bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A First-in-Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates Robust and Safe Targeting of AKT in Patients with Solid Tumors
Authors: Saura Cristina , Roda Desamparados , Roselló Susana , Oliveira Mafalda , Macarulla Teresa , Pérez-Fidalgo José Alejandro , Morales-Barrera Rafael , Sanchis-García Juan Manuel , Musib Luna , Budha Nageshwar , Zhu Jin , Nannini Michelle , Chan Wai Y. , Sanabria Bohórquez Sandra M. , Meng Raymond D. , Lin Kui , Yan Yibing , Patel Premal , Baselga José , Tabernero Josep , Cervantes Andrés
Published: March 2024

Abstract
Activation of AKT signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers, but targeting AKT has been difficult due to the mechanism-based toxicities of inhibitors that target the inactive conformation of AKT. Ipatasertib (GDC-0068) is a novel selective ATP-competitive small-molecule inhibitor of AKT that preferentially targets active phosphorylated AKT (pAKT) and is potent in cell lines with evidence of AKT activation. In this phase I study, ipatasertib was well tolerated; most adverse events were gastrointestinal and grade 1–2 in severity. The exposures of ipatasertib ≥200 mg daily in patients correlated with preclinical TGI90, and pharmacodynamic studies confirmed that multiple targets (i.e., PRAS40, GSK3β, and mTOR) were inhibited in paired on-treatment biopsies. Preliminary antitumor activity was observed; 16 of 52 patients (30%), with diverse solid tumors and who progressed on prior therapies, had radiographic stable disease, and many of their tumors had activation of AKT.

Significance: Potent inhibition of AKT signaling with ipatasertib was associated with a tolerable safety profile and meaningful disease control in a subgroup of patients. Targeting pAKT with an ATP-competitive inhibitor provides a greater therapeutic window than allosteric inhibitors. Further investigation with ipatasertib is ongoing in phase II studies. Cancer Discov; 7(1); 102–13. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 1
Data from Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma
Authors: Eskiocak Banu , McMillan Elizabeth A. , Mendiratta Saurabh , Kollipara Rahul K. , Zhang Hailei , Humphries Caroline G. , Wang Changguang , Garcia-Rodriguez Jose , Ding Ming , Zaman Aubhishek , Rosales Tracy I. , Eskiocak Ugur , Smith Michael P. , Sudderth Jessica , Komurov Kakajan , Deberardinis Ralph J. , Wellbrock Claudia , Davies Michael A. , Wargo Jennifer A. , Yu Yonghao , De Brabander Jef K. , Williams Noelle S. , Chin Lynda , Rizos Helen , Long Georgina V. , Kittler Ralf , White Michael A.
Published: March 2024

Abstract
Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathologic activation of the ERK1/2 pathway is a linchpin tumorigenic mechanism associated with the majority of primary and recurrent disease. Therefore, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathologic ERK1/2 signaling. By integration of multigenome chemical and genetic screens, recurrent architectural variants in melanoma tumor genomes, and patient outcome data, we identified two mechanistic subtypes of BRAFV600 melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKϵ inhibitors. Importantly, subtype membership can be predicted using a robust quantitative five-feature genetic biomarker. This biomarker, and the mechanistic relationships linked to it, can identify a cohort of best responders to clinical MEK inhibitors and identify a cohort of TBK1/IKBKϵ inhibitor–sensitive disease among nonresponders to current targeted therapy.

Significance: This study identified two mechanistic subtypes of melanoma: (1) the best responders to clinical BRAF/MEK inhibitors (25%) and (2) nonresponders due to primary resistance mechanisms (9.9%). We identified robust biomarkers that can detect these subtypes in patient samples and predict clinical outcome. TBK1/IKBKϵ inhibitors were selectively toxic to drug-resistant melanoma. Cancer Discov; 7(8); 832–51. ©2017 AACR.

See related commentary by Jenkins and Barbie, p. 799.

This article is highlighted in the In This Issue feature, p. 783
Data from Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness
Authors: Renz Bernhard W. , Tanaka Takayuki , Sunagawa Masaki , Takahashi Ryota , Jiang Zhengyu , Macchini Marina , Dantes Zahra , Valenti Giovanni , White Ruth A. , Middelhoff Moritz A. , Ilmer Matthias , Oberstein Paul E. , Angele Martin K. , Deng Huan , Hayakawa Yoku , Westphalen C. Benedikt , Werner Jens , Remotti Helen , Reichert Maximilian , Tailor Yagnesh H. , Nagar Karan , Friedman Richard A. , Iuga Alina C. , Olive Kenneth P. , Wang Timothy C.
Published: March 2024

Abstract
In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL-Kras+/G12D;Pdx1-Cre (KC) mice accelerated PDAC development, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype, thereby suppressing the accelerated tumorigenesis caused by vagotomy. In LSL-Kras+/G12D;LSL-Trp53+/R172H;Pdx1-Cre mice with established PDAC, bethanechol significantly extended survival. These effects were mediated in part through CHRM1, which inhibited downstream MAPK/EGFR and PI3K/AKT pathways in PDAC cells. Enhanced cholinergic signaling led to a suppression of the cancer stem cell (CSC) compartment, CD11b+ myeloid cells, TNFα levels, and metastatic growth in the liver. Therefore, these data suggest that cholinergic signaling directly and indirectly suppresses growth of PDAC cells, and therapies that stimulate muscarinic receptors may be useful in the treatment of PDAC.

Significance: Subdiaphragmatic vagotomy or Chrm1 knockout accelerates pancreatic tumorigenesis, in part via expansion of the CSC compartment. Systemic administration of a muscarinic agonist suppresses tumorigenesis through MAPK and PI3K/AKT signaling, in early stages of tumor growth and in more advanced, metastatic disease. Therefore, CHRM1 may represent a potentially attractive therapeutic target. Cancer Discov; 8(11); 1458–73. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1333
Data from A Digital RNA Signature of Circulating Tumor Cells Predicting Early Therapeutic Response in Localized and Metastatic Breast Cancer
Authors: Kwan Tanya T. , Bardia Aditya , Spring Laura M. , Giobbie-Hurder Anita , Kalinich Mark , Dubash Taronish , Sundaresan Tilak , Hong Xin , LiCausi Joseph A. , Ho Uyen , Silva Erin J. , Wittner Ben S. , Sequist Lecia V. , Kapur Ravi , Miyamoto David T. , Toner Mehmet , Haber Daniel A. , Maheswaran Shyamala
Published: March 2024

Abstract
The multiplicity of new therapies for breast cancer presents a challenge for treatment selection. We describe a 17-gene digital signature of breast circulating tumor cell (CTC)–derived transcripts enriched from blood, enabling high-sensitivity early monitoring of response. In a prospective cohort of localized breast cancer, an elevated CTC score after three cycles of neoadjuvant therapy is associated with residual disease at surgery (P = 0.047). In a second prospective cohort with metastatic breast cancer, baseline CTC score correlates with overall survival (P = 0.02), as does persistent CTC signal after 4 weeks of treatment (P = 0.01). In the subset with estrogen receptor (ER)–positive disease, failure to suppress ER signaling within CTCs after 3 weeks of endocrine therapy predicts early progression (P = 0.008). Drug-refractory ER signaling within CTCs overlaps partially with presence of ESR1 mutations, pointing to diverse mechanisms of acquired endocrine drug resistance. Thus, CTC-derived digital RNA signatures enable noninvasive pharmacodynamic measurements to inform therapy in breast cancer.

Significance: Digital analysis of RNA from CTCs interrogates treatment responses of both localized and metastatic breast cancer. Quantifying CTC-derived ER signaling during treatment identifies patients failing to respond to ER suppression despite having functional ESR1. Thus, noninvasive scoring of CTC-RNA signatures may help guide therapeutic choices in localized and advanced breast cancer. Cancer Discov; 8(10); 1286–99. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1195
Data from Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199
Authors: Chonghaile Triona Ni , Roderick Justine E. , Glenfield Cian , Ryan Jeremy , Sallan Stephen E. , Silverman Lewis B. , Loh Mignon L. , Hunger Stephen P. , Wood Brent , DeAngelo Daniel J. , Stone Richard , Harris Marian , Gutierrez Alejandro , Kelliher Michelle A. , Letai Anthony
Published: March 2024

Abstract
Acute lymphoblastic leukemia (ALL) is a hematopoietic malignancy derived from immature B-lymphoid and T-lymphoid cells (T-ALL). In T-ALL, there is an early T-cell progenitor (ETP) subgroup that has a very high risk for relapse. In this study, we used mitochondrial BH3 profiling to determine antiapoptotic protein dependencies in T-ALL. We found that T-ALL cell lines and primary patient samples are dependent upon BCL-XL, except when the cancer bears an ETP phenotype, in which case it is BCL-2 dependent. These distinctions directly relate to differential sensitivity to the BH3 mimetics ABT-263 and ABT-199, both in vitro and in vivo. We thus describe for the first time a change of antiapoptotic protein dependence that is related to the differentiation stage of the leukemic clone. Our findings demonstrate that BCL-2 is a clinically relevant target for therapeutic intervention with ABT-199 in ETP-ALL.

Significance: ETP T-ALL is a treatment-resistant subtype of T-ALL for which novel targeted therapies are urgently needed. We have discovered, through BH3 profiling, that ETP-ALL is BCL-2 dependent and is very sensitive to in vitro and in vivo treatment with ABT-199, a drug well tolerated in clinical trials. Cancer Discov; 4(9); 1074–87. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 973
Data from The Rodent Liver Undergoes Weaning-Induced Involution and Supports Breast Cancer Metastasis
Authors: Goddard Erica T. , Hill Ryan C. , Nemkov Travis , D'Alessandro Angelo , Hansen Kirk C. , Maller Ori , Mongoue-Tchokote Solange , Mori Motomi , Partridge Ann H. , Borges Virginia F. , Schedin Pepper
Published: March 2024

Abstract
Patients with postpartum breast cancer are at increased risk for metastasis compared with age-matched nulliparous or pregnant patients. Here, we address whether circulating tumor cells have a metastatic advantage in the postpartum host and find the postlactation rodent liver preferentially supports metastasis. Upon weaning, we observed liver weight loss, hepatocyte apoptosis, extracellular matrix remodeling including deposition of collagen and tenascin-C, and myeloid cell influx, data consistent with weaning-induced liver involution and establishment of a prometastatic microenvironment. Using intracardiac and intraportal metastasis models, we observed increased liver metastasis in post-weaning BALB/c mice compared with nulliparous controls. Human relevance is suggested by a ∼3-fold increase in liver metastasis in patients with postpartum breast cancer (n = 564) and by liver-specific tropism (n = 117). In sum, our data reveal a previously unknown biology of the rodent liver, weaning-induced liver involution, which may provide insight into the increased liver metastasis and poor prognosis of women diagnosed with postpartum breast cancer.

Significance: We find that patients with postpartum breast cancer are at elevated risk for liver metastasis. We identify a previously unrecognized biology, namely weaning-induced liver involution, that establishes a prometastatic microenvironment, and which may account in part for the poor prognosis of patients with postpartum breast cancer. Cancer Discov; 7(2); 177–87. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 115
Data from Accelerating Discovery of Functional Mutant Alleles in Cancer
Authors: Chang Matthew T. , Bhattarai Tripti Shrestha , Schram Alison M. , Bielski Craig M. , Donoghue Mark T.A. , Jonsson Philip , Chakravarty Debyani , Phillips Sarah , Kandoth Cyriac , Penson Alexander , Gorelick Alexander , Shamu Tambudzai , Patel Swati , Harris Christopher , Gao JianJiong , Sumer Selcuk Onur , Kundra Ritika , Razavi Pedram , Li Bob T. , Reales Dalicia N. , Socci Nicholas D. , Jayakumaran Gowtham , Zehir Ahmet , Benayed Ryma , Arcila Maria E. , Chandarlapaty Sarat , Ladanyi Marc , Schultz Nikolaus , Baselga José , Berger Michael F. , Rosen Neal , Solit David B. , Hyman David M. , Taylor Barry S.
Published: March 2024

Abstract
Most mutations in cancer are rare, which complicates the identification of therapeutically significant mutations and thus limits the clinical impact of genomic profiling in patients with cancer. Here, we analyzed 24,592 cancers including 10,336 prospectively sequenced patients with advanced disease to identify mutant residues arising more frequently than expected in the absence of selection. We identified 1,165 statistically significant hotspot mutations of which 80% arose in 1 in 1,000 or fewer patients. Of 55 recurrent in-frame indels, we validated that novel AKT1 duplications induced pathway hyperactivation and conferred AKT inhibitor sensitivity. Cancer genes exhibit different rates of hotspot discovery with increasing sample size, with few approaching saturation. Consequently, 26% of all hotspots in therapeutically actionable oncogenes were novel. Upon matching a subset of affected patients directly to molecularly targeted therapy, we observed radiographic and clinical responses. Population-scale mutant allele discovery illustrates how the identification of driver mutations in cancer is far from complete.

Significance: Our systematic computational, experimental, and clinical analysis of hotspot mutations in approximately 25,000 human cancers demonstrates that the long right tail of biologically and therapeutically significant mutant alleles is still incompletely characterized. Sharing prospective genomic data will accelerate hotspot identification, thereby expanding the reach of precision oncology in patients with cancer. Cancer Discov; 8(2); 174–83. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 127
Data from Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin
Authors: Yang Dian , Denny Sarah K. , Greenside Peyton G. , Chaikovsky Andrea C. , Brady Jennifer J. , Ouadah Youcef , Granja Jeffrey M. , Jahchan Nadine S. , Lim Jing Shan , Kwok Shirley , Kong Christina S. , Berghoff Anna S. , Schmitt Anna , Reinhardt H. Christian , Park Kwon-Sik , Preusser Matthias , Kundaje Anshul , Greenleaf William J. , Sage Julien , Winslow Monte M.
Published: March 2024

Abstract
The extent to which early events shape tumor evolution is largely uncharacterized, even though a better understanding of these early events may help identify key vulnerabilities in advanced tumors. Here, using genetically defined mouse models of small cell lung cancer (SCLC), we uncovered distinct metastatic programs attributable to the cell type of origin. In one model, tumors gain metastatic ability through amplification of the transcription factor NFIB and a widespread increase in chromatin accessibility, whereas in the other model, tumors become metastatic in the absence of NFIB-driven chromatin alterations. Gene-expression and chromatin accessibility analyses identify distinct mechanisms as well as markers predictive of metastatic progression in both groups. Underlying the difference between the two programs was the cell type of origin of the tumors, with NFIB-independent metastases arising from mature neuroendocrine cells. Our findings underscore the importance of the identity of cell type of origin in influencing tumor evolution and metastatic mechanisms.

Significance: We show that SCLC can arise from different cell types of origin, which profoundly influences the eventual genetic and epigenetic changes that enable metastatic progression. Understanding intertumoral heterogeneity in SCLC, and across cancer types, may illuminate mechanisms of tumor progression and uncover how the cell type of origin affects tumor evolution. Cancer Discov; 8(10); 1316–31. ©2018 AACR.

See related commentary by Pozo et al., p. 1216.

This article is highlighted in the In This Issue feature, p. 1195
Data from Overcoming the Immunosuppressive Tumor Microenvironment of Hodgkin Lymphoma Using Chimeric Antigen Receptor T Cells
Authors: Ruella Marco , Klichinsky Michael , Kenderian Saad S. , Shestova Olga , Ziober Amy , Kraft Daniel O. , Feldman Michael , Wasik Mariusz A. , June Carl H. , Gill Saar
Published: March 2024

Abstract
Patients with otherwise treatment-resistant Hodgkin lymphoma could benefit from chimeric antigen receptor T-cell (CART) therapy. However, Hodgkin lymphoma lacks CD19 and contains a highly immunosuppressive tumor microenvironment (TME). We hypothesized that in Hodgkin lymphoma, CART should target both malignant cells and the TME. We demonstrated CD123 on both Hodgkin lymphoma cells and TME, including tumor-associated macrophages (TAM). In vitro, Hodgkin lymphoma cells convert macrophages toward immunosuppressive TAMs that inhibit T-cell proliferation. In contrast, anti-CD123 CART recognized and killed TAMs, thus overcoming immunosuppression. Finally, we showed in immunodeficient mouse models that CART123 eradicated Hodgkin lymphoma and established long-term immune memory. A novel platform that targets malignant cells and the microenvironment may be needed to successfully treat malignancies with an immunosuppressive milieu.

Significance: Anti-CD123 chimeric antigen receptor T cells target both the malignant cells and TAMs in Hodgkin lymphoma, thereby eliminating an important immunosuppressive component of the tumor microenvironment. Cancer Discov; 7(10); 1154–67. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 1047
Data from A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion–Positive Solid Tumors
Authors: Drilon Alexander , Nagasubramanian Ramamoorthy , Blake James F. , Ku Nora , Tuch Brian B. , Ebata Kevin , Smith Steve , Lauriault Veronique , Kolakowski Gabrielle R. , Brandhuber Barbara J. , Larsen Paul D. , Bouhana Karyn S. , Winski Shannon L. , Hamor Robyn , Wu Wen-I , Parker Andrew , Morales Tony H. , Sullivan Francis X. , DeWolf Walter E. , Wollenberg Lance A. , Gordon Paul R. , Douglas-Lindsay Dorothea N. , Scaltriti Maurizio , Benayed Ryma , Raj Sandeep , Hanusch Bethany , Schram Alison M. , Jonsson Philip , Berger Michael F. , Hechtman Jaclyn F. , Taylor Barry S. , Andrews Steve , Rothenberg S. Michael , Hyman David M.
Published: March 2024

Abstract
Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion–positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion–positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.

Significance: LOXO-195 abrogated resistance in TRK fusion–positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963–72. ©2017 AACR.

See related commentary by Parikh and Corcoran, p. 934.

This article is highlighted in the In This Issue feature, p. 920
Data from Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations
Authors: Shin Daniel Sanghoon , Zaretsky Jesse M. , Escuin-Ordinas Helena , Garcia-Diaz Angel , Hu-Lieskovan Siwen , Kalbasi Anusha , Grasso Catherine S. , Hugo Willy , Sandoval Salemiz , Torrejon Davis Y. , Palaskas Nicolaos , Rodriguez Gabriel Abril , Parisi Giulia , Azhdam Ariel , Chmielowski Bartosz , Cherry Grace , Seja Elizabeth , Berent-Maoz Beata , Shintaku I. Peter , Le Dung T. , Pardoll Drew M. , Diaz Luis A. , Tumeh Paul C. , Graeber Thomas G. , Lo Roger S. , Comin-Anduix Begoña , Ribas Antoni
Published: March 2024

Abstract
Loss-of-function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned that they may also be involved in primary resistance to anti–PD-1 therapy. JAK1/2-inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair–deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti–PD-1 therapy. Two out of 48 human melanoma cell lines had JAK1/2 mutations, which led to a lack of PD-L1 expression upon interferon gamma exposure mediated by an inability to signal through the interferon gamma receptor pathway. JAK1/2 loss-of-function alterations in The Cancer Genome Atlas confer adverse outcomes in patients. We propose that JAK1/2 loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary resistance to PD-1 blockade therapy.

Significance: A key functional result from somatic JAK1/2 mutations in a cancer cell is the inability to respond to interferon gamma by expressing PD-L1 and many other interferon-stimulated genes. These mutations result in a genetic mechanism for the absence of reactive PD-L1 expression, and patients harboring such tumors would be unlikely to respond to PD-1 blockade therapy. Cancer Discov; 7(2); 188–201. ©2016 AACR.

See related commentary by Marabelle et al., p. 128.

This article is highlighted in the In This Issue feature, p. 115
Data from A Secondary Mutation in BRAF Confers Resistance to RAF Inhibition in a BRAFV600E-Mutant Brain Tumor
Authors: Wang Jiawan , Yao Zhan , Jonsson Philip , Allen Amy N. , Qin Alice Can Ran , Uddin Sharmeen , Dunkel Ira J. , Petriccione Mary , Manova Katia , Haque Sofia , Rosenblum Marc K. , Pisapia David J. , Rosen Neal , Taylor Barry S. , Pratilas Christine A.
Published: March 2024

Abstract
BRAFV600E hyperactivates ERK and signals as a RAF inhibitor–sensitive monomer. Although RAF inhibitors can produce impressive clinical responses in patients with mutant BRAF tumors, the mechanisms of resistance to these drugs are incompletely characterized. Here, we report a complete response followed by clinical progression in a patient with a BRAFV600E-mutant brain tumor treated with dabrafenib. Whole-exome sequencing revealed a secondary BRAFL514V mutation at progression that was not present in the pretreatment tumor. Expressing BRAFV600E/L514V induces ERK signaling, promotes RAF dimer formation, and is sufficient to confer resistance to dabrafenib. Newer RAF dimer inhibitors and an ERK inhibitor are effective against BRAFL514V-mediated resistance. Collectively, our results validate a novel biochemical mechanism of RAF inhibitor resistance mediated by a secondary mutation, emphasizing that, like driver mutations in cancer, the spectrum of mutations that drive resistance to targeted therapy are heterogeneous and perhaps emerge with a lineage-specific prevalence.

Significance: In contrast to receptor tyrosine kinases, in which secondary mutations are often responsible for acquired resistance, second-site mutations in BRAF have not been validated in clinically acquired resistance to RAF inhibitors. We demonstrate a secondary mutation in BRAF (V600E/L514V) following progression on dabrafenib and confirm functionally that this mutation is responsible for resistance. Cancer Discov; 8(9); 1130–41. ©2018 AACR.

See related commentary by Romano and Kwong, p. 1064.

This article is highlighted in the In This Issue feature, p. 1047
Data from Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins
Authors: Zhang Maomao , Di Martino Julie S. , Bowman Robert L. , Campbell Nathaniel R. , Baksh Sanjeethan C. , Simon-Vermot Theresa , Kim Isabella S. , Haldeman Pearce , Mondal Chandrani , Yong-Gonzales Vladimir , Abu-Akeel Mohsen , Merghoub Taha , Jones Drew R. , Zhu Xiphias Ge , Arora Arshi , Ariyan Charlotte E. , Birsoy Kivanç , Wolchok Jedd D. , Panageas Katherine S. , Hollmann Travis , Bravo-Cordero Jose Javier , White Richard M.
Published: March 2024

Abstract
Advanced, metastatic melanomas frequently grow in subcutaneous tissues and portend a poor prognosis. Though subcutaneous tissues are largely composed of adipocytes, the mechanisms by which adipocytes influence melanoma are poorly understood. Using in vitro and in vivo models, we find that adipocytes increase proliferation and invasion of adjacent melanoma cells. Additionally, adipocytes directly transfer lipids to melanoma cells, which alters tumor cell metabolism. Adipocyte-derived lipids are transferred to melanoma cells through the FATP/SLC27A family of lipid transporters expressed on the tumor cell surface. Among the six FATP/SLC27A family members, melanomas significantly overexpress FATP1/SLC27A1. Melanocyte-specific FATP1 expression cooperates with BRAFV600E in transgenic zebrafish to accelerate melanoma development, an effect that is similarly seen in mouse xenograft studies. Pharmacologic blockade of FATPs with the small-molecule inhibitor Lipofermata abrogates lipid transport into melanoma cells and reduces melanoma growth and invasion. These data demonstrate that stromal adipocytes can drive melanoma progression through FATP lipid transporters and represent a new target aimed at interrupting adipocyte–melanoma cross-talk.

Significance: We demonstrate that stromal adipocytes are donors of lipids that mediate melanoma progression. Adipocyte-derived lipids are taken up by FATP proteins that are aberrantly expressed in melanoma. Inhibition of FATPs decreases melanoma lipid uptake, invasion, and growth. We provide a mechanism for how stromal adipocytes drive tumor progression and demonstrate a novel microenvironmental therapeutic target. Cancer Discov; 8(8); 1006–25. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 899
Data from iNKT Cell Cytotoxic Responses Control T-Lymphoma Growth In Vitro and In Vivo
Authors: Bassiri Hamid , Das Rupali , Guan Peng , Barrett David M. , Brennan Patrick J. , Banerjee Pinaki P. , Wiener Susan J. , Orange Jordan S. , Brenner Michael B. , Grupp Stephan A. , Nichols Kim E.
Published: March 2024

Abstract
Invariant natural killer T (iNKT) cells comprise a lineage of CD1d-restricted glycolipid-reactive T lymphocytes with important roles in host immunity to cancer. iNKT cells indirectly participate in antitumor responses by inducing dendritic cell maturation and producing cytokines that promote tumor clearance by CD8+ T and NK cells. Although iNKT cells thereby act as potent cellular adjuvants, it is less clear whether they directly control the growth of tumors. To gain insights into the direct contribution of iNKT cells to tumor immune surveillance, we developed in vitro and in vivo systems to selectively examine the antitumor activity of iNKT cells in the absence of other cytolytic effectors. Using the EL4 T-lymphoma cell line as a model, we found that iNKT cells exert robust and specific lysis of tumor cells in vitro in a manner that is differentially induced by iNKT cell agonists of varying T-cell receptor (TCR) affinities, such as OCH, α-galactosyl ceramide, and PBS44. In vitro blockade of CD1d-mediated lipid antigen presentation, disruption of TCR signaling, or loss of perforin expression significantly reduce iNKT cell killing. Consistent with these findings, iNKT cell reconstitution of T, B, and NK cell–deficient mice slows EL4 growth in vivo via TCR-CD1d and perforin-dependent mechanisms. Together, these observations establish that iNKT cells are sufficient to control the growth of T lymphoma in vitro and in vivo. They also suggest that the induction of iNKT cell cytotoxic responses in situ might serve as a more effective strategy to prevent and/or treat CD1d+ cancers, such as T lymphoma. Cancer Immunol Res; 2(1); 59–69. ©2013 AACR.
Data from Mesothelin-Specific Chimeric Antigen Receptor mRNA-Engineered T Cells Induce Antitumor Activity in Solid Malignancies
Authors: Beatty Gregory L. , Haas Andrew R. , Maus Marcela V. , Torigian Drew A. , Soulen Michael C. , Plesa Gabriela , Chew Anne , Zhao Yangbing , Levine Bruce L. , Albelda Steven M. , Kalos Michael , June Carl H.
Published: March 2024

Abstract
Off-target toxicity due to the expression of target antigens in normal tissue represents a major obstacle to the use of chimeric antigen receptor (CAR)-engineered T cells for treatment of solid malignancies. To circumvent this issue, we established a clinical platform for engineering T cells with transient CAR expression by using in vitro transcribed mRNA encoding a CAR that includes both the CD3-ζ and 4-1BB costimulatory domains. We present two case reports from ongoing trials indicating that adoptive transfer of mRNA CAR T cells that target mesothelin (CARTmeso cells) is feasible and safe without overt evidence of off-tumor on-target toxicity against normal tissues. CARTmeso cells persisted transiently within the peripheral blood after intravenous administration and migrated to primary and metastatic tumor sites. Clinical and laboratory evidence of antitumor activity was shown in both patients, and the CARTmeso cells elicited an antitumor immune response revealed by the development of novel antiself antibodies. These data show the potential of using mRNA-engineered T cells to evaluate, in a controlled manner, potential off-tumor on-target toxicities and show that short-lived CAR T cells can induce epitope spreading and mediate antitumor activity in patients with advanced cancer. Thus, these findings support the development of mRNA CAR-based strategies for carcinoma and other solid tumors. Cancer Immunol Res; 2(2); 112–20. ©2013 AACR.
Data from Improving CART-Cell Therapy of Solid Tumors with Oncolytic Virus–Driven Production of a Bispecific T-cell Engager
Authors: Wing Anna , Fajardo Carlos Alberto , Posey Avery D. , Shaw Carolyn , Da Tong , Young Regina M. , Alemany Ramon , June Carl H. , Guedan Sonia
Published: March 2024

