scholarly journals Liver sinusoidal endothelial cell ICAM-1 mediated tumor/endothelial crosstalk drives the development of liver metastasis by initiating inflammatory and angiogenic responses

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Aitor Benedicto ◽  
Alba Herrero ◽  
Irene Romayor ◽  
Joana Marquez ◽  
Bård Smedsrød ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Tumor Cells ◽  
Cell Activation ◽  
Tumor Burden ◽  
Host Cells ◽  
Liver Sinusoidal Endothelial Cell ◽  
Metastatic Progression ◽  
Liver Sinusoidal Endothelial Cells

Abstract The prometastatic stroma generated through tumor cells/host cells interaction is critical for metastatic growth. To elucidate the role of ICAM-1 on the crosstalk between tumor and primary liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), implicated in tumor adhesion and angiogenesis, we performed in vitro cocultures and an in vivo model of liver metastasis of colorectal cancer (CRC). ICAM-1 blockade in the LSECs decreased the adhesion and transmigration of tumor cells through an LSEC in vitro and vivo. Cocultures of C26 cells and LSECs contained higher amounts of IL-1β, IL-6, PGE-2, TNF-α and ICAM-1 than monocultures. C26 cells incubated with sICAM-1 secreted higher amounts of PGE-2, IL-6, VEGF, and MMPs, while enhanced the migration of LSECs and HSCs. HSCs cultures activated by media from C26 cells pretreated with sICAM-1 contained the largest amounts of VEGF and MMPs. C26 cell activation with sICAM-1 enhanced their metastasizing potential in vivo, while tumor LFA-1 blockade reduced tumor burden and LSECs and HSC-derived myofibroblasts recruitment. In vivo ICAM-1 silencing produced similar results. These findings uncover LSEC ICAM-1 as a mediator of the CRC metastatic cascade in the liver and identifies it as target for the inhibition of liver colonization and metastatic progression.

scholarly journals Dual-Function Anti-CD47mAbs Induce Tumor Cell Death and Promote Phagocytosis Resulting in Enhanced in Vivo Efficacy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 991-991
Author(s):  
Pamela T. Manning ◽  
Benjamin J. Capoccia ◽  
Michael P. Rettig ◽  
Ronald R. Hiebsch ◽  
Robert W. Karr ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Tumor Burden ◽  
Dual Function ◽  
Employment Equity ◽  
Hematologic Cancer ◽  
Equity Ownership

Abstract Recent success in immunomodulation of cancer has targeted immune checkpoints such as CTLA-4, PD-1 and PDL-1 to enhance adaptive immunity by stimulating production of tumor-selective, cytotoxic T cells. Anti-CD47mAbs enhance innate immunity by increasing the phagocytosis of tumor cells by macrophages leading to processing and presentation of tumor antigens to prime the adaptive T cell response. Many cancers, including hematologic cancers, up-regulate the expression of CD47 presumably to avoid immune destruction. Increased CD47 expression protects cancer cells from phagocytosis by sending a “don't eat me” signal to macrophages via SIRPalpha, an inhibitory receptor that prevents phagocytosis of CD47-bearing cells. CD47mAbs that block the CD47/SIRPalpha interaction (“blocking-only” mAbs) enhance phagocytosis of cancer cells in vitro. We have identified two CD47mAbs, Vx-1000 and Vx-1004, both of which block the CD47/SIRPalpha interaction and promote phagocytosis of tumor cells by macrophages equally well. However, Vx-1004 also has the unique property of killing cancer cells, but not normal blood cells, via a direct, cell-autonomous, cytotoxic mechanism. Therefore, Vx-1004 is a dual-function antibody. Vx-1004 selectively kills a variety of hematologic cancer cells in vitro, while Vx-1000, the blocking-only mAb, does not as assessed by annexin V staining and flow cytometry (Figure 1). In dose-response studies, cell death in leukemia cells was induced in 2 hrs by <1 ug="" vx-1004="" whereas="" normal="" peripheral="" blood="" mononuclear="" cells="" are="" resistant="" to="" the="" induction="" of="" cell="" death="" by="" following="" incubation="" with="" 10="" for="" 24="" hrs="" both="" these="" cd47mabs="" bind="" many="" species="" cd47="" including="" mouse="" and="" human="" p=""> To determine if the tumor-toxic activity of Vx-1004 confers enhanced efficacy in vivo compared to Vx-1000, we compared them in two mouse hematologic cancer models: murine acute promyelocytic leukemia (APL) and B cell lymphoma (BCL). Briefly, 1x106 GFP-labeled C57BL/6 APL cells were injected IV into wild-type C57BL/6 mice that were then treated IP with 0.4 mg/kg of either Vx-1000 or Vx-1004 on the day of tumor injection and on days 3 and 6 following tumor injection, a very low dose and limited dosing regimen. On day 25, the blood of these mice was analyzed for the number of circulating APL cells. As shown in Figure 2, Vx-1000 did not significantly reduce tumor burden compared to the control group. In contrast, Vx-1004 significantly reduced tumor burden compared to controls, demonstrating greater efficacy of the dual-function CD47mAb. In addition, enhanced efficacy of Vx-1004 compared to Vx-1000 was demonstrated in BCL (Figure 3). In this model, NSG mice were injected with 1x106 murine A20 lymphoma cells subcutaneously and then treated with 0.4mg/kg/day of the CD47mAbs IP for the first five days following tumor injection. In this model, Vx-1000 also failed to inhibit tumor growth compared to controls while Vx-1004 significantly reduced tumor burden at 35 days compared to both the control and Vx-1000 groups, nearly four weeks after treatment was stopped. These data demonstrate increased anti-cancer efficacy with a dual-function CD47mAb that not only blocks the CD47/SIRPalpha interaction to increase phagocytosis of cancer cells, but also selectively kills cancer cells. These studies indicate that dual-function CD47mAbs may have better anti-tumor activity in vivo and support their use in human clinical trials. Figure 1 Figure 1. Disclosures Manning: Corvus Pharmaceutical: Employment, Equity Ownership. Capoccia:Corvus Pharmaceutical: Employment, Equity Ownership. Hiebsch:Corvus Pharmaceutical: Employment, Equity Ownership. Karr:Corvus Pharmaceutical: Employment, Equity Ownership. Frazier:Corvus Pharmaceutical: Consultancy, Equity Ownership.

