Oncolytic Measles Virus Encoding Interleukin-12 Mediated Antitumor Activity and Immunologic Control of Colon Cancer In Vivo and Ex Vivo

2020 ◽  
Author(s):  
Jian Wang ◽  
Tao Liu ◽  
Jie Chen
Keyword(s):  
Colon Cancer ◽  
Antitumor Activity ◽  
Measles Virus ◽  
Ex Vivo ◽  
Interleukin 12 ◽  
Immunologic Control

scholarly journals 852 Trifunctional NKp46/CD16a-NK cell engager targeting CD123 overcomes acute myeloid leukemia resistance to ADCC

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A893-A893
Author(s):  
Laurent Gauthier ◽  
Angela Virone-Oddos ◽  
Angela Virone-Oddos ◽  
Jochen Beninga ◽  
Benjamin Rossi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Antitumor Activity ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Ex Vivo ◽  
Activating Receptors ◽  
Acute Myeloid

BackgroundThere is a clear need for targeted therapies to treat acute myeloid leukemia (AML), the most common acute leukemia in adults. CD123 (IL-3 receptor alpha chain) is an attractive target for AML treatment.1 However, cytotoxic antibody targeting CD123 proved insufficiently effective in a combination setting in phase II/III clinical trials.2 T-cell engagers targeting CD123 displayed some clinical efficacy but were often associated with cytokine release syndrome and neurotoxicity.3 Interest in the use of NK cells for therapeutic interventions has increased in recent years, as a potential safer alternative to T cells. Several NK-cell activating receptors, such as CD16a, NKG2D, and the natural cytotoxicity receptors NKp30 and NKp46, can be targeted to induce antitumor immunity. We previously reported the development of trifunctional NK-cell engagers (NKCEs) targeting a tumor antigen on cancer cells and co-engaging NKp46 and CD16a on NK cells.4MethodsWe report here the design, characterization and preclinical development of a novel trifunctional NK cell engager (NKCE) targeting CD123 on AML cells and engaging the activating receptors NKp46 and CD16a on NK cells. The CD123 NKCE therapeutic molecule was engineered with humanized antibodies targeting NKp464 and CD123.5 We compared CD123-NKCE and a cytotoxic ADCC-enhanced antibody (Ab) targeting CD123, in terms of antitumor activity in vitro, ex vivo and in vivo. Pharmacokinetic, pharmacodynamic and safety profile of CD123-NKCE were evaluated in non-human primate (NHP) studies.ResultsThe expression of the high affinity Fc gamma receptor CD64 on patient-derived AML cells inhibited the ADCC of the Ab targeting CD123 in vitro and ex vivo, but not the antitumor activity of CD123-NKCE. CD123-NKCE had potent antitumor activity against primary AML blasts and AML cell lines, promoted strong NK-cell activation and induced cytokine secretion only in the presence of AML target cells. Its antitumor activity in mouse model was greater than that of the comparator antibody. Moreover, CD123-NKCE had strong and prolonged pharmacodynamic effects in NHP when used at very low doses, was well-tolerated up to high 3 mg/kg dose and triggered only minor cytokine release.ConclusionsThe data for activity, safety, pharmacokinetics, and pharmacodynamics provided here demonstrate the superiority of CD123-NKCE over comparator cytotoxic antibody, in terms of antitumor activity in vitro, ex vivo, in vivo, and its favorable safety profile, as compared to T-cell therapies. These results constitute proof-of-principle for the efficacy of CD123-NKCE for controlling AML tumors in vivo, and provide consistent support for their clinical development.ReferencesEhninger A, Kramer M, Rollig C, et al. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer J 2014;4:e218.Montesinos P, Gail J Roboz GJ, et al. Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study. Leukemia 2021;35(1):62–74.Uy GL, Aldoss I, Foster MC, et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood 2021;137(6):751–762.Gauthier L, Morel A, Anceriz N, et al. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Cell 2019;177(7):1701–13.Jin L, Lee EM, Ramshaw HS, et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell 2009;5:31–42.

In vitro and in vivo antitumor activity of Yerba Mate extract in colon cancer models

2020 ◽  
Vol 85 (7) ◽  
pp. 2186-2197 ◽  
Author(s):  
Rocio S. Garcia‐Lazaro ◽  
Humberto Lamdan ◽  
Lorena G. Caligiuri ◽  
Norailys Lorenzo ◽  
Andrea L. Berengeno ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Antitumor Activity ◽  
Yerba Mate ◽  
Cancer Models ◽  
In Vivo Antitumor Activity

scholarly journals In Vitro and in Vivo antitumor activity and the mechanism of siphonodictyal B in human colon cancer cells

2019 ◽  
Vol 8 (12) ◽  
pp. 5662-5672 ◽  
Author(s):  
Sonoko Chikamatsu ◽  
Ken Saijo ◽  
Hiroo Imai ◽  
Koichi Narita ◽  
Yoshifumi Kawamura ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Antitumor Activity ◽  
Cancer Cells ◽  
Human Colon ◽  
Colon Cancer Cells ◽  
Human Colon Cancer ◽  
In Vivo Antitumor Activity ◽  
Human Colon Cancer Cells