Abstract
T cells expressing chimeric antigen receptors (CART) have shown significant promise in clinical trials to treat hematologic malignancies, but their efficacy in solid tumors has been limited. Oncolytic viruses have the potential to act in synergy with immunotherapies due to their immunogenic oncolytic properties and the opportunity of incorporating therapeutic transgenes in their genomes. Here, we hypothesized that an oncolytic adenovirus armed with an EGFR-targeting, bispecific T-cell engager (OAd-BiTE) would improve the outcome of CART-cell therapy in solid tumors. We report that CART cells targeting the folate receptor alpha (FR-α) successfully infiltrated preestablished xenograft tumors but failed to induce complete responses, presumably due to the presence of antigen-negative cancer cells. We demonstrated that OAd-BiTE–mediated oncolysis significantly improved CART-cell activation and proliferation, while increasing cytokine production and cytotoxicity, and showed an in vitro favorable safety profile compared with EGFR-targeting CARTs. BiTEs secreted from infected cells redirected CART cells toward EGFR in the absence of FR-α, thereby addressing tumor heterogeneity. BiTE secretion also redirected CAR-negative, nonspecific T cells found in CART-cell preparations toward tumor cells. The combinatorial approach improved antitumor efficacy and prolonged survival in mouse models of cancer when compared with the monotherapies, and this was the result of an increased BiTE-mediated T-cell activation in tumors. Overall, these results demonstrated that the combination of a BiTE-expressing oncolytic virus with adoptive CART-cell therapy overcomes key limitations of CART cells and BiTEs as monotherapies in solid tumors and encourage its further evaluation in human trials. Cancer Immunol Res; 6(5); 605–16. ©2018 AACR.
Data from Peptide Vaccination in Montanide Adjuvant Induces and GM-CSF Increases CXCR3 and Cutaneous Lymphocyte Antigen Expression by Tumor Antigen–Specific CD8 T Cells
Authors: Clancy-Thompson Eleanor , King Laura K. , Nunnley Lenora D. , Mullins Irene M. , Slingluff Craig L. , Mullins David W.
Published: March 2024

Abstract
T-cell infiltration of melanoma is associated with enhanced clinical efficacy and is a desirable endpoint of immunotherapeutic vaccination. Infiltration is regulated, in part, by chemokine receptors and selectin ligands on the surface of tumor-specific lymphocytes. Therefore, we investigated the expression of two homing molecules, CXC chemokine receptor 3 (CXCR3) and cutaneous lymphocyte antigen (CLA), on vaccine-induced CD8 T cells, in the context of a clinical trial of a melanoma-specific peptide vaccine. Both CXCR3 and CLA have been associated with T-cell infiltration of melanoma. We show that a single subcutaneous/intradermal administration of peptide vaccine in Montanide adjuvant induces tumor-specific CD8 T cells that are predominantly positive for CXCR3, with a subpopulation of CXCR3+CLA+ cells. Addition of granulocyte macrophage colony—stimulating factor (GM-CSF) significantly enhances CXCR3 expression and increases the proportion of CLA-expressing cells. Concurrent with CXCR3 and CLA expression, vaccine-induced CD8 cells express high levels of T-bet, IFN-γ, and interleukin-12 receptor (IL-12Rβ1). Collectively, these studies show that peptide vaccination in adjuvant induces CD8 T cells with a phenotype that may support infiltration of melanoma. Cancer Immunol Res; 1(5); 332–9. ©2013 AACR.
Data from Assessment of MAGE-A Expression in Resected Non–Small Cell Lung Cancer in Relation to Clinicopathologic Features and Mutational Status of EGFR and KRAS
Authors: Ayyoub Maha , Memeo Lorenzo , Álvarez-Fernández Emilio , Colarossi Cristina , Costanzo Rosario , Aiello Eleonora , Martinetti Daniela , Valmori Danila
Published: March 2024

Abstract
Non–small cell lung cancer (NSCLC) is a major public health problem, accounting for more cancer-related deaths than any other cancer. Both immunotherapy, based on the expression of tumor-specific antigens, and targeted therapy, based on the presence of oncogenic mutations, are under development for NSCLC. In this study, we analyzed the expression of MAGE-A, a cancer–testis antigen, in tumors from a cohort of patients with resected NSCLC with respect to their clinicopathologic characteristics and their mutational status for the EGFR and KRAS genes. We found MAGE-A expression by IHC in 43% of the tumors. MAGE-A expression was significantly more frequent in squamous tumors than in adenocarcinomas, did not correlate with disease stage, but was correlated significantly with high tumor grade and worse survival. EGFR and KRAS mutations were present in adenocarcinomas, but not in squamous tumors. Whereas the presence of EGFR mutations did not seem to affect survival, the presence of KRAS mutations was associated with early-stage disease and better survival. MAGE-A expression was absent from adenocarcinomas with KRAS mutations, but not significantly different in tumors with or without EGFR mutations. Together, the reported results provide guidance for the design of combination therapies in patients with NSCLC. Cancer Immunol Res; 2(10); 943–8. ©2014 AACR.
Data from PD-L1 microSPECT/CT Imaging for Longitudinal Monitoring of PD-L1 Expression in Syngeneic and Humanized Mouse Models for Cancer
Authors: Heskamp Sandra , Wierstra Peter J. , Molkenboer-Kuenen Janneke D.M. , Sandker Gerwin W. , Thordardottir Soley , Cany Jeannette , Olive Daniel , Bussink Johan , Boerman Otto C. , Dolstra Harry , Aarntzen Erik H.J.G. , Hobo Willemijn A.
Published: March 2024

