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1.
J Immunother Cancer ; 11(2)2023 02.
Article in English | MEDLINE | ID: mdl-36746510

ABSTRACT

BACKGROUND: Cluster of differentiation (CD)73-adenosine and transforming growth factor (TGF)-ß pathways are involved in abrogated antitumor immune responses and can lead to protumor conditions. This Phase 1 study (NCT03954704) evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of dalutrafusp alfa (also known as GS-1423 and AGEN1423), a bifunctional, humanized, aglycosylated immunoglobulin G1 kappa antibody that selectively inhibits CD73-adenosine production and neutralizes active TGF-ß signaling in patients with advanced solid tumors. METHODS: Dose escalation started with an accelerated titration followed by a 3+3 design. Patients received dalutrafusp alfa (0.3, 1, 3, 10, 20, 30, or 45 mg/kg) intravenously every 2 weeks (Q2W) up to 1 year or until progressive disease (PD) or unacceptable toxicity. RESULTS: In total, 21/22 patients received at least one dose of dalutrafusp alfa. The median number of dalutrafusp alfa doses administered was 3 (range 1-14). All patients had at least one adverse event (AE), most commonly fatigue (47.6%), nausea (33.3%), diarrhea (28.6%), and vomiting (28.6%). Nine (42.9%) patients had a Grade 3 or 4 AE; two had Grade 5 AEs of pulmonary embolism and PD, both unrelated to dalutrafusp alfa. Target-mediated drug disposition appears to be saturated at dalutrafusp alfa doses above 20 mg/kg. Complete CD73 target occupancy on B cells and CD8+ T cells was observed, and TGF-ß 1/2/3 levels were undetectable at dalutrafusp alfa doses of 20 mg/kg and higher. Free soluble (s)CD73 levels and sCD73 activity increased with dalutrafusp alfa treatment. Seventeen patients reached the first response assessment, with complete response, partial response, stable disease, and PD in 0, 1 (4.8%), 7 (33.3%), and 9 (42.9%) patients, respectively. CONCLUSIONS: Dalutrafusp alfa doses up to 45 mg/kg Q2W were well tolerated in patients with advanced solid tumors. Additional evaluation of dalutrafusp alfa could further elucidate the clinical utility of targeting CD73-adenosine and TGF-ß pathways in oncology.


Subject(s)
Antibodies, Bispecific , Neoplasms , Humans , Antibodies, Monoclonal, Humanized/adverse effects , Treatment Outcome , Neoplasms/pathology , Immunoglobulin G , Transforming Growth Factor beta , Antibodies, Bispecific/therapeutic use
2.
Nature ; 615(7950): 158-167, 2023 03.
Article in English | MEDLINE | ID: mdl-36634707

ABSTRACT

Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking1,2. Here we identify the innate immune kinase TANK-binding kinase 1 (TBK1)3 as a candidate immune-evasion gene in a pooled genetic screen4. Using a suite of genetic and pharmacological tools across multiple experimental model systems, we confirm a role for TBK1 as an immune-evasion gene. Targeting TBK1 enhances responses to PD-1 blockade by decreasing the cytotoxicity threshold to effector cytokines (TNF and IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumour models, with concordant findings in matched patient-derived organotypic tumour spheroids and matched patient-derived organoids. Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNF and IFNγ in a JAK-STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is an effective strategy to overcome resistance to cancer immunotherapy.


Subject(s)
Drug Resistance, Neoplasm , Immune Evasion , Immunotherapy , Protein Serine-Threonine Kinases , Humans , Immune Evasion/genetics , Immune Evasion/immunology , Immunotherapy/methods , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Organoids , Tumor Necrosis Factors/immunology , Interferon-gamma/immunology , Spheroids, Cellular , Caspases , Janus Kinases , STAT Transcription Factors
3.
Cancer Cell ; 34(3): 439-452.e6, 2018 09 10.
Article in English | MEDLINE | ID: mdl-30205046