scholarly journals Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Nataša Pavlović ◽  
Carlemi Calitz ◽  
Kess Thanapirom ◽  
Guiseppe Mazza ◽  
Krista Rombouts ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Cells ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Tumor Burden ◽  
And Migration ◽  
Hcc Cells ◽  
Proliferation And Migration

Hepatocellular carcinoma (HCC) is a liver tumor that usually arises in patients with cirrhosis. Hepatic stellate cells are key players in the progression of HCC, as they create a fibrotic micro-environment and produce growth factors and cytokines that enhance tumor cell proliferation and migration. We assessed the role of endoplasmic reticulum (ER) stress in the cross-talk between stellate cells and HCC cells. Mice with a fibrotic HCC were treated with the IRE1α-inhibitor 4μ8C, which reduced tumor burden and collagen deposition. By co-culturing HCC-cells with stellate cells, we found that HCC-cells activate IREα in stellate cells, thereby contributing to their activation. Inhibiting IRE1α blocked stellate cell activation, which then decreased proliferation and migration of tumor cells in different in vitro 2D and 3D co-cultures. In addition, we also observed cell-line-specific direct effects of inhibiting IRE1α in tumor cells.

550 An Axl-targeting monoclonal antibody that inhibits Axl activity and potently stimulates the innate immune response

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A587-A587
Author(s):  
Diego Alvarado ◽  
Laura Vitale ◽  
Mike Murphy ◽  
Thomas O’Neill ◽  
Edward Natoli ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Cancer ◽  
Cell Activity ◽  
Negative Regulator

BackgroundAxl is a member of the TAM (Tyro3/Axl/MerTK) family of receptor tyrosine kinases and a negative regulator of innate immunity. Activation of Axl through its ligand Gas6 leads to suppression of myeloid cell activity, while its activation in tumor cells drives tumor growth, metastasis, and is associated with acquired resistance to targeted therapies, radiotherapy and chemotherapy.MethodsPurified monoclonal antibodies and variants thereof were tested in human cancer lines and primary human myeloid cells for effects on Axl signaling and immune activation, respectively.ResultsWe describe a humanized IgG1 Axl-targeting monoclonal antibody (mAb), CDX-0168, that binds to the ligand-binding domain of Axl with sub-nanomolar affinity and potently inhibits Gas6 binding. In tumor cells, CDX-0168 inhibits Gas6-dependent Axl phosphorylation and signaling and elicits tumor cell killing via ADCC in vitro and in vivo. In primary human immune cells, CDX-0168 treatment induces potent release of pro-inflammatory cytokines and chemokines from dendritic cells, monocytes and macrophages through an Fc receptor-dependent mechanism and enhanced T cell activation in mixed lymphocyte reactions. Axl inhibition may further enhance antitumor activity associated with PD-(L)1 blockade. To this end, we generated a tetravalent bispecific Axl x PD-L1 antibody combining CDX-0168 with a potent anti-PD-L1 mAb (9H9) using an IgG-scFv format. The bispecific antibody elicits greater cytokine release and T cell activation in vitro than the combination of the parental antibodies, while maintaining robust Axl and PD-L1 blockade.ConclusionsAdditional studies investigating simultaneous blockade of the Axl and PD-L1 pathways with other agents may further exploit the potential for this novel anti-cancer therapeutic approach.

scholarly journals Leptin deficiency suppresses MMTV-Wnt-1 mammary tumor growth in obese mice and abrogates tumor initiating cell survival

2011 ◽  
Vol 18 (4) ◽  
pp. 491-503 ◽  
Author(s):  
Qiao Zheng ◽  
Sarah M Dunlap ◽  
Jinling Zhu ◽  
Erinn Downs-Kelly ◽  
Jeremy Rich ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Mammary Tumor ◽  
Leptin Receptor ◽  
Tumor Burden ◽  
Obese Mice ◽  
Leptin Deficiency ◽  
Phosphorylated Akt

Obesity increases both the risk and mortality associated with many types of cancer including that of the breast. In mice, obesity increases both incidence of spontaneous tumors and burden of transplanted tumors. Our findings identify leptin, an adipose secreted cytokine, in promoting increased mammary tumor burden in obese mice and provide a link between this adipokine and cancer. Using a transplantable tumor that develops spontaneously in the murine mammary tumor virus-Wnt-1 transgenic mice, we show that tumors transplanted into obese leptin receptor (LepRb)-deficient (db/db) mice grow to eight times the volume of tumors transplanted into lean wild-type (WT) mice. However, tumor outgrowth and overall tumor burden is reduced in obese, leptin-deficient (ob/ob) mice. The residual tumors in ob/ob mice contain fewer undifferentiated tumor cells (keratin 6 immunopositive) compared with WT or db/db mice. Furthermore, tumors in ob/ob mice contain fewer cells expressing phosphorylated Akt, a growth promoting kinase activated by the LepRb, compared with WT and db/db mice.In vivolimiting dilution analysis of residual tumors from ob/ob mice indicated reduced tumor initiating activity suggesting fewer cancer stem cells (CSCs). The tumor cell populations reduced by leptin deficiency were identified by fluorescence-activated cell sorting and found to express LepRb. Finally, LepRb expressing tumor cells exhibit stem cell characteristics based on the ability to form tumorspheresin vitroand leptin promotes their survival. These studies provide critical new insight on the role of leptin in tumor growth and implicate LepRb as a CSC target.

scholarly journals Osteopontin Blockade Immunotherapy Increases Cytotoxic T Lymphocyte Lytic Activity and Suppresses Colon Tumor Progression

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1006
Author(s):  
John D. Klement ◽  
Dakota B. Poschel ◽  
Chunwan Lu ◽  
Alyssa D. Merting ◽  
Dafeng Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphoid Cells ◽  
Colon Tumor ◽  
Tumor Bearing

Human colorectal cancers are mostly microsatellite-stable with no response to anti-PD-1 blockade immunotherapy, necessitating the development of a new immunotherapy. Osteopontin (OPN) is elevated in human colorectal cancer and may function as an immune checkpoint. We aimed at elucidating the mechanism of action of OPN and determining the efficacy of OPN blockade immunotherapy in suppression of colon cancer. We report here that OPN is primarily expressed in tumor cells, myeloid cells, and innate lymphoid cells in human colorectal carcinoma. Spp1 knock out mice exhibit a high incidence and fast growth rate of carcinogen-induced tumors. Knocking out Spp1 in colon tumor cells increased tumor-specific CTL cytotoxicity in vitro and resulted in decreased tumor growth in vivo. The OPN protein level is elevated in the peripheral blood of tumor-bearing mice. We developed four OPN neutralization monoclonal antibodies based on their efficacy in blocking OPN inhibition of T cell activation. OPN clones 100D3 and 103D6 increased the efficacy of tumor-specific CTLs in killing colon tumor cells in vitro and suppressed colon tumor growth in tumor-bearing mice in vivo. Our data indicate that OPN blockade immunotherapy with 100D3 and 103D6 has great potential to be further developed for colorectal cancer immunotherapy and for rendering a colorectal cancer response to anti-PD-1 immunotherapy.