MLN9708 Elicits Pharmacodynamic Response in the Bone Marrow Compartment and Has Strong Antitumor Activity in a Preclinical Intraosseous Model of Plasma Cell Malignancy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1834-1834 ◽  
Author(s):  
Edmund Lee ◽  
Bret Bannerman ◽  
Michael Fitzgerald ◽  
Jennifer Terkelsen ◽  
Daniel Bradley ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Antitumor Activity ◽  
Plasma Cell ◽  
Research Funding ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Tumor Burden ◽  
Human Multiple Myeloma ◽  
Cell Malignancy

Abstract Abstract 1834 Poster Board I-860 Introduction The clinical success of VELCADE® (bortezomib) for Injection has validated the proteasome as a therapeutic target for the treatment of human cancer. The novel proteasome inhibitor MLN9708 is a potent, reversible, and specific inhibitor of the b5 site of the 20S proteasome identified in preclinical studies. MLN9708 is currently in human clinical development for both hematological and non-hematological malignancies. Here we describe the pharmacodynamic (PD) response of MLN9708 in the murine bone marrow compartment and its strong antitumor activity in an intraosseous xenograft model of plasma cell malignancy. Materials MLN9708 immediately hydrolyzes to MLN2238, the biologically active form, upon exposure to aqueous solutions or plasma. MLN2238 was used for all preclinical studies described below. Methods It has been previously shown that double transgenic iMycCa/Bcl-XL mice develop de novo plasma cell malignancies (J. Clin. Invest. 113:1763-1773, 2004) in which neoplastic plasma cell development is driven by the targeted expression of the transgene Myc (c-myc; myelocytomatosis oncogene) and Bcl-x (Bcl2l1; encodes the oncoprotein Bcl-XL). DP54 is a plasma cell tumor cell line derived from the bone marrow of a syngeneic mouse previously inoculated with an iMycCa/Bcl-XL tumor (Cancer Res. 67:4069-4078, 2007). In vitro, DP54 cells express both the Myc and Bcl-XL transgenes, various plasma cell and B-cell markers including CD38, CD138 and B220, and has gene expression profile very similar to human multiple myeloma. To establish a preclinical intraosseous model of plasma cell malignancy for efficacy studies, freshly dissociated DP54-Luc cells (constitutively expressing firefly luciferase under a mouse Ig-k promoter) were aseptically injected into the bone marrow space of the upper shaft of the right tibia of NOD-SCID mice. Once tumor growth has been established, mice were randomized into treatment groups and then treated intravenously (IV) with vehicle, bortezomib (at 0.8 mg/kg twice weekly [BIW]) or MLN2238 (at 11 mg/kg BIW) for 3 consecutive weeks. Tumor burden was measured by bioluminescent imaging. Results MLN2238 strongly inhibited proteasome activity in the blood and bone marrow compartments of mice (maximum b5 inhibition of 84% and 83%, respectively). In vivo, when DP54 cells were aseptically injected into the bone marrow space of the mouse tibia, signs of bone erosion in the tibia, femur and cranial sagittal sultures (as determined by ex-vivo mCT imaging) were observed which resembled osteolytic lesions frequently seen in human multiple myeloma. Dissemination of DP54-Luc cells after intratibia inoculations were detected by in vivo bioluminescent and confirmed by ex vivo imaging where luminescent tumor nodules were detected in the spleen, kidneys, intestine, lymph nodes and bones including right tibia, spine and cranium. To assess the antitumor activity of MLN2238 in the bone marrow compartment, an efficacy study was performed using the DP54-Luc intraosseous xenograft model of plasma cell malignancy. Tumor burden (bioluminescence), osteolytic lesions (mCT) and overall survival after treatment with bortezomib and MLN2238 will be presented. Conclusion The novel proteasome inhibitor MLN9708 demonstrates strong activity in the bone marrow compartment in vivo. MLN9708 is currently in human clinical development for both hematological and solid tumor indications. Disclosures Lee: Milllennium: Employment, Equity Ownership. Bannerman:Milllennium: Employment. Terkelsen:Milllennium: Employment. Bradley:Milllennium: Employment, Equity Ownership, Research Funding. Li:Milllennium: Employment. Li:Milllennium: Employment. Janz:Milllennium: Research Funding. Van Ness:Milllennium: Research Funding. Manfredi:Milllennium: Employment. Kupperman:Milllennium: Employment.

In Vivo and Ex Vivo Sentinel Node Mapping Does Not Identify the Same Lymph Nodes in Colon Cancer

2016 ◽  
Vol 223 (4) ◽  
pp. S32-S33
Author(s):  
Helene S. Andersen ◽  
Astrid LB. Bennedsