 of 13 patients with immune checkpoint inhibitor (ICI)-naïve melanoma achieved a response (ORR, 62%; 95% confidence interval, 32–86; 5 complete responses and 3 partial responses). None of the ICI-pretreated patients (n = 7) responded. High response rates were observed in ICI-naïve patients irrespective of GEP status.
Conclusions:
MK-4166 900 mg i.v. every 3 weeks as monotherapy and with pembrolizumab was tolerable. Responses were observed with combination therapy, mostly in patients with ICI-naïve melanoma.
Data from Preclinical and Clinical Characterization of Fibroblast-derived Neuregulin-1 on Trastuzumab and Pertuzumab Activity in HER2-positive Breast Cancer
Authors: Guardia Cristina , Bianchini Giampaolo , Arpí-LLucià Oriol , Menendez Silvia , Casadevall David , Galbardi Barbara , Dugo Matteo , Servitja Sonia , Montero Juan Carlos , Soria-Jiménez Luis , Sabbaghi MohammadA , Peña Raul , Madoz-Gúrpide Juan , Lloveras Belen , Lluch Ana , Eroles Pilar , Arribas Joaquin , Pandiella Atanasio , Gianni Luca , Rojo Federico , Rovira Ana , Albanell Joan
Published: April 2023

AbstractPurpose:
To characterize expression of neuregulin-1 (NRG1), an HER3 ligand, in HER2-positive breast cancer and its relation with the efficacy of trastuzumab with or without pertuzumab.
Experimental Design:
Characterization of NRG1 expression in tumor cell lines, in tumor specimens, and in cancer-associated fibroblasts (CAFs). Patient-derived CAFs were used to investigate NRG1 impact on the activity of trastuzumab with or without pertuzumab in HER2-positive breast cancer cells. The relationship between NRG1 expression and pathologic response to anti-HER2–based neoadjuvant therapy was assessed in a retrospective patient cohort and in the NeoSphere trial.
Results:
NRG1 was expressed in HER2-positive breast cancer–derived fibroblasts at significantly higher levels than in cancer cells. NRG1 and the conditioned media (CM) from CAFs phosphorylated HER3 and AKT in cancer cells and mediated trastuzumab resistance. Stable genetic depletion of NRG1 from CAFs overcame trastuzumab resistance. Pertuzumab effectively suppressed trastuzumab resistance mediated by either NRG1 or CAF's CM. NRG1 engaged an epithelial-to-mesenchymal transition that was prevented by trastuzumab and pertuzumab. In clinical samples, stromal and/or tumor cell expression of NRG1 determined by immunohistochemistry was uncommon (13.2%) yet significantly linked with residual disease following trastuzumab-based neoadjuvant therapy. In the NeoSphere trial, the magnitude of the difference of pathologic complete response rates favoring the pertuzumab arm was higher in the NRG1-high group.
Conclusions:
CAF-derived NRG1 mediates trastuzumab resistance through HER3/AKT, which might be reverted by pertuzumab. In patients with HER2-positive breast cancer, high expression of NRG1 was associated to poor response to trastuzumab, but not in combination with pertuzumab.
Data from Single-Cell Characterization of the Immune Microenvironment of Melanoma Brain and Leptomeningeal Metastases
Authors: Smalley Inna , Chen Zhihua , Phadke Manali , Li Jiannong , Yu Xiaoqing , Wyatt Clayton , Evernden Brittany , Messina Jane L. , Sarnaik Amod , Sondak Vernon K. , Zhang Chaomei , Law Vincent , Tran Nam , Etame Arnold , Macaulay Robert J.B. , Eroglu Zeynep , Forsyth Peter A. , Rodriguez Paulo C. , Chen Y. Ann , Smalley Keiran S.M.
Published: April 2023