scholarly journals Dynamic BH3 profiling identifies active BH3 mimetic combinations in non-small cell lung cancer

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Danielle S. Potter ◽  
Ruochen Du ◽  
Patrick Bhola ◽  
Raphael Bueno ◽  
Anthony Letai
Keyword(s):  
Lung Cancer ◽  
Tumor Cells ◽  
Tumor Burden ◽  
Small Cell ◽  
Targeted Agents ◽  
Small Cell Lung ◽  
Conventional Chemotherapy ◽  
Bh3 Mimetic

AbstractConventional chemotherapy is still of great utility in oncology and rationally constructing combinations with it remains a top priority. Drug-induced mitochondrial apoptotic priming, measured by dynamic BH3 profiling (DBP), has been shown in multiple cancers to identify drugs that promote apoptosis in vivo. We therefore hypothesized that we could use DBP to identify drugs that would render cancers more sensitive to conventional chemotherapy. We found that targeted agents that increased priming of non-small cell lung cancer (NSCLC) tumor cells resulted in increased sensitivity to chemotherapy in vitro. To assess whether targeted agents that increase priming might enhance the efficacy of cytotoxic agents in vivo as well, we carried out an efficacy study in a PC9 xenograft mouse model. The BH3 mimetic navitoclax, which antagonizes BCL-xL, BCL-w, and BCL-2, consistently primed NSCLC tumors in vitro and in vivo. The BH3 mimetic venetoclax, which electively antagonizes BCL-2, did not. Combining navitoclax with etoposide significantly reduced tumor burden compared to either single agent, while adding venetoclax to etoposide had no effect on tumor burden. Next, we assessed priming of primary patient NSCLC tumor cells on drugs from a clinically relevant oncology combination screen (CROCS). Results confirmed for the first time the utility of BCL-xL inhibition by navitoclax in priming primary NSCLC tumor cells and identified combinations that primed further. This is a demonstration of the principle that DBP can be used as a functional precision medicine tool to rationally construct combination drug regimens that include BH3 mimetics in solid tumors like NSCLC.

Efficacy of LY2784544, a Small Molecule Inhibitor Selective for Mutant JAK2 Kinase, In JAK2 V617F-Induced Hematologic Malignancy Models

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4087-4087 ◽  
Author(s):  
Liandong Ma ◽  
Baohui Zhao ◽  
Richard Walgren ◽  
Joshua A Clayton ◽  
Wayne D Blosser ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Tumor Cells ◽  
Oral Treatment ◽  
Jak2 V617f ◽  
Tumor Burden ◽  
Ascites Tumor ◽  
Wild Type ◽  
Erythroid Progenitor