ABSTRACT

Despite extensive efforts, oncogenic KRAS remains resistant to targeted therapy. Combined downstream RAL-TBK1 and MEK inhibition induces only transient lung tumor shrinkage in KRAS-driven genetically engineered mouse models (GEMMs). Using the sensitive KRAS;LKB1 (KL) mutant background, we identify YAP1 upregulation and a therapy-induced secretome as mediators of acquired resistance. This program is reversible, associated with H3K27 promoter acetylation, and suppressed by BET inhibition, resensitizing resistant KL cells to TBK1/MEK inhibition. Constitutive YAP1 signaling promotes intrinsic resistance in KRAS;TP53 (KP) mutant lung cancer. Intermittent treatment with the BET inhibitor JQ1 thus overcomes resistance to combined pathway inhibition in KL and KP GEMMs. Using potent and selective TBK1 and BET inhibitors we further develop an effective therapeutic strategy with potential translatability to the clinic.


Subject(s)
Antineoplastic Agents, Immunological/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , AMP-Activated Protein Kinase Kinases , AMP-Activated Protein Kinases , Adaptor Proteins, Signal Transducing/immunology , Adaptor Proteins, Signal Transducing/metabolism , Animals , Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Disease Models, Animal , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/immunology , HEK293 Cells , Humans , Immunity, Innate/drug effects , Insulin-Like Growth Factor I/immunology , Insulin-Like Growth Factor I/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Mice , Mice, Transgenic , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinase Kinases/metabolism , Phosphoproteins/immunology , Phosphoproteins/metabolism , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/immunology , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Transcription Factors , YAP-Signaling Proteins
4.
Cancer Discov ; 8(2): 196-215, 2018 02.
Article in English | MEDLINE | ID: mdl-29101162

ABSTRACT

Ex vivo systems that incorporate features of the tumor microenvironment and model the dynamic response to immune checkpoint blockade (ICB) may facilitate efforts in precision immuno-oncology and the development of effective combination therapies. Here, we demonstrate the ability to interrogate ex vivo response to ICB using murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS). MDOTS/PDOTS isolated from mouse and human tumors retain autologous lymphoid and myeloid cell populations and respond to ICB in short-term three-dimensional microfluidic culture. Response and resistance to ICB was recapitulated using MDOTS derived from established immunocompetent mouse tumor models. MDOTS profiling demonstrated that TBK1/IKKε inhibition enhanced response to PD-1 blockade, which effectively predicted tumor response in vivo Systematic profiling of secreted cytokines in PDOTS captured key features associated with response and resistance to PD-1 blockade. Thus, MDOTS/PDOTS profiling represents a novel platform to evaluate ICB using established murine models as well as clinically relevant patient specimens.Significance: Resistance to PD-1 blockade remains a challenge for many patients, and biomarkers to guide treatment are lacking. Here, we demonstrate feasibility of ex vivo profiling of PD-1 blockade to interrogate the tumor immune microenvironment, develop therapeutic combinations, and facilitate precision immuno-oncology efforts. Cancer Discov; 8(2); 196-215. ©2017 AACR.See related commentary by Balko and Sosman, p. 143See related article by Deng et al., p. 216This article is highlighted in the In This Issue feature, p. 127.


Subject(s)
Antineoplastic Agents, Immunological/pharmacology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Animals , Cell Culture Techniques , Cell Line, Tumor , Cytokines/metabolism , Drug Resistance, Neoplasm , Flow Cytometry , Humans , Immunohistochemistry , Immunophenotyping , Mice , Microfluidic Analytical Techniques , Programmed Cell Death 1 Receptor/metabolism , Spheroids, Cellular , Time-Lapse Imaging , Tumor Cells, Cultured
5.
Blood ; 124(3): 420-5, 2014 Jul 17.
Article in English | MEDLINE | ID: mdl-24916506

ABSTRACT

Addition of rituximab (R) to fludarabine and cyclophosphamide (FC) has significantly improved patient outcomes in chronic lymphocytic leukemia (CLL). Whether baseline gene expression can identify patients who will benefit from immunochemotherapy over chemotherapy alone has not been determined. We assessed genome-wide expression of 300 pretreatment specimens from a subset of 552 patients in REACH, a study of FC or R-FC in relapsed CLL. An independent test set was derived from 282 pretreatment specimens from CLL8, a study of FC or R-FC in treatment-naïve patients. Genes specific for benefit from R-FC were determined by assessing treatment-gene interactions in Cox proportional hazards models. REACH patients with higher pretreatment protein tyrosine kinase 2 (PTK2) messenger RNA levels derived greater benefit from R-FC, with significant improvements in progression-free survival, independent of known prognostic factors in a multivariate model. Examination of PTK2 gene expression in CLL8 patients yielded similar results. Furthermore, PTK2 inhibition blunted R-dependent cell death in vitro. This retrospective analysis from 2 independent trials revealed that increased PTK2 expression is associated with improved outcomes for CLL patients treated with R-FC vs FC. PTK2 expression may be a useful biomarker for patient selection in future trials. These trials were registered at www.clinicaltrials.gov as #NCT00090051 (REACH) and #NCT00281918 (CLL8).


Subject(s)
Focal Adhesion Kinase 1/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Disease-Free Survival , Gene Expression , Humans , Immunotherapy , Leukemia, Lymphocytic, Chronic, B-Cell/enzymology , Proportional Hazards Models , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Recurrence , Retrospective Studies , Rituximab , Vidarabine/administration & dosage , Vidarabine/analogs & derivatives
6.
PLoS One ; 8(6): e66502, 2013.
Article in English | MEDLINE | ID: mdl-23776679

ABSTRACT

The epithelial-to-mesenchymal transition (EMT) is a highly conserved physiological program involved in development and tissue repair; however, its aberrant activation has been implicated in accelerating the progression of a variety of cancers. In breast cancer, the microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) are differentially expressed in the clinically more aggressive basal-like subtype compared to luminal subtype of breast cancer and upregulation of miR-221/222 induces the EMT by targeting the 3' untranslated region (3'UTR) of the GATA family transcriptional repressor TRPS1 (tricho-rhino-phalangeal syndrome type 1). The complete mechanism through which miR-221/222 promotes the EMT, however, is not fully understood. We identified adiponectin receptor 1 (ADIPOR1), a receptor for the adipocytokine adiponectin, as a direct target of miR-221/222. ADIPOR1 is expressed at higher levels in the luminal compared to the basal-like subtype of breast cancer cell lines, which can be reduced by miR-221/222 targeting of its 3'UTR. In addition, miR-221/222 were negatively correlated with ADIPOR1 expression across breast cancer cell lines and tumors. ADIPOR1 depletion by siRNA in MCF10A cells induced the EMT and increased cell invasion. Depletion of ADIPOR1 by siRNA induced activation of the canonical nuclear factor-kappaB (NF-κB) and subsequent phosphorylation of signal transducer and activator of transcription 3 (STAT3) in an interleukin 6 (IL6)-dependent manner. Finally, overexpression of ADIPOR1 in the basal-like cell line, MDA-MB-231, attenuated cell invasion and promoted the mesenchymal-to-epithelial transition (MET). We conclude that ADIPOR1 negatively regulates EMT in breast cancer and provides an additional node by which miR-221/222 induces the EMT. These results suggest that ADIPOR1 may play an important role in breast cancer progression and metastasis, and could potentially offer an alternative therapeutic strategy for basal-like breast cancer patients.


Subject(s)
Breast Neoplasms/metabolism , Epithelial-Mesenchymal Transition/physiology , MicroRNAs/metabolism , Receptors, Adiponectin/metabolism , Blotting, Western , Breast Neoplasms/genetics , Cell Line, Tumor , Epithelial-Mesenchymal Transition/genetics , Female , Fluorescent Antibody Technique , Gene Expression Regulation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/physiology , Humans , MicroRNAs/genetics , Real-Time Polymerase Chain Reaction , Receptors, Adiponectin/genetics
7.
Sci Signal ; 4(186): pt5, 2011 Aug 09.
Article in English | MEDLINE | ID: mdl-21868360