AbstractPurpose:
Melanoma brain metastases (MBM) and leptomeningeal melanoma metastases (LMM) are two different manifestations of melanoma CNS metastasis. Here, we used single-cell RNA sequencing (scRNA-seq) to define the immune landscape of MBM, LMM, and melanoma skin metastases.
Experimental Design:
scRNA-seq was undertaken on 43 patient specimens, including 8 skin metastases, 14 MBM, and 19 serial LMM specimens. Detailed cell type curation was performed, the immune landscapes were mapped, and key results were validated by IHC and flow cytometry. Association analyses were undertaken to identify immune cell subsets correlated with overall survival.
Results:
The LMM microenvironment was characterized by an immune-suppressed T-cell landscape distinct from that of brain and skin metastases. An LMM patient with long-term survival demonstrated an immune repertoire distinct from that of poor survivors and more similar to normal cerebrospinal fluid (CSF). Upon response to PD-1 therapy, this extreme responder showed increased levels of T cells and dendritic cells in their CSF, whereas poor survivors showed little improvement in their T-cell responses. In MBM patients, therapy led to increased immune infiltrate, with similar T-cell transcriptional diversity noted between skin metastases and MBM. A correlation analysis across the entire immune landscape identified the presence of a rare population of dendritic cells (DC3) that was associated with increased overall survival and positively regulated the immune environment through modulation of activated T cells and MHC expression.
Conclusions:
Our study provides the first atlas of two distinct sites of melanoma CNS metastases and defines the immune cell landscape that underlies the biology of this devastating disease.
Data from Biomarker Discovery in Patients with Immunotherapy-Treated Melanoma with Imaging Mass Cytometry
Authors: Martinez-Morilla Sandra , Villarroel-Espindola Franz , Wong Pok Fai , Toki Maria I. , Aung Thazin Nwe , Pelekanou Vasiliki , Bourke-Martin Brian , Schalper Kurt A. , Kluger Harriet M. , Rimm David L.
Published: April 2023

AbstractPurpose:
Imaging mass cytometry (IMC) is among the first tools with the capacity for multiplex analysis of more than 40 targets, which provides a novel approach to biomarker discovery. Here, we used IMC to characterize the tumor microenvironment of patients with metastatic melanoma who received immunotherapy in efforts to find indicative factors of treatment response. In spite of the new power of IMC, the image analysis aspects are still limited by the challenges of cell segmentation.
Experimental Design:
Here, rather than segment, we performed image analysis using a newly designed version of the AQUA software to measure marker intensity in molecularly defined compartments: tumor cells, stroma, T cells, B cells, and macrophages. IMC data were compared with quantitative immunofluorescence (QIF) and digital spatial profiling.
Results:
Validation of IMC results for immune markers was confirmed by regression with additional multiplexing methods and outcome assessment. Multivariable analyses by each compartment revealed significant associations of 12 markers for progression-free survival and seven markers for overall survival (OS). The most compelling indicative biomarker, beta2-microglobulin (B2M), was confirmed by correlation with OS by QIF in the discovery cohort and validated in an independent published cohort profiled by mRNA expression.
Conclusions:
Using digital image analysis based on pixel colocalization to assess IMC data allowed us to quantitively measure 25 markers simultaneously on formalin-fixed, paraffin-embedded tissue microarray samples. In addition to showing high concordance with other multiplexing technologies, we identified a series of potentially indicative biomarkers for immunotherapy in metastatic melanoma, including B2M.
Data from Immune Activation and Microbial Translocation as Prognostic Biomarkers for AIDS-Related Non-Hodgkin Lymphoma in the AMC-034 Study
Authors: Martínez Laura E. , Lensing Shelly , Chang Di , Magpantay Larry I. , Mitsuyasu Ronald , Ambinder Richard F. , Sparano Joseph A. , Martínez-Maza Otoniel , Epeldegui Marta
Published: April 2023