Abstract Abstract 4087 Introduction: The JAK2-V617F mutation is the most common molecular abnormality in the BCR/ABL-negative myeloid proliferative neoplasms (MPNs) and is present in approximately 95% of patients with polycythemia vera (PV) and roughly 60% of patients with either essential thrombocythemia (ET) or primary myelofibrosis (PMF). The JAK2 V617F kinase is constitutively active, oncogenic and recapitulates MPN in murine models. Therefore, mutant JAK2 is a potential therapeutic target for MPNs. Here, we describe the efficacy of the clinical candidate LY2784544; a novel small molecule inhibitor selective for JAK2 V617F mutant, in JAK2 V617F-induced in vitro and in vivo models. Methods: Assessment of the ability of LY2784544 to inhibit the signaling of the V617F mutant or wild type JAK2 was evaluated in Ba/F3 cells expressing V617F or wild type JAK2, whereby the cellular level of phospho-STAT5 (pSTAT5) was measured by a high content imaging (Cellomics) assay. The antiproliferative activity of LY2784544 and its ability to induce apoptosis were examined by Celltiter-Glo Cell Viability and Caspase-Glo 3/7 Apoptosis Assays, respectively. The effect of LY2784544 on JAK3 was investigated in IL-2 stimulated NK-92 (nature killer) cells by measuring the inhibition of JAK3-STAT5 signaling with the Cellomics assay. To examine the in vivo target inhibition, a JAK2 V617F-induced ascites tumor model was established by implanting Ba/F3-JAK2 V617F-GFP cells into the intraperitoneal cavity of severe combined immunodeficiency (SCID) mice. After orally administering LY2784544, the inhibition of pSTAT5 was measured in Ba/F3-JAK2 V617F-GFP ascites tumor cells by fluorescence activated cell sorting (FACS) assay. The anti-tumor efficacy of LY2784544 was investigated in a SCID mouse model of MPN developed by intravenously implanting Ba/F3-JAK2 V617F-GFP cells. After oral treatment for 7 or 14 days, twice daily (BID), tumor burden reduction and the effect on erythroid progenitor cells were determined by measuring the GFP positive tumor cells and CD71/Ter119 positive cells in the spleens with FACS assays, respectively. Results: In the in vitro tests using Ba/F3 cells expressing either wild type or V617F mutant JAK2, LY2784544 potently inhibited the JAK2 V617F-STAT5 signaling at a concentration that was 41-fold lower than that required to inhibit IL-3-activated wild type JAK2-STAT5 signaling (IC50=0.055 μ M for JAK2 V617F vs. 2.26 μ M for WT JAK2). Similarly in the proliferation assay, LY2784544 selectively inhibited the JAK2 V617F-driven cell proliferation (IC50= 0.068 μ M). Inhibition of JAK2 V617F signaling correlated well with the induction of apoptosis (EC50= 0.113 μ M) in Ba/F3 cell model. Consistent with the observed apparent selectivity for the V617F mutant and reduced sensitivity against wild type JAK2, a lower potency was observed with LY2784544 in the IL-3-dependent cell proliferation assay (IC50=1.356 μ M) as well as less effective inhibition of IL-2 dependent JAK3-STAT5 signaling in NK-92 cells (IC50=0.94 μ M). In vivo, LY2784544 effectively inhibited STAT5 phosphorylation in Ba/F3-JAK2 V617F-GFP ascites tumor cells with a Threshold Effective Dose 50 (TED50) of 12.7 mg/kg. Consistent with this effective inhibition of JAK2V617F, LY2784544 also significantly reduced Ba/F3-JAK2 V617F-GFP tumor burden in the JAK2 V617F-induced MPN model with a TED50 of 13.7 mg/kg after oral treatment (BID) for 14 days, indicating that the efficacy of LY2784544 is mediated by pharmacological inhibition of JAK2 V16F-STAT5 pathway. Furthermore, LY2784544 selectively reduced Ba/F3-JAK2 V617F-GFP tumor cells with no effect on CD71/Ter119 positive erythroid progenitors in spleens of SCID mice after oral treatment (BID) for seven days. Conclusions: The in vitro data suggest that constitutively active JAK2 V617F is more sensitive to LY2784544 than cytokine-activated wild type JAK2. Consistent with this observation, in MPN disease model testing, LY2784544 selectively reduces JAK2 V617F tumor cell burden with no effect on erythroid progenitor cells. These findings suggest that as a JAK2 V617F selective targeted therapy, LY2784544 has the potential to induce apoptosis in JAK2 V617F malignant clones while potentially minimizing unintended effects on the normal hematopoietic progenitor cells. These results helped to support the advancement of LY2784544 into an ongoing phase I trial in the MPNs (I3X-MC-JHTA, NCT01134120). Disclosures: Ma: Eli Lilly and Company: Employment. Zhao:Eli Lilly and Company: Employment. Walgren:Eli Lilly and Company: Employment. Clayton:Eli Lilly and Company: Employment. Blosser:Eli Lilly and Company: Employment. Burkholder:Eli Lilly and Company: Employment. Smith:Eli Lilly and Company: Employment.

Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3571-3578 ◽  
Author(s):  
Jérôme D. Coudert ◽  
Léonardo Scarpellino ◽  
Frédéric Gros ◽  
Eric Vivier ◽  
Werner Held
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Host Cells ◽  
Cross Tolerance ◽  
Self Recognition ◽  
Missing Self ◽  
Activation Pathways

