706 BT7480, a fully synthetic tumor-targeted immune cell agonist (TICA™) induces tumor localized CD137 agonism and modulation of tumor immune microenvironment

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A748-A748
Author(s):  
Punit Upadhyaya ◽  
Kristen Hurov ◽  
Jessica Kublin ◽  
Jun Ma ◽  
Elizabeth Repash ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cell ◽  
Immune Microenvironment ◽  
Plasma Exposure ◽  
Tumor Models ◽  
Human Pbmc ◽  
Tumor Immune Microenvironment ◽  
Animal Care ◽  
Anti Tumor Activity

BackgroundAfter disappointing first clinical experiences with agonistic anti-CD137 (4-1BB) antibodies, a new generation of both systemic and targeted CD137 agonists is entering clinical development.1–3 These strategies rely on biologic agents with suboptimal properties for CD137 agonism due to their relatively large sizes and long circulating half-lives. These properties may limit their tissue penetration and cause sustained agonism resulting in overstimulation and activation-induced cell death of lymphocytes due to continuous exposure.Fully synthetic constrained bicyclic peptides (Bicycles™) with antibody-like affinities and target selectivity are uniquely suited to circumvent the above barriers to optimal targeted CD137 agonistic therapeutics. BT7480 is a tumor-targeted immune cell agonist (TICA) designed to deliver a highly potent CD137 agonist to Nectin-4 overexpressing tumor tissue with a flexible dosing schedule maximizing anti-tumor activity while circumventing the need for continuous systemic exposure.MethodsBT7480 functional activity in vitro was analyzed by measuring IL-2 and IFN gamma production from primary human PBMC/tumor cell co-cultures. BT7480 in vivo activity was determined in huCD137-syngeneic tumor models using tumor immune cell and transcriptional profiling by FACS, IHC, and Nanostring as well as tumor growth kinetics as read-outs.ResultsBT7480 binds potently and simultaneously to Nectin-4 and CD137 as assessed biochemically and caused Nectin-4-dependent CD137 agonism in primary human PBMC co-cultured with tumor cells. Treatment of Nectin-4 expressing tumors in immunocompetent mice with BT7480 leads to profound reprogramming of the tumor immune microenvironment including increased T cell infiltration and upregulation of a cytotoxic cell gene signature. BT7480 treatment induces complete tumor regressions and subsequent resistance to tumor re-challenge. TICA-dependent anti-tumor activity and established immunologic memory are dependent on cytotoxic T cells. Importantly, BT7480 in vivo activity is not dependent on continuous plasma exposure since once weekly dosing of BT7480 provides a maximum anti-tumor activity despite minimal BT7480 plasma exposure after day 2.BT7480 demonstrates linear pharmacokinetics in non-human primates and appears well tolerated at exposures in excess of the predicted efficacious exposure in humans.ConclusionsBT7480 is a highly potent Nectin-4 expression dependent CD137 agonist with optimal target binding, pharmacologic, and pharmacokinetic properties that enable intermittent dosing for curative effect through modulation of tumor immune microenvironment in syngeneic mouse tumor models. BT7480 is currently being evaluated in IND-enabling safety studies.Ethics ApprovalThe care and use of animals were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of WuXi AppTec and conducted in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).ReferencesHinner, et al. Tumor-localized costimulatory t-cell engagement by the 4-1BB/HER2 Bispecific antibody-anticalin fusion PRS-343. Clin. Cancer Res 2019 Oct 1;25(19):5878–5889.Claus, et al. Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. Sci. Transl. Med 2019 Jun 12;11(496):eaav5989.Eskiocak, et al. Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity. JCI Insight 2020 Mar 12;5(5):e133647.

scholarly journals 700 EphA2/CD137 Bicycle tumor-targeted immune cell agonists (TICAsTM) induce tumor regressions, immunogenic memory, and reprogramming of the tumor immune microenvironment

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A742-A742
Author(s):  
Kristen Hurov ◽  
Johanna lahdenranta ◽  
Gemma Mudd ◽  
Punit Upadhyaya ◽  
Elizabeth Repash ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cell ◽  
Immune Cell ◽  
Immune Microenvironment ◽  
New Class ◽  
Tumor Immune Microenvironment ◽  
Nf Kappab ◽  
Animal Care ◽  
Anti Tumor Activity

BackgroundDespite compelling preclinical data, agonistic anti-CD137 antibodies have been hampered by failure to delineate hepatotoxicity from efficacy in clinical studies.1 2 A new generation of both systemic and targeted CD137 agonists that are now entering clinical development rely on biologic agents with suboptimal properties for CD137 agonism due to their relatively large sizes and long circulating half-lives.3–5 These properties may limit their tissue penetration and cause sustained agonism resulting in overstimulation and activation-induced cell death of lymphocytes due to continuous exposure.BCY12491 is a tumor-targeted immune cell agonist (TICATM) that exemplifies a new class of fully synthetic immunomodulators with constrained bicyclic peptides (Bicycles®) targeting a tumor antigen and a co-stimulatory molecule. We developed this new class of synthetic molecules with antibody-like affinities and target selectivity to circumvent the beforementioned barriers to optimal targeted CD137 agonistic therapeutics. BCY12491 (EphA2/CD137 TICA) is designed to deliver a highly potent CD137 agonist to EphA2 overexpressing tumor tissue with an intermittent dosing schedule maximizing anti-tumor activity while circumventing the need for continuous systemic exposure.MethodsBCY12491 bioactivity was assessed in vitro using a CD137 reporter assay and by measuring cytokine production from primary human PBMC/tumor cell co-cultures. BCY12491 in vivo activity was determined in huCD137-syngeneic tumor models by measuring tumor growth kinetics and using tumor immune cell and transcriptional profiling by FACS, IHC, and Nanostring.ResultsBCY12491 engages EphA2 and CD137 with high affinity resulting in picomolar potency in co-culture assays consisting of EphA2-expressing tumor cell lines and CD137-expressing Jurkat NF-kappaB-luciferase reporter cells. Moreover, BCY12491 caused EphA2-dependent CD137 agonism in primary human PBMCs co-cultured with tumor cells with varied levels of EphA2 expression. Treatment of MC38 tumors in immunocompetent mice with BCY12491 leads to a profound reprogramming of the tumor immune microenvironment including increased T cell infiltration and stimulation of NF-kappaB signaling, costimulatory signaling, cytotoxicity and cytokine/chemokine signaling functional pathways. BCY12491 treatment leads to MC38 tumor regressions, complete responses, and immunogenic memory without continuous drug exposure in the periphery. This anti-tumor activity is dependent on CD8+ T cells, but not on NK 1.1+ cells.ConclusionsBCY12491 is a potent EphA2-dependent CD137 agonist with optimal target binding, pharmacologic, and pharmacokinetic properties that enable anti-tumor TME remodeling and complete responses in vivo with intermittent dosing. This work unleashes a new and tractable avenue to testing a novel class of therapeutic CD137 agonists in humans for the treatment of cancer.Ethics ApprovalThe care and use of animals were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of WuXi AppTec and conducted in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).ReferencesSegal NH, Logan TF, Hodi FS, et al. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res 2017;23(8):1929–1936.Chester C, Sanmamed MF, Wang J, Melero I. Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood 2018;131(1): 49–57.Hinner MJ, Aiba RSB, Jaquin TJ, et al. Tumor-Localized Costimulatory T-Cell Engagement by the 4-1BB/HER2 Bispecific Antibody-Anticalin Fusion PRS-343. Clin Cancer Res. 2019;25(19):5878–5889.Claus C, Ferrara, C, Xu W, et al. Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. Sci Transl Med 2019;11(496): eaav5989.Eskiocak U, Guzman W, Wolf B, et al. Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity. JCI Insight 2020;5(5):e133647.

scholarly journals Single cell transcriptomics reveals the effect of PD-L1/TGF-β blockade on the tumor microenvironment

2020 ◽  
Author(s):  
Yoong Wearn Lim ◽  
Garry L. Coles ◽  
Savreet K. Sandhu ◽  
David S. Johnson ◽  
Adam S. Adler ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Cell ◽  
Single Cells ◽  
Cell Infiltration ◽  
Cytotoxic Lymphocytes ◽  
T Cell Infiltration ◽  
Anti Tumor Activity

AbstractBackgroundThe anti-tumor activity of anti-PD-1/PD-L1 therapies correlates with T cell infiltration in tumors. Thus, a major goal in oncology is to find strategies that enhance T cell infiltration and efficacy of anti-PD-1/PD-L1 therapy. TGF-β has been shown to contribute to T cell exclusion and anti-TGF-β improves anti-PD-L1 efficacy in vivo. However, TGF-β inhibition has frequently been shown to induce toxicity in the clinic, and the clinical efficacy of combination PD-L1 and TGF-β blockade has not yet been proven. To identify strategies to overcome resistance to PD-L1 blockade, the transcriptional programs associated with PD-L1 and/or TGF-β blockade in the tumor microenvironment should be further elucidated.ResultsFor the first time, we used single-cell RNA sequencing to characterize the transcriptomic effects of PD-L1 and/or TGF-β blockade on nearly 30,000 single cells in the tumor and surrounding microenvironment. Combination treatment led to upregulation of immune response genes, including multiple chemokine genes such as CCL5, in CD45+ cells, and down-regulation of extracellular matrix genes in CD45-cells. Analysis of publicly available tumor transcriptome profiles showed that the chemokine CCL5 was strongly associated with immune cell infiltration in various human cancers. Further investigation with in vivo models showed that intratumorally administered CCL5 enhanced cytotoxic lymphocytes and the anti-tumor activity of anti-PD-L1.ConclusionsTaken together, our data could be leveraged translationally to improve anti-PD-L1 plus anti-TGF-β combination therapy, for example through companion biomarkers, and/or to identify novel targets that could be modulated to overcome resistance.

scholarly journals 420 PROSTVAC in combination with nivolumab enhanced immune cell infiltration in prostate cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A450-A450
Author(s):  
Shania Bailey ◽  
Wiem Lassoued ◽  
Antonios Papanicolau-Sengos ◽  
Jennifer Marte ◽  
Nikki Williams ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Microenvironment ◽  
Invasive Margin ◽  
Control Tumor Growth ◽  
Tumor Immune Microenvironment ◽  
Control Tumor

BackgroundProstate cancer (PC) is the most common non-cutaneous diagnosed cancer among men in USA.1 Although clinical outcomes are favorable for patients with localized disease, 20–30% of patients will develop metastatic prostate cancer (mPC) and have poor prognosis. Immunotherapy, as a single agent, provides benefit to a small subset of PC patients, which is thought to be partially due to its known cold tumor immune microenvironment (TIME). Combination studies are needed to enhance benefit.2 Prostvac is a therapeutic cancer vaccine engineered to activate an immune response against prostate-specific Antigen (PSA).3 Prostvac alone could induce systemic immune response by increasing immune-cell infiltrates in and around the tumor.4 In this study, we are exploring the effect of Prostvac in combination with nivolumab in TIME in prostate cancer.MethodsWe treated locally advanced prostate cancer patients (n=6) undergoing radical prostatectomy (RP) with neoadjuvant Prostvac in combination with nivolumab, an immune checkpoint PD-1 inhibitor. Dynamic changes in TIME before and after treatment were studied using multiplex immunofluorescence (Opal Method). Formalin fixed paraffin-embedded sections from matched pre-treated prostate biopsies and post-treated RP samples were stained with a validated T cell panel (DAPI, CD4, CD8, FOXP3, Ki67, Pan CK and PD-L1). To analyze the data, TIME was segmented into 3 compartments: intratumoral, invasive margin and benign.ResultsCombination immunotherapy significantly increased CD4+ T cell density in the invasive margin (mean 211.5 cells/mm2 vs 592.2 cells/mm2, p<0.05), with similar trend in the intratumoral and the benign compartments. CD8+ T cell density increased after treatment in the invasive margin (mean 47.25 cells/mm2 vs 157cells/mm2) and the benign compartment. 5/6 and 4/6 patients showed more than 2-fold increase of CD4 and CD8 T cells in the TIME, respectively, in at least one of the three compartments. Increased proliferative indices in CD4+ and CD8+ T cells were also seen after treatment. Tregs were present in low frequencies in TIME (maximum of 12 cells/mm2) with no significant changes. Moreover, a significant drop in tumor cell Ki67 after treatment (mean 252.8 cells/mm2 vs 100.5 cells/332, p<0.05) suggests that the combination may control tumor growth.ConclusionsThe combination of Neoadjuvant Prostvac and nivolumab was associated with increased immune cell infiltration in a cohort of early prostate cancer patients. A broader examination of the TIME and the role immune cells undertake to control tumor growth is on-going.Trial RegistrationNCT02933255ReferencesSiegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin (Internet) 2020;70:7–3Zhao SG, Lehrer J, Chang SL, et al. The immune landscape of prostate cancer and nomination of PD-L2 as a potential therapeutic target. J Natl Cancer Inst 2018;111:301–10.Madan RA, Arlen PM, Mohebtash M, et al. Prostvac-VF: a vectorbased vaccine targeting PSA in prostate cancer. Expert Opin Investig Drugs 2009;18:1001–11Abdul Sater H, Marté JL, Donahue RN, et al. Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer. J Immunother Cancer 2020;8(1):655–64Ethics ApprovalThis study was performed in compliance with ethical standard and was approved by the NIH IRB, 17C-0007. All patients participating in this study gave an informed consent before taking part.

scholarly journals Single-cell transcriptomics reveals the effect of PD-L1/TGF-β blockade on the tumor microenvironment

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yoong Wearn Lim ◽  
Garry L. Coles ◽  
Savreet K. Sandhu ◽  
David S. Johnson ◽  
Adam S. Adler ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Cell ◽  
Single Cells ◽  
Cell Infiltration ◽  
In Vivo Models ◽  
T Cell Infiltration ◽  
Anti Tumor Activity

Abstract Background The anti-tumor activity of anti-PD-1/PD-L1 therapies correlates with T cell infiltration in tumors. Thus, a major goal in oncology is to find strategies that enhance T cell infiltration and efficacy of anti-PD-1/PD-L1 therapy. TGF-β has been shown to contribute to T cell exclusion, and anti-TGF-β improves anti-PD-L1 efficacy in vivo. However, TGF-β inhibition has frequently been shown to induce toxicity in the clinic, and the clinical efficacy of combination PD-L1 and TGF-β blockade has not yet been proven. To identify strategies to overcome resistance to PD-L1 blockade, the transcriptional programs associated with PD-L1 and/or TGF-β blockade in the tumor microenvironment should be further elucidated. Results We used single-cell RNA sequencing in a mouse model to characterize the transcriptomic effects of PD-L1 and/or TGF-β blockade on nearly 30,000 single cells in the tumor and surrounding microenvironment. Combination treatment led to upregulation of immune response genes, including multiple chemokine genes such as CCL5, in macrophages, and downregulation of extracellular matrix genes in fibroblasts. Analysis of publicly available tumor transcriptome profiles showed that the chemokine CCL5 was strongly associated with immune cell infiltration in various human cancers. Further investigation with in vivo models showed that intratumorally administered CCL5 enhanced cytotoxic lymphocytes and the anti-tumor activity of anti-PD-L1. Conclusions Taken together, our data could be leveraged translationally to complement or find alternatives to anti-PD-L1 plus anti-TGF-β combination therapy, for example through companion biomarkers, and/or to identify novel targets that could be modulated to overcome resistance.

561 DuoBody®-PD-L1×4–1BB (GEN1046) induces superior immune-cell activation, cytokine production and cytotoxicity by combining PD-L1 blockade with conditional 4–1BB co-stimulation

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A595-A595
Author(s):  
Alexander Muik ◽  
Isil Altintas ◽  
Rachelle Kosoff ◽  
Friederike Gieseke ◽  
Kristina Schödel ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cytokine Production ◽  
Immune Cell ◽  
Anti Tumor Activity

BackgroundCheckpoint inhibitors targeting the PD-1/PD-L1 axis (CPI) have changed the treatment paradigm and prognosis for patients with advanced solid tumors; however, many patients experience limited benefit due to treatment resistance. 4-1BB co-stimulation can activate cytotoxic T-cell- and NK-cell-mediated anti-tumor immunity and has been shown to synergize with CPI in preclinical models. DuoBody-PD­L1×4-1BB is a first-in-class, Fc-silenced, bispecific next-generation checkpoint immunotherapy that activates T cells through PD-L1 blockade and simultaneous PD-L1-dependent 4-1BB co-stimulation. Here we present preclinical evidence for the mechanism of action of DuoBody-PD-L1×4-1BB, and proof-of-concept using mouse-reactive mbsAb-PD-L1×4-1BB in vivo.MethodsRNA sequencing analyses was performed on primary human CD8+ T cells that were co-cultured with PD-L1+ monocytes in the presence of anti-CD3/anti-CD28 and test compounds. T-cell proliferation and cytokine production were analyzed in primary human T-cell and mixed lymphocyte reaction (MLR) assays in vitro, and using patient-derived tumor-infiltrating lymphocytes (TILs). Cytotoxic activity was assessed in co-cultures of CLDN6+PD-L1+ MDA-MB-231 tumor cells and CLDN6-TCR+CD8+ T cells. Anti-tumor activity of mbsAb-PD-L1×4-1BB was tested in vivo using the CT26 mouse tumor model. Immunophenotyping of the tumor microenvironment (TME), tumor-draining lymph nodes (tdLNs) and peripheral blood was performed by flow cytometry.ResultsDuoBody-PD-L1×4-1BB significantly induced expression of genes associated with immune cell proliferation, migration and cytokine production in activated CD8+ T cells, which were not altered by CPI. DuoBody-PD-L1×4-1BB dose-dependently enhanced expansion of human TILs ex vivo. DuoBody-PD-L1×4-1BB dose-dependently enhanced T-cell proliferation and pro-inflammatory cytokine production in vitro (e.g. IFNγ and TNFα; in polyclonal and antigen-specific T-cell proliferation assays and MLR), which was dependent on crosslinking to PD-L1+ cells and superior to CPI or the combination of Fc-silenced PD-L1- and 4-1BB-specific antibodies. DuoBody-PD-L1x4-1BB induced upregulation of degranulation marker CD107a and granzyme B in CD8+ T cells, resulting in antigen-specific T-cell-mediated cytotoxicity of MDA-MB-231 tumor cells in vitro, superior to CPI. In mice bearing subcutaneous CT26 tumors, a model that was insensitive to PD-L1 blockade, mbsAb-PD-L1×4-1BB elicited tumor rejection in the majority of the mice at active dose levels and significantly improved survival. Dose-dependent anti-tumor activity was associated with expansion of tumor antigen-specific T cells in the blood and enhanced immune-cell activation in tdLNs and TME.ConclusionsCombining PD-L1 blockade with conditional 4-1BB co-stimulation using bispecific antibodies induced T-cell activation, expansion, and cytotoxic activity in vitro and potent anti-tumor activity in vivo superior to CPI. DuoBody-PD-L1×4-1BB is currently being evaluated in patients with advanced solid tumors in a first-in-human trial (NCT03917381).Ethics ApprovalAll mice studies were performed by BioNTech SE at its research facilities in Germany, and the mice were housed in accordance with German federal and state policies on animal research. All experiments were approved by the regulatory authorities for animal welfare in Germany. The use of tumor tissue resections was approved by BioNTech SE‘s Ethics Board, approval number 837.309.12 (8410-F).