AbstractPurpose:
AIDS-related non-Hodgkin lymphoma (ARL) is the most common cancer in HIV-infected individuals in the United States and other countries in which HIV-positive persons have access to effective combination antiretroviral therapy (cART). Our prior work showed that pretreatment/postdiagnosis plasma levels of some cytokines, such as IL6, IL10, and CXCL13, have the potential to serve as indicators of clinical response to treatment and survival in ARL. The aims of this study were to identify novel prognostic biomarkers for response to treatment and/or survival in persons with ARL, including biomarkers of microbial translocation and inflammation.
Experimental Design:
We quantified plasma levels of several biomarkers (sCD14, LBP, FABP2, EndoCab IgM, IL18, CCL2/MCP-1, sCD163, IP-10/CXCL10, TARC/CCL17, TNFα, BAFF/BLyS, sTNFRII, sCD44, and sIL2Rα/sCD25) by multiplexed immunometric assays (Luminex) or ELISA in plasma specimens obtained from ARL patients enrolled in the AMC-034 trial, which compared infusional combination chemotherapy (EPOCH: etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone) with concurrent or sequential rituximab. Plasma was collected prior to the initiation of therapy (n = 57) and after treatment initiation (n = 55).
Results:
We found that several biomarkers decreased significantly after treatment, including TNFα, sCD25, LBP, and TARC (CCL17). Moreover, pretreatment plasma levels of BAFF, sCD14, sTNFRII, and CCL2/MCP-1 were univariately associated with overall survival, and pretreatment levels of BAFF, sTNFRII, and CCL2/MCP-1 were also associated with progression-free survival.
Conclusions:
Our results suggest that patients with ARL who responded to therapy had lower pretreatment levels of inflammation and microbial translocation as compared with those who did not respond optimally.
Data from Phase I Trial of DNA Methyltransferase Inhibitor Guadecitabine Combined with Cisplatin and Gemcitabine for Solid Malignancies Including Urothelial Carcinoma (SPIRE)
Authors: Crabb Simon J. , Danson Sarah , Catto James W.F. , Hussain Syed , Chan Danna , Dunkley Denise , Downs Nichola , Marwood Ellice , Day Laura , Saunders Geoff , Light Michelle , Whitehead Amy , Ellis Deborah , Sarwar Naveed , Enting Deborah , Birtle Alison , Johnson Bernadette , Huddart Robert , Griffiths Gareth
Published: April 2023

AbstractPurpose:
Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers.
Patient and Methods:
SPIRE comprised a dose-escalation phase for incurable metastatic solid cancers, followed by a randomized dose expansion phase for neoadjuvant treatment of T2–4a N0 M0 bladder urothelial carcinoma. The primary objective was a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin. Treatment comprised 21-day gemcitabine and cisplatin cycles (cisplatin 70 mg/m2, i.v., day 8 and gemcitabine 1,000 mg/m2, i.v., days 8 + 15). Guadecitabine was injected subcutaneously on days 1–5, within escalation phase cohorts, and to half of 20 patients in the expansion phase. Registration ID: ISRCTN 16332228.
Results:
Within the escalation phase, dose-limiting toxicities related predominantly to myelosuppression requiring G-CSF prophylaxis from cohort 2 (guadecitabine 20 mg/m2, days 1–5). The most common grade ≥3 adverse events in 17 patients in the dose-escalation phase were neutropenia (76.5%), thrombocytopenia (64.7%), leukopenia (29.4%), and anemia (29.4%). Addition of guadecitabine to gemcitabine and cisplatin in the expansion phase resulted in similar rates of severe hematologic adverse events, similar cisplatin dose intensity, but modestly reduced gemcitabine dose intensity. Radical treatment options after chemotherapy were not compromised. Pharmacodynamics evaluations indicated guadecitabine maximal target effect at the point of cisplatin administration. Pharmacokinetics were consistent with prior data. No treatment-related deaths occurred.
Conclusions:
The guadecitabine RP2D was 20 mg/m2, days 1–5, in combination with gemcitabine and cisplatin and required GCSF prophylaxis. Gene promoter methylation pharmacodynamics are optimal with this schedule. Addition of guadecitabine to gemcitabine and cisplatin was tolerable, despite some additional myelosuppression, and warrants further investigation to assess efficacy.
Data from FLT3L Release by Natural Killer Cells Enhances Response to Radioimmunotherapy in Preclinical Models of HNSCC
Authors: Bickett Thomas E. , Knitz Michael , Darragh Laurel B. , Bhatia Shilpa , Van Court Benjamin , Gadwa Jacob , Bhuvane Shiv , Piper Miles , Nguyen Diemmy , Tu Hua , Lenz Laurel , Clambey Eric T. , Barry Kevin , Karam Sana D.
Published: April 2023