Abstract
Antibodies that block the interaction between programmed death ligand 1 (PD-L1) and PD-1 have shown impressive responses in subgroups of patients with cancer. PD-L1 expression in tumors seems to be a prerequisite for treatment response. However, PD-L1 is heterogeneously expressed within tumor lesions and may change upon disease progression and treatment. Imaging of PD-L1 could aid in patient selection. Previously, we showed the feasibility to image PD-L1+ tumors in immunodeficient mice. However, PD-L1 is also expressed on immune cell subsets. Therefore, the aim of this study was to assess the potential of PD-L1 micro single-photon emission tomography/computed tomography (microSPECT/CT) using radiolabeled PD-L1 antibodies to (i) measure PD-L1 expression in two immunocompetent tumor models (syngeneic mice and humanized mice harboring PD-L1 expressing immune cells) and (ii) monitor therapy-induced changes in tumor PD-L1 expression. We showed that radiolabeled PD-L1 antibodies accumulated preferentially in PD-L1+ tumors, despite considerable uptake in certain normal lymphoid tissues (spleen and lymph nodes) and nonlymphoid tissues (duodenum and brown fat). PD-L1 microSPECT/CT imaging could also distinguish between high and low PD-L1–expressing tumors. The presence of PD-L1+ immune cells did not compromise tumor uptake of the human PD-L1 antibodies in humanized mice, and we demonstrated that radiotherapy-induced upregulation of PD-L1 expression in murine tumors could be monitored with microSPECT/CT imaging. Together, these data demonstrate that PD-L1 microSPECT/CT is a sensitive technique to detect variations in tumor PD-L1 expression, and in the future, this technique may enable patient selection for PD-1/PD-L1–targeted therapy.
Data from Concurrent Radiotherapy and Ipilimumab Immunotherapy for Patients with Melanoma
Authors: Barker Christopher A. , Postow Michael A. , Khan Shaheer A. , Beal Kathryn , Parhar Preeti K. , Yamada Yoshiya , Lee Nancy Y. , Wolchok Jedd D.
Published: March 2024

Abstract
Ipilimumab and radiotherapy are commonly used to treat unresectable and metastatic melanoma. Results from preclinical studies and case reports suggest a biologic interaction between these two treatments. To understand the clinical implications of the interaction, we carried out a retrospective study reviewing records of patients treated with ipilimumab and radiotherapy for melanoma at our institution between 2005 and 2011. The review included details of treatment, response, adverse events (AE), and overall survival (OS). Twenty-nine patients underwent 33 courses of non-brain radiotherapy between their first and last dose of ipilimumab. Immune-related AEs (ir-AEs) were observed in 43% of patients receiving ipilimumab at 10 mg/kg and in 22% of patients receiving 3 mg/kg; the frequency of ir-AEs was not significantly different compared with previous studies of ipilimumab alone. Radiotherapy-related AEs were significantly more common in patients receiving higher doses of radiation. Palliation of symptoms was reported by 77% of patients after radiotherapy. Median OS was 9 and 39 months in patients receiving radiotherapy during induction and maintenance with ipilimumab, respectively. In this retrospective study, concurrent ipilimumab and radiotherapy was neither associated with higher than expected rates of AEs nor did it abrogate palliative effects of radiotherapy or survival benefits of ipilimumab. Further studies to prospectively explore the efficacy of this therapeutic combination are warranted. Cancer Immunol Res; 1(2); 92–98. ©2013 AACR.
Data from Spontaneous Peripheral T-cell Responses toward the Tumor-Associated Antigen Cyclin D1 in Patients with Clear Cell Renal Cell Carcinoma
Authors: Dannenmann Stefanie R. , Hermanns Thomas , Bransi Ali , Matter Claudia , von Boehmer Lotta , Stevanovic Stefan , Schraml Peter , Moch Holger , Knuth Alexander , van den Broek Maries
Published: March 2024

Abstract
Renal cell carcinoma (RCC) is a heterogeneous group of kidney cancers with clear cell RCC (ccRCC) as the major subgroup. To expand the number of clinically relevant tumor-associated antigens (TAA) that can be targeted by immunotherapy, we analyzed samples from 23 patients with primary ccRCC for the expression and immunogenicity of various TAAs. We found high-frequency expression of MAGE-A9 and NY-ESO-1 in 36% and 55% of samples, respectively, and overexpression of PRAME, RAGE-1, CA-IX, Cyclin D1, ADFP, C-MET, and RGS-5 in many of the tumor samples. We analyzed the blood of patients with HLA-A2+ ccRCC for the presence of CD8+ T cells specific for TAA-derived HLA-A2–restricted peptides and found spontaneous responses to cyclin D1 in 5 of 6 patients with Cyclin D1–positive tumors. Cyclin D1–specific CD8+ T cells secreted TNF-α, IFN-γ, and interleukin-2 (IL-2), and degranulated, indicating the presence of polyfunctional tumor-specific CD8+ T cells in the blood of these patients with ccRCC. The high frequency (43%) of Cyclin D1 overexpression and the presence of functional cyclin D1–specific T cells in 83% of these patients with ccRCC suggest that cyclin D1 may be a target for immunotherapeutic strategies. Cancer Immunol Res; 1(5); 288–95. ©2013 AACR.
Data from Immune Consequences of Decreasing Tumor Vasculature with Antiangiogenic Tyrosine Kinase Inhibitors in Combination with Therapeutic Vaccines
Authors: Farsaci Benedetto , Donahue Renee N. , Coplin Michael A. , Grenga Italia , Lepone Lauren M. , Molinolo Alfredo A. , Hodge James W.
Published: March 2024