scholarly journals 888 An integrative approach to optimize a synthetic EphA2/CD137 agonist: balancing potency, physiochemical properties, and pharmacokinetics to achieve robust anti-tumor activity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A931-A931
Author(s):  
Punit Upadhyaya ◽  
Gemma Mudd ◽  
Kristen Hurov ◽  
Johanna Lahdenranta ◽  
Elizabeth Repash ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cell ◽  
Immune Cell ◽  
List Type ◽  
Continuous Exposure ◽  
Target Engagement ◽  
In Vivo Models ◽  
Anti Tumor Activity

BackgroundCD137 (4-1BB) is a resurging target in immunotherapy after the first generation of monoclonal antibodies were limited by hepatotoxicity1 or lack of efficacy.2 A new generation of CD137 agonists are now in clinical development but they exclusively utilize large molecules derived from recombinant technology and are associated with long circulating terminal half-lives.3–6 Unlike checkpoint inhibition where complete saturation of the receptors drives the reversal of immunosuppression, intermittent target engagement that reflects the physiological context of T cell co-stimulation may be more appropriate for a CD137 agonist.7 Bicyclic peptides or Bicycles are a class of small (MW~2kDa), highly constrained peptides characterized by formation of two loops cyclized around a symmetric scaffold. To develop a differentiated tumor antigen dependent CD137 agonist for treating EphA2 expressing solid tumors, we integrated structure activity relationship (SAR) data from biochemical binding studies and in-vitro and in-vivo models to understand the relationship between exposure, target engagement and preclinical efficacy.MethodsOver 150 different EphA2/CD137 tumor-targeted immune cell agonists (Bicycle TICAs) were synthesized by linking Bicycle® binders to EphA2 to those binding CD137.8 The molecules were assessed in vitro using a CD137 reporter assay and by measuring cytokine production from primary human PBMC in tumor cell co-cultures. The pharmacokinetics were evaluated in rodents using Phoenix WinNonlin. The in vivo activity was determined in syngeneic mouse tumor models by measuring tumor growth kinetics and using tumor immune cell and transcriptional profiling by IHC and NanoString.ResultsEvaluation of the Bicycle TICAs in co-culture assays with EphA2-expressing tumor cell lines and Jurkat reporter cells overexpressing CD137 or human PBMCs demonstrated that constructs bearing two CD137 binding Bicycles to one EphA2 binding Bicycle (1:2 format) were more potent than the 1:1 format.8 Several Bicycle TICAs with amino acid substitutions to the EphA2 binding Bicycle maintained sub-nanomolar potency in-vitro and exhibited a plasma terminal half-life (t1/2) in rodents ranging from 0.4 and 4.0 h. Modifications that conferred aqueous solubility of greater than 10 mg/mL were considered suitable for further development. Treatment of MC38 tumors in immunocompetent mice with this series of molecules demonstrated that low MW Bicycle TICAs with sub-nanomolar potency and a t½ of ~1 h in mouse maintained target coverages necessary to produce robust modulation of the tumor immune microenvironment and tumor regression.ConclusionsA differentiated EphA2-dependent CD137 agonist was developed that exploits intermittent rather than continuous exposure for robust anti-tumor activity.ReferencesSegal NH, Logan TF, Hodi FS, et al. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res 2017;23(8):1929–1936.Segal NH, Aiwu RH, Toshihiko D, et al. Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin Cancer Res 2018;24(8):1816–1823.Chester C, Sanmamed MF, Wang J, Melero I. Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood 2018;131(1):49–57.Hinner MJ, Aiba RSB, Jaquin TJ, et al. Tumor-localized costimulatory T-cell engagement by the 4-1BB/HER2 bispecific antibody-anticalin fusion PRS-343. Clin Cancer Res 2019;25(19):5878–5889.Claus C, Ferrara, C, Xu W, et al. Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. Sci Transl Med 2019;11(496):eaav5989.Eskiocak U, Guzman W, Wolf B, et al. Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity. JCI Insight 2020;5(5):e133647.Mayes PA, Hance KW, Hoos A. The promise and challenges of immune agonist antibody development in cancer. Nat Rev Drug Discov 2018;17:509–27.Upadhyaya P, Lahdenranta J, Hurov K, et al. Anticancer immunity induced by a synthetic tumor-targeted CD137 agonist. J Immunother Cancer 2021;9:e001762.