AbstractPurpose:
Natural killer (NK) cells are type I innate lymphoid cells that are known for their role in killing virally infected cells or cancer cells through direct cytotoxicity. In addition to direct tumor cell killing, NK cells are known to play fundamental roles in the tumor microenvironment through secretion of key cytokines, such as FMS-like tyrosine kinase 3 ligand (FLT3L). Although radiotherapy is the mainstay treatment in most cancers, the role of radiotherapy on NK cells is not well characterized.
Experimental Design:
This study combines radiation, immunotherapies, genetic mouse models, and antibody depletion experiments to identify the role of NK cells in overcoming resistance to radiotherapy in orthotopic models of head and neck squamous cell carcinoma.
Results:
We have found that NK cells are a crucial component in the development of an antitumor response, as depleting them removes efficacy of the previously successful combination treatment of radiotherapy, anti-CD25, and anti-CD137. However, in the absence of NK cells, the effect can be rescued through treatment with FLT3L. But neither radiotherapy with FLT3L therapy alone nor radiotherapy with anti-NKG2A yields any meaningful tumor growth delay. We also identify a role for IL2 in activating NK cells to secrete FLT3L. This activity, we show, is mediated through CD122, the intermediate affinity IL2 receptor, and can be targeted with anti-CD25 therapy.
Conclusions:
These findings highlight the complexity of using radio-immunotherapies to activate NK cells within the tumor microenvironment, and the importance of NK cells in activating dendritic cells for increased tumor surveillance.
Data from A Phase 1a/b Open-Label, Dose-Escalation Study of Etigilimab Alone or in Combination with Nivolumab in Patients with Locally Advanced or Metastatic Solid Tumors
Authors: Mettu Niharika B. , Ulahannan Susanna V. , Bendell Johanna C. , Garrido-Laguna Ignacio , Strickler John H. , Moore Kathleen N. , Stagg Robert , Kapoun Ann M. , Faoro Leonardo , Sharma Sunil
Published: April 2023

AbstractPurpose:
TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain) is a co-inhibitory receptor of T-cell and natural killer cell activity. Targeting TIGIT with or without PD-1/PD-L1 checkpoint inhibition may enhance antitumor immunity.
Patients and Methods:
This Phase 1a/b trial was a first-in-human, open-label, multicenter, dose-escalation and -expansion study in patients with locally advanced or metastatic solid tumors. Using 3 + 3 design, patients underwent 14-day treatment cycles with anti-TIGIT antibody etigilimab alone (Phase 1a; 0.3, 1.0, 3.0, 10.0, 20.0 mg/kg intravenously) or in combination with anti–PD-1 antibody nivolumab (Phase 1b; 3.0, 10.0, 20.0 mg/kg etigilimab and 240 mg nivolumab). Primary objective was safety and tolerability.
Results:
Thirty-three patients were enrolled (Phase 1a, n = 23; Phase 1b, n = 10). There were no dose-limiting toxicities (DLT). MTD for single and combination therapy was not determined; maximum administered dose was 20 mg/kg. The most commonly reported adverse events (AE) were rash (43.5%), nausea (34.8%), and fatigue (30.4%) in Phase 1a and decreased appetite (50.0%), nausea (50.0%), and rash (40%) in Phase 1b. Six patients experienced Grade ≥3 treatment-related AEs. In Phase 1a, 7 patients (30.0%) had stable disease. In Phase 1b, 1 patient had a partial response; 1 patient had prolonged stable disease of nearly 8 months. Median progression-free survival was 56.0 days (Phase 1a) and 57.5 days (Phase 1b). Biomarker correlative analyses demonstrated evidence of clear dose-dependent target engagement by etigilimab.
Conclusions:
Etigilimab had an acceptable safety profile with preliminary evidence of clinical benefit alone and in combination with nivolumab and warrants further investigation in clinical trials.
Data from Phase I/Ib Study of the Efficacy and Safety of Buparlisib and Ibrutinib Therapy in MCL, FL, and DLBCL with Serial Cell-Free DNA Monitoring
Authors: Stewart Caitlin M. , Michaud Laure , Whiting Karissa , Nakajima Reiko , Nichols Chelsea , De Frank Stephanie , Hamlin Paul A. , Matasar Matthew J. , Gerecitano John F. , Drullinsky Pamela , Hamilton Audrey , Straus David , Horwitz Steven M. , Kumar Anita , Moskowitz Craig H. , Moskowitz Alison , Zelenetz Andrew D. , Rademaker Jurgen , Salles Gilles , Seshan Venkatraman , Schöder Heiko , Younes Anas , Tsui Dana W.Y. , Batlevi Connie Lee
Published: April 2023

AbstractPurpose:
Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kδ inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition.
Patients and Methods:
We conducted a single-center phase I/Ib trial combining a BTK inhibitor (ibrutinib) and a pan-PI3K inhibitor (buparlisib) in 37 patients with relapsed/refractory (R/R) B-cell lymphoma. Buparlisib and ibrutinib were administered orally, once daily in 28-day cycles until progression or unacceptable toxicity. The clinical trial is registered with clinicaltrials.gov, NCT02756247.
Results:
Patients with mantle cell lymphoma (MCL) receiving the combination had a 94% overall response rate (ORR) and 33-month median progression-free survival; ORR of 31% and 20% were observed in patients with diffuse large B-cell lymphoma and follicular lymphoma, respectively. The maximum tolerated dose was ibrutinib 560 mg plus buparlisib 100 mg and the recommended phase II dose was ibrutinib 560 mg plus buparlisib 80 mg. The most common grade 3 adverse events were rash/pruritis/dermatitis (19%), diarrhea (11%), hyperglycemia (11%), and hypertension (11%). All grade mood disturbances ranging from anxiety, depression, to agitation were observed in 22% of patients. Results from serial monitoring of cell-free DNA samples corresponded to radiographic resolution of disease and tracked the emergence of mutations known to promote BTK inhibitor resistance.
Conclusions:
BTK and pan-PI3K inhibition in mantle cell lymphoma demonstrates a promising efficacy signal. Addition of BCL2 inhibitors to a BTK and pan-PI3K combination remain suitable for further development in mantle cell lymphoma.
Data from Prognostic Relevance of Pancreatic Adenocarcinoma Whole-Tumor Transcriptomic Subtypes and Components
Authors: Zhao Shulin , Nicolle Rémy , Augustin Jérémy , Svrcek Magali , de Mestier Louis , Le Corre Delphine , Pietrasz Daniel , Caliez Olivier , Cros Jérôme , Laurent-Puig Pierre , Bachet Jean-Baptiste
Published: April 2023

AbstractPurpose:
Our team previously defined six quantitative transcriptomic components, and a classification in five subtypes by association of these components. In this study, we compared the robustness of quantitative components and qualitative classifications from different transcriptomic profiling techniques, investigated their clinical relevance, and proposed a new prognostic model.
Experimental Design:
A total of 210 patients from a multicentric cohort and 149 patients from a monocentric cohort were included in this study. RNA microarray profiles were obtained from 165 patients of the multicentric cohort. RNA sequencing (RNA-seq) profiles were obtained from all the patients.
Results:
For the patients with both RNA microarray and RNA-seq profiles, the concordance in subtype assignment was partial with an 82.4% coherence rate. The correlation between the two technique projections of the six components ranged from 0.85 to 0.95, demonstrating an advantage of robustness. On the basis of the Akaike information criterion, the RNA components showed more prognostic value in univariate or multivariate models than the subtypes. Using the monocentric cohort for training, we developed a multivariate Cox regression model using all six components and clinicopathologic characteristics (node invasion and resection margins) on disease-free survival (DFS). This prognostic model was highly associated with DFS (P < 0.001). The evaluation of the model in the multicentric cohort showed significant association with DFS and overall survival (P < 0.001).
Conclusions:
We described the advantage of the prognostic value and robustness of the whole-tumor transcriptomic components than subtypes. We created and validated a new DFS-based multivariate Cox regression prognostic model, including six pancreatic adenocarcinoma transcriptomic component levels and pathologic characteristics.
Data from Circulating Tumor DNA in Stage III Colorectal Cancer, beyond Minimal Residual Disease Detection, toward Assessment of Adjuvant Therapy Efficacy and Clinical Behavior of Recurrences
Authors: Henriksen Tenna Vesterman , Tarazona Noelia , Frydendahl Amanda , Reinert Thomas , Gimeno-Valiente Francisco , Carbonell-Asins Juan Antonio , Sharma Shruti , Renner Derrick , Hafez Dina , Roda Desamparados , Huerta Marisol , Roselló Susana , Madsen Anders Husted , Løve Uffe S. , Andersen Per Vadgaard , Thorlacius-Ussing Ole , Iversen Lene Hjerrild , Gotschalck Kåre Andersson , Sethi Himanshu , Aleshin Alexey , Cervantes Andres , Andersen Claus Lindbjerg
Published: April 2023