Abstract
This study investigated the effects on the tumor microenvironment (TME) of combining antiangiogenic tyrosine kinase inhibitors (TKI) with therapeutic vaccines, and in particular, how vascular changes affect tumor-infiltrating immune cells. We conducted studies using a TKI (sunitinib or sorafenib) in combination with recombinant vaccines in two murine tumor models: colon carcinoma (MC38-CEA) and breast cancer (4T1). Tumor vasculature was measured by immunohistochemistry using three endothelial cell markers: CD31 (mature), CD105 (immature/proliferating), and CD11b (monocytic). We assessed oxygenation, tight junctions, compactness, and pressure within tumors, along with the frequency and phenotype of tumor-infiltrating lymphocytes (TIL), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM) following treatment with antiangiogenic TKIs alone, vaccine alone, or the combination of a TKI with vaccine. The combined regimen decreased tumor vasculature, compactness, tight junctions, and pressure, leading to vascular normalization and increased tumor oxygenation. This combination therapy also increased TILs, including tumor antigen–specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals. The improved antitumor activity induced by combining antiangiogenic TKIs with vaccine may be the result of activated lymphoid and myeloid cells in the TME, resulting from vascular normalization, decreased tumor-cell density, and the consequent improvement in vascular perfusion and oxygenation. Therapies that alter tumor architecture can, thus, have a dramatic impact on the effectiveness of cancer immunotherapy. Cancer Immunol Res; 2(11); 1090–102. ©2014 AACR.
Data from Chimeric Antigen Receptor T Cells with Dissociated Signaling Domains Exhibit Focused Antitumor Activity with Reduced Potential for Toxicity In Vivo
Authors: Lanitis Evripidis , Poussin Mathilde , Klattenhoff Alex W. , Song Degang , Sandaltzopoulos Raphael , June Carl H. , Powell Daniel J.
Published: March 2024

Abstract
Adoptive immunotherapy using T lymphocytes genetically modified to express a chimeric antigen receptor (CAR-T) holds considerable promise for the treatment of cancer. However, CAR-based therapies may involve on-target toxicity against normal tissues expressing low amounts of the targeted tumor-associated antigen (TAA). To specify T cells for robust effector function that is selective for tumor but not normal tissue, we developed a trans-signaling CAR strategy, whereby T-cell activation signal 1 (CD3ζ) is physically dissociated from costimulatory signal 2 (CD28) in two CARs of differing antigen specificity: mesothelin and a-folate receptor (FRa). Human T cells were genetically modified to coexpress signal 1 (anti-Meso scFv-CD3ζ) and signal 2 (anti-FRa scFv-CD28) CARs in trans. Trans-signaling CAR-T cells showed weak cytokine secretion against target cells expressing only one TAA in vitro, similar to first-generation CAR-T cells bearing CD3ζ only, but showed enhanced cytokine secretion upon encountering natural or engineered tumor cells coexpressing both antigens, equivalent to that of second-generation CAR-T cells with dual signaling in cis. CAR-T cells with dual specificity also showed potent anticancer activity and persistence in vivo, which was superior to first-generation CAR-T cells and equivalent to second-generation CARs. Importantly, second-generation CAR-T cells exhibited potent activity against cells expressing mesothelin alone, recapitulating normal tissue, whereas trans-signaling CAR-T cells did not. Thus, a dual specificity, trans-signaling CAR approach can potentiate the therapeutic efficacy of CAR-T cells against cancer while minimizing parallel reactivity against normal tissues bearing single antigen. Cancer Immunol Res; 1(1); 43–53. ©2013 AACR.
Data from Neoadjuvant Interferons: Critical for Effective PD-1–Based Immunotherapy in TNBC
Authors: Brockwell Natasha K. , Owen Katie L. , Zanker Damien , Spurling Alex , Rautela Jai , Duivenvoorden Hendrika M. , Baschuk Nikola , Caramia Franco , Loi Sherene , Darcy Phillip K. , Lim Elgene , Parker Belinda S.
Published: March 2024

Abstract
The lack of targeted therapies available for triple-negative breast cancer (TNBC) patients who fail to respond to first-line chemotherapy has sparked interest in immunotherapeutic approaches. However, trials utilizing checkpoint inhibitors targeting the PD-1/PD-L1 axis in TNBC have had underwhelming responses. Here, we investigated the interplay between type I IFN signaling and the PD-1/PD-L1 axis and tested the impact of combining IFN inducers, as immune activators, with anti–PD-1, to induce an antimetastatic immune response. Using models of TNBC, we demonstrated an interplay between type I IFN signaling and tumor cell PD-L1 expression that affected therapeutic response. The data revealed that the type I IFN-inducer poly(I:C) was an effective immune activator and antimetastatic agent, functioning better than anti–PD-1, which was ineffective as a single agent. Poly(I:C) treatment induced PD-L1 expression on TNBC cells, and combined poly(I:C) and anti–PD-1 treatment prolonged metastasis-free survival in a neoadjuvant setting via the induction of a tumor-specific T-cell response. Use of this combination in a late treatment setting did not impact metastasis-free survival, indicating that timing was critical for immunotherapeutic benefit. Together, these data demonstrated anti–PD-1 as an ineffective single agent in preclinical models of TNBC. However, type I IFN inducers were effective immune activators, and neoadjuvant trials combining them with anti–PD-1 to induce a sustained antitumor immune response are warranted. Cancer Immunol Res; 5(10); 871–84. ©2017 AACR.