Abstract NKG2D is a multisubunit activation receptor that allows natural killer (NK) cells to detect and eliminate stressed, infected, and transformed host cells. However, the chronic exposure of NK cells to cell-bound NKG2D ligands has been shown to impair NKG2D function both in vitro and in vivo. Here we have tested whether continuous NKG2D engagement selectively impacted NKG2D function or whether heterologous NK cell activation pathways were also affected. We found that sustained NKG2D engagement induced cross-tolerization of several unrelated NK cell activation receptors. We show that receptors that activate NK cells via the DAP12/KARAP and DAP10 signaling adaptors, such as murine NKG2D and Ly49D, cross-tolerize preferentially NK cell activation pathways that function independent of DAP10/12, such as antibody-dependent cell-mediated cytotoxicity and missing-self recognition. Conversely, DAP10/12-independent pathways are unable to cross-tolerize unrelated NK cell activation receptors such as NKG2D or Ly49D. These data define a class of NK cell activation receptors that can tolerize mature NK cells. The reversible suppression of the NK cells' cytolytic function probably reduces the NK cells' efficacy to control endogenous and exogenous stress yet may be needed to limit tissue damage.

scholarly journals Potent and Selective Antitumor Activity of a T-Cell Engaging Bispecific Antibody Targeting a Membrane-Proximal Epitope of ROR1

2017 ◽  
Author(s):  
Junpeng Qi ◽  
Xiuling Li ◽  
Haiyong Peng ◽  
HaJeung Park ◽  
Christoph Rader
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Three Dimensional ◽  
Bispecific Antibodies ◽  
Dimensional Structure

AbstractT-cell engaging bispecific antibodies present a promising strategy for cancer immunotherapy and numerous bispecific formats have been developed for retargeting cytolytic T cells toward tumor cells. To explore the therapeutic utility of T-cell engaging bispecific antibodies targeting the receptor tyrosine kinase ROR1, which is expressed by tumor cells of various hematologic and solid malignancies, we used a bispecific ROR1 × CD3 scFv-Fc format based on a heterodimeric and aglycosylated Fc domain designed for extended circulatory half-life and diminished systemic T-cell activation. A diverse panel of ROR1-targeting scFv derived from immune and naïve rabbit antibody repertoires was compared in this bispecific format for target-dependent T-cell recruitment and activation. A ROR1-targeting scFv with a membrane-proximal epitope, R11, revealed potent and selective antitumor activity in vitro and in vivo and emerged as a prime candidate for further preclinical and clinical studies. To elucidate the precise location and engagement of this membrane-proximal epitope, which is conserved between human and mouse ROR1, the three-dimensional structure of scFv R11 in complex with the kringle domain of ROR1 was determined by X-ray crystallography at 1.6-Å resolution.

scholarly journals Immune regulation of the L5178Y murine tumor-dormant state. I. In vivo and in vitro effects of prostaglandin E2 and indomethacin on tumor cell growth.

1986 ◽  
Vol 164 (4) ◽  
pp. 1259-1273 ◽  
Author(s):  
C M Liu ◽  
T Okayasu ◽  
P Goldman ◽  
Y Suzuki ◽  
K Suzuki ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Peritoneal Cavity ◽  
Host Cells ◽  
Tumor Cell Growth ◽  
Dormant State ◽  
Peritoneal Cells

Immunization and intraperitoneal challenge of DBA/2 mice with L5178Y lymphoma cells results in the suppression and maintenance of the L5178Y cells in a tumor-dormant state in the peritoneal cavity for many months. Cell-mediated immune responses involving lymphocytes and macrophages are involved in maintenance of the tumor-dormant state. Macrophages that have increased immunosuppressive activity and that produce increased amounts of PGE2 appear in the peritoneal cavity of tumor-dormant mice before the breakdown of the tumor-dormant state and formation of ascitic tumors. We report here that the tumor-dormant state can be terminated with formation of ascitic tumors by treatment of tumor-dormant mice with PGE2. Treatment with indomethacin results in inhibition of tumor cell growth and elimination of all recoverable tumor cells. Cultures of peritoneal cells (PC) from mice harboring L5178Y cells in a tumor-dormant state were used to analyze the PGE2 and indomethacin effects. Tumor cells did not grow out in the high-cell density PC cultures prepared from many tumor-dormant mice, but addition of PGE2 to these cultures resulted in tumor cell growth. The tumor cell growth that did occur in the PC cultures from some tumor-dormant mice was associated with PGE2 production by the associated host cells, and the addition of indomethacin to these cultures inhibited both PGE2 synthesis and tumor cell growth. Removal of plastic-adherent cells from the PC cultures eliminated the restraint on tumor cell growth. These experiments suggest that L5178Y tumor cells are maintained in a tumor-dormant state by host peritoneal cells, which are under PGE2 regulation.

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