AbstractPurpose:
Sensitive methods for risk stratification, monitoring therapeutic efficacy, and early relapse detection may have a major impact on treatment decisions and patient management for stage III colorectal cancer patients. Beyond assessing the predictive power of postoperative ctDNA detection, we explored the added benefits of serial analysis: assessing adjuvant chemotherapy (ACT) efficacy, early relapse detection, and ctDNA growth rates.
Experimental Design:
We recruited 168 patients with stage III colorectal cancer treated with curative intent at Danish and Spanish hospitals between 2014 and 2019. To quantify ctDNA in plasma samples (n = 1,204), 16 patient-specific somatic single-nucleotide variants were profiled using multiplex-PCR, next-generation sequencing.
Results:
Detection of ctDNA was a strong recurrence predictor postoperatively [HR = 7.0; 95% confidence interval (CI), 3.7–13.5; P < 0.001] and directly after ACT (HR = 50.76; 95% CI, 15.4–167; P < 0.001). The recurrence rate of postoperative ctDNA-positive patients treated with ACT was 80% (16/20). Only patients who cleared ctDNA permanently during ACT did not relapse. Serial ctDNA assessment after the end of treatment was similarly predictive of recurrence (HR = 50.80; 95% CI, 14.9–172; P < 0.001), and revealed two distinct rates of exponential ctDNA growth, slow (25% ctDNA-increase/month) and fast (143% ctDNA-increase/month; P < 0.001). The ctDNA growth rate was prognostic of survival (HR = 2.7; 95% CI, 1.1–6.7; P = 0.039). Serial ctDNA analysis every 3 months detected recurrence with a median lead-time of 9.8 months compared with standard-of-care computed tomography.
Conclusions:
Serial postoperative ctDNA analysis has a strong prognostic value and enables tumor growth rate assessment. The novel combination of ctDNA detection and growth rate assessment provides unique opportunities for guiding decision-making.

See related commentary by Morris and George, p. 438
Data from Neoadjuvant and Adjuvant Nivolumab and Lirilumab in Patients with Recurrent, Resectable Squamous Cell Carcinoma of the Head and Neck
Authors: Hanna Glenn J. , O'Neill Anne , Shin Kee-Young , Wong Kristine , Jo Vickie Y. , Quinn Charles T. , Cutler Jennifer M. , Flynn Michelle , Lizotte Patrick H. , Annino Donald J. , Goguen Laura A. , Kass Jason I. , Rettig Eleni M. , Sethi Rosh K.V. , Lorch Jochen H. , Schoenfeld Jonathan D. , Margalit Danielle N. , Tishler Roy B. , Everett Peter C. , Desai Anupam M. , Cavanaugh Megan E. , Paweletz Cloud P. , Egloff Ann Marie , Uppaluri Ravindra , Haddad Robert I.
Published: April 2023

AbstractPurpose:
Surgery often represents the best chance for disease control in locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We investigated dual immune-checkpoint inhibition [anti–PD-1, nivolumab (N), and anti-KIR, lirilumab (L)] before and after salvage surgery to improve disease-free survival (DFS).
Patients and Methods:
In this phase II study, patients received N (240 mg) + L (240 mg) 7 to 21 days before surgery, followed by six cycles of adjuvant N + L. Primary endpoint was 1-year DFS; secondary endpoints were safety, pre-op radiologic response, and overall survival (OS). Correlatives included tumor sequencing, PD-L1 scoring, and immunoprofiling.
Results:
Among 28 patients, the median age was 66, 86% were smokers; primary site: 9 oral cavity, 9 oropharynx, and 10 larynx/hypopharynx; 96% had prior radiation. There were no delays to surgery. Grade 3+ adverse events: 11%. At the time of surgery, 96% had stable disease radiologically, one had progression. Pathologic response to N + L was observed in 43% (12/28): 4/28 (14%) major (tumor viability, TV ≤ 10%) and 8/28 (29%) partial (TV ≤ 50%). PD-L1 combined positive score (CPS) at surgery was similar regardless of pathologic response (P = 0.71). Thirteen (46%) recurred (loco-regional = 10, distant = 3). Five of 28 (18%) had positive margins, 4 later recurred. At median follow-up of 22.8 months, 1-year DFS was 55.2% (95% CI, 34.8–71.7) and 1-year OS was 85.7% (95% CI, 66.3–94.4). Two-year DFS and OS were 64% and 80% among pathologic responders.
Conclusions:
(Neo)adjuvant N + L was well tolerated, with a 43% pathologic response rate. We observed favorable DFS and excellent 2-year OS among high-risk, previously treated patients exhibiting a pathologic response. Further evaluation of this strategy is warranted.
Data from Intralesional SD-101 in Combination with Pembrolizumab in Anti-PD-1 Treatment-Naïve Head and Neck Squamous Cell Carcinoma: Results from a Multicenter, Phase II Trial
Authors: Cohen Ezra E.W. , Nabell Lisle , Wong Deborah J. , Day Terry , Daniels Gregory A. , Milhem Mohammed , Deva Sanjeev , Jameson Michael , Guntinas-Lichius Orlando , Almubarak Mohammed , Strother Matthew , Whitman Eric , Chisamore Michael , Obiozor Cynthia , Bagulho Teresa , Gomez-Romo Jose , Guiducci Cristiana , Janssen Robert , Gamelin Erick , Algazi Alain P.
Published: April 2023