ABSTRACT

Compared with the luminal subtype, the basal-like subtype of breast cancer has an aggressive clinical behavior, but the reasons for this difference between the two subtypes are poorly understood. We identified microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs that decrease expression of epithelial-specific genes and increase expression of mesenchymal-specific genes. In addition, expression of these miRNAs increased cell migration and invasion, which collectively are characteristics of the epithelial-to-mesenchymal transition (EMT). The basal-like transcription factor FOSL1 (also known as Fra-1) directly stimulated the transcription of miR-221/222, and the abundance of these miRNAs decreased with inhibition of MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), placing miR-221/222 downstream of the RAS pathway. The miR-221/222-mediated reduction in E-cadherin abundance depended on their targeting of the 3' untranslated region (3'UTR) of TRPS1 (trichorhinophalangeal syndrome type 1), which is a member of the GATA family of transcriptional repressors. TRPS1 inhibited EMT by directly repressing expression of ZEB2 (Zinc finger E-box-binding homeobox 2). Therefore, miR-221/222 may contribute to the aggressive clinical behavior of basal-like breast cancers.


Subject(s)
Breast Neoplasms/metabolism , DNA-Binding Proteins/biosynthesis , Epithelial-Mesenchymal Transition , MicroRNAs/metabolism , Neoplasm Proteins/metabolism , RNA, Neoplasm/metabolism , Transcription Factors/biosynthesis , 3' Untranslated Regions/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Movement/genetics , DNA-Binding Proteins/genetics , Female , Gene Expression Regulation, Neoplastic/genetics , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , MAP Kinase Kinase Kinases/genetics , MAP Kinase Kinase Kinases/metabolism , MicroRNAs/genetics , Neoplasm Invasiveness , Neoplasm Proteins/genetics , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , RNA, Neoplasm/genetics , Repressor Proteins/genetics , Repressor Proteins/metabolism , Transcription Factors/genetics , Zinc Finger E-box Binding Homeobox 2
8.
Sci Signal ; 4(177): ra41, 2011 Jun 14.
Article in English | MEDLINE | ID: mdl-21673316

ABSTRACT

The basal-like subtype of breast cancer has an aggressive clinical behavior compared to that of the luminal subtype. We identified the microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs and showed that expression of miR-221/222 decreased expression of epithelial-specific genes and increased expression of mesenchymal-specific genes, and increased cell migration and invasion in a manner characteristic of the epithelial-to-mesenchymal transition (EMT). The transcription factor FOSL1 (also known as Fra-1), which is found in basal-like breast cancers but not in the luminal subtype, stimulated the transcription of miR-221/222, and the abundance of these miRNAs decreased with inhibition of the epidermal growth factor receptor (EGFR) or MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), placing miR-221/222 downstream of the RAS pathway. Furthermore, miR-221/222-mediated reduction in E-cadherin abundance depended on their targeting the 3' untranslated region of the GATA family transcriptional repressor TRPS1 (tricho-rhino-phalangeal syndrome type 1), which inhibited EMT by decreasing ZEB2 (zinc finger E-box-binding homeobox2) expression. We conclude that by promoting EMT, miR-221/222 may contribute to the more aggressive clinical behavior of basal-like breast cancers.


Subject(s)
Breast Neoplasms/metabolism , DNA-Binding Proteins/biosynthesis , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , MicroRNAs/biosynthesis , RNA, Neoplasm/biosynthesis , Transcription Factors/biosynthesis , 3' Untranslated Regions/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , DNA-Binding Proteins/genetics , ErbB Receptors/genetics , ErbB Receptors/metabolism , Female , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , MAP Kinase Kinase Kinases/genetics , MAP Kinase Kinase Kinases/metabolism , MicroRNAs/genetics , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , RNA, Neoplasm/genetics , Repressor Proteins/genetics , Repressor Proteins/metabolism , Transcription Factors/genetics , Zinc Finger E-box Binding Homeobox 2 , ras Proteins/genetics , ras Proteins/metabolism
9.
Sci Transl Med ; 3(74): 74ra22, 2011 Mar 16.
Article in English | MEDLINE | ID: mdl-21411738

ABSTRACT

The primary function of B cells, critical components of the adaptive immune response, is to produce antibodies against foreign antigens, as well as to perform isotype class switching, which changes the heavy chain of an antibody so that it can interact with different repertoires of effector cells. CD40 is a member of the tumor necrosis factor superfamily of cell surface receptors that transmits survival signals to B cells. In contrast, in B cell cancers, stimulation of CD40 signaling results in a heterogeneous response in which cells can sometimes undergo cell death in response to treatment, depending on the system studied. We found an association between sensitivity to CD40 stimulation and mutation of the tumor suppressor p53 in a panel of non-Hodgkin's lymphoma cell lines. Consistent with p53's tumor suppressor role, we found that higher levels of intrinsic DNA damage and increased proliferation rates, as well as higher levels of BCL6, a transcriptional repressor proto-oncogene, were associated with sensitivity to CD40 stimulation. In addition, CD40 treatment-resistant cell lines were sensitized to CD40 stimulation after the introduction of DNA-damaging agents. Using gene expression analysis, we also showed that resistant cell lines exhibited a preexisting activated CD40 pathway and that an mRNA expression signature comprising CD40 target genes predicted sensitivity and resistance to CD40-activating agents in cell lines and mouse xenograft models. Finally, the gene signature predicted tumor shrinkage and progression-free survival in patients with diffuse large B cell lymphoma treated with dacetuzumab, a monoclonal antibody with partial CD40 agonist activity. These data show that CD40 pathway activation status may be useful in predicting the antitumor activity of CD40-stimulating therapeutic drugs.


Subject(s)
Antibodies, Monoclonal/therapeutic use , CD40 Antigens/immunology , Immunotherapy/methods , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/immunology , Animals , Antibodies, Monoclonal, Humanized , B-Lymphocytes/immunology , CD40 Antigens/genetics , CD40 Ligand/genetics , CD40 Ligand/immunology , Cell Line, Tumor , Gene Expression Profiling , Humans , In Situ Hybridization, Fluorescence , Mice , Microarray Analysis , Proto-Oncogene Mas , Transplantation, Heterologous , Tumor Suppressor Protein p53/immunology
10.
J Clin Invest ; 119(5): 1216-29, 2009 May.
Article in English | MEDLINE | ID: mdl-19381019

ABSTRACT

Overexpression of FGF receptor 3 (FGFR3) is implicated in the development of t(4;14)-positive multiple myeloma. While FGFR3 is frequently overexpressed and/or activated through mutations in bladder cancer, the functional importance of FGFR3 and its potential as a specific therapeutic target in this disease have not been elucidated in vivo. Here we report that inducible knockdown of FGFR3 in human bladder carcinoma cells arrested cell-cycle progression in culture and markedly attenuated tumor progression in xenografted mice. Further, we developed a unique antibody (R3Mab) that inhibited not only WT FGFR3, but also various mutants of the receptor, including disulfide-linked cysteine mutants. Biochemical analysis and 2.1-A resolution crystallography revealed that R3Mab bound to a specific FGFR3 epitope that simultaneously blocked ligand binding, prevented receptor dimerization, and induced substantial conformational changes in the receptor. R3Mab exerted potent antitumor activity against bladder carcinoma and t(4;14)-positive multiple myeloma xenografts in mice by antagonizing FGFR3 signaling and eliciting antibody-dependent cell-mediated cytotoxicity (ADCC). These studies provide in vivo evidence demonstrating an oncogenic role of FGFR3 in bladder cancer and support antibody-based targeting of FGFR3 in hematologic and epithelial cancers driven by WT or mutant FGFR3.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Multiple Myeloma/therapy , Receptor, Fibroblast Growth Factor, Type 3/immunology , Translocation, Genetic/genetics , Urinary Bladder Neoplasms/therapy , Adaptor Proteins, Signal Transducing/metabolism , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antibody-Dependent Cell Cytotoxicity/immunology , Antigen-Antibody Complex/chemistry , Cell Line, Tumor/drug effects , Cell Proliferation/drug effects , Epitopes/chemistry , Epitopes/immunology , Female , Fibroblast Growth Factors/metabolism , Humans , Membrane Proteins/metabolism , Mice , Mice, Nude , Mice, SCID , Mitogen-Activated Protein Kinases/metabolism , Models, Molecular , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Phosphorylation/drug effects , Protein Binding/drug effects , Protein Conformation/drug effects , RNA Interference , Receptor, Fibroblast Growth Factor, Type 3/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 3/metabolism , Signal Transduction/drug effects , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/pathology , Xenograft Model Antitumor Assays
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