scholarly journals Association of CLDN6 and CLDN10 With Immune Microenvironment in Ovarian Cancer: A Study of the Claudin Family

2021 ◽  
Vol 12 ◽  
Author(s):  
Peipei Gao ◽  
Ting Peng ◽  
Canhui Cao ◽  
Shitong Lin ◽  
Ping Wu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cell ◽  
Immune Cell ◽  
Gene Set Enrichment Analysis ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Immune Microenvironment ◽  
Gene Markers ◽  
Expression Levels ◽  
Tumor Immune Microenvironment

BackgroundThe claudin family is a group of transmembrane proteins related to tight junctions. While their involvement in cancer has been studied extensively, their relationship with the tumor immune microenvironment remains poorly understood. In this research, we focused on genes related to the prognosis of ovarian cancer and explored their relationship with the tumor immune microenvironment.MethodsThe cBioPortal for Cancer Genomics database was used to obtain the genetic variation pattern of the claudin family in ovarian cancer. The ONCOMINE and Gene Expression Profiling Interactive Analysis (GEPIA) databases were used to explore the mRNA expression of claudins in cancers. The prognostic potential of these genes was examined via the Kaplan-Meier plotter. The enrichment of immunological signatures was determined by gene set enrichment analysis (GSEA). The correlations between claudins and the tumor immune microenvironment in ovarian cancer were investigated via the Tumor Immune Estimation Resource (TIMER).ResultsClaudin genes were altered in 363 (62%) of queried patients/samples. Abnormal expression levels of claudins were observed in various cancers. Among them, CLDN3, CLDN4, CLDN6, CLDN10, CLDN15, and CLDN16 were significantly correlated with overall survival in patients with ovarian cancer. GSEA revealed that CLDN6 and CLDN10 were significantly enriched in immunological signatures of B cell, CD4 T cell, and CD8 T cell. Furthermore, CLDN6 and CLDN10 were negatively correlated and positively correlated, respectively, with immune cell infiltration in ovarian cancer. The expression levels of CLDN6 and CLDN10 were also negatively correlated and positively correlated, respectively, with various gene markers of immune cells in ovarian cancer. Thus, CLDN6 and CLDN10 may participate in immune cell infiltration in ovarian cancer, and these mechanisms may be the reason for poor prognosis.ConclusionOur study showed that CLDN6 and CLDN10 were prognostic biomarkers correlated with the immune microenvironment in ovarian cancer. These results reveal new roles for CLDN6 and CLDN10 as potential therapeutic targets in the treatment of ovarian cancer.

scholarly journals PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emily Lee ◽  
Sarah Szvetecz ◽  
Ryan Polli ◽  
Angelo Grauel ◽  
Jayson Chen ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Standard Of Care ◽  
Tumor Growth Inhibition ◽  
High Grade ◽  
Ovarian Cancers ◽  
Late Stage Diagnosis ◽  
Anti Tumor Activity

AbstractHigh-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.

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