AbstractPurpose:
To determine whether SD-101, a Toll-like receptor 9 agonist, potentiates the antitumor activity of anti-PD-1 antibodies in patients with anti-PD-1/PD-L1 naïve, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC).
Patients and Methods:
Patients with PD-1 Ab-naïve HNSCC received either 2 mg SD-101 injected in one to four lesions or 8 mg SD-101 injected into a single lesion weekly × 4 doses then every 3 weeks × 7 doses. Pembrolizumab was administered at 200 mg every 3 weeks.
Results:
A total of 28 patients received 2 mg and 23 received 8 mg per injection, respectively. A total of 76% of patients had received prior systemic therapy. Combined positive score was ≥1 to < 20 in 35 patients (70%) and ≥ 20 in 15 patients (30%) of 50 patients with available data. There were 12 patients with grade ≥3 treatment-related adverse events (24%), and no treatment-related deaths. The objective response rate was 24% including 2 complete and 10 partial responses. The median duration of response was 7.0 [95% confidence interval (CI): 2.1–11.1] months. The response rate was higher in human papillomavirus–positive (HPV+) patients (44%, N = 16). Responses were not associated with PD-L1 expression levels or IFNγ-related gene expression at baseline. Responses were observed both in injected (32%) and in noninjected lesions (29%). Progression-free and overall survival at 9 months were 19.0% (95% CI: 9.1–31.7) and 64.7% (95% CI: 45.3–78.7), respectively.
Conclusions:
SD-101 combined with pembrolizumab induced objective responses, especially in HPV+ tumors, which were frequently associated with increased intratumoral inflammation and effector immune cell activity.
Data from Establishment of Patient-Derived Succinate Dehydrogenase–Deficient Gastrointestinal Stromal Tumor Models for Predicting Therapeutic Response
Authors: Yebra Mayra , Bhargava Shruti , Kumar Avi , Burgoyne Adam M. , Tang Chih-Min , Yoon Hyunho , Banerjee Sudeep , Aguilera Joseph , Cordes Thekla , Sheth Vipul , Noh Sangkyu , Ustoy Rowan , Li Sam , Advani Sunil J. , Corless Christopher L. , Heinrich Michael C. , Kurzrock Razelle , Lippman Scott M. , Fanta Paul T. , Harismendy Olivier , Metallo Christian , Sicklick Jason K.
Published: April 2023

AbstractPurpose:
Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract, with mutant succinate dehydrogenase (SDH) subunits (A–D) comprising less than 7.5% (i.e., 150–200/year) of new cases annually in the United States. Contrary to GISTs harboring KIT or PDGFRA mutations, SDH-mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKI). Lack of human models for any SDH-mutant tumors, including GIST, has limited molecular characterization and drug discovery.
Experimental Design:
We describe methods for establishing novel patient-derived SDH-mutant (mSDH) GIST models and interrogated the efficacy of temozolomide on these tumor models in vitro and in clinical trials of patients with mSDH GIST.
Results:
Molecular and metabolic characterization of our patient-derived mSDH GIST models revealed that these models recapitulate the transcriptional and metabolic hallmarks of parent tumors and SDH deficiency. We further demonstrate that temozolomide elicits DNA damage and apoptosis in our mSDH GIST models. Translating our in vitro discovery to the clinic, a cohort of patients with SDH-mutant GIST treated with temozolomide (n = 5) demonstrated a 40% objective response rate and 100% disease control rate, suggesting that temozolomide represents a promising therapy for this subset of GIST.
Conclusions:
We report the first methods to establish patient-derived mSDH tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in patients with mSDH GIST who are refractory to existing chemotherapeutic drugs (namely, TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic.

See related commentary by Blakely et al., p. 3
Data from Tumor Drug Concentration and Phosphoproteomic Profiles After Two Weeks of Treatment With Sunitinib in Patients with Newly Diagnosed Glioblastoma
Authors: van Linde Myra E. , Labots Mariette , Brahm Cyrillo G. , Hovinga Koos E. , De Witt Hamer Philip C. , Honeywell Richard J. , de Goeij-de Haas Richard , Henneman Alex A. , Knol Jaco C. , Peters Godefridus J. , Dekker Henk , Piersma Sander R. , Pham Thang V. , Vandertop William P. , Jiménez Connie R. , Verheul Henk M.W.
Published: April 2023

AbstractPurpose:
Tyrosine kinase inhibitors (TKI) have poor efficacy in patients with glioblastoma (GBM). Here, we studied whether this is predominantly due to restricted blood–brain barrier penetration or more to biological characteristics of GBM.
Patients and Methods:
Tumor drug concentrations of the TKI sunitinib after 2 weeks of preoperative treatment was determined in 5 patients with GBM and compared with its in vitro inhibitory concentration (IC50) in GBM cell lines. In addition, phosphotyrosine (pTyr)-directed mass spectrometry (MS)-based proteomics was performed to evaluate sunitinib-treated versus control GBM tumors.
Results:
The median tumor sunitinib concentration of 1.9 μmol/L (range 1.0–3.4) was 10-fold higher than in concurrent plasma, but three times lower than sunitinib IC50s in GBM cell lines (median 5.4 μmol/L, 3.0–8.5; P = 0.01). pTyr-phosphoproteomic profiles of tumor samples from 4 sunitinib-treated versus 7 control patients revealed 108 significantly up- and 23 downregulated (P < 0.05) phosphopeptides for sunitinib treatment, resulting in an EGFR-centered signaling network. Outlier analysis of kinase activities as a potential strategy to identify drug targets in individual tumors identified nine kinases, including MAPK10 and INSR/IGF1R.
Conclusions:
Achieved tumor sunitinib concentrations in patients with GBM are higher than in plasma, but lower than reported for other tumor types and insufficient to significantly inhibit tumor cell growth in vitro. Therefore, alternative TKI dosing to increase intratumoral sunitinib concentrations might improve clinical benefit for patients with GBM. In parallel, a complex profile of kinase activity in GBM was found, supporting the potential of (phospho)proteomic analysis for the identification of targets for (combination) treatment.
Data from 18F-FMISO PET Imaging Identifies Hypoxia and Immunosuppressive Tumor Microenvironments and Guides Targeted Evofosfamide Therapy in Tumors Refractory to PD-1 and CTLA-4 Inhibition
Authors: Reeves Kirsten M. , Song Patrick N. , Angermeier Allyson , Manna Deborah Della , Li Yufeng , Wang Jianbo , Yang Eddy S. , Sorace Anna G. , Larimer Benjamin M.
Published: April 2023

AbstractPurpose:
Hypoxia is a common characteristic of many tumor microenvironments, and it has been shown to promote suppression of antitumor immunity. Despite strong biological rationale, longitudinal correlation of hypoxia and response to immunotherapy has not been investigated.
Experimental Design:
In this study, we probed the tumor and its surrounding microenvironment with 18F-FMISO PET imaging to noninvasively quantify tumor hypoxia in vivo prior to and during PD-1 and CTLA-4 checkpoint blockade in preclinical models of breast and colon cancer.
Results:
Longitudinal imaging identified hypoxia as an early predictive biomarker of therapeutic response (prior to anatomic changes in tumor volume) with a decreasing standard uptake value (SUV) ratio in tumors that effectively respond to therapy. PET signal correlated with ex vivo markers of tumor immune response including cytokines (IFNγ, GZMB, and TNF), damage-associated molecular pattern receptors (TLR2/4), and immune cell populations (macrophages, dendritic cells, and cytotoxic T cells). Responding tumors were marked by increased inflammation that were spatially distinct from hypoxic regions, providing a mechanistic understanding of the immune signaling pathways activated. To exploit image-guided combination therapy, hypoxia signal from PET imaging was used to guide the addition of a hypoxia targeted treatment to nonresponsive tumors, which ultimately provided therapeutic synergy and rescued response as determined by longitudinal changes in tumor volume.
Conclusions:
The results generated from this work provide an immediately translatable paradigm for measuring and targeting hypoxia to increase response to immune checkpoint therapy and using hypoxia imaging to guide combinatory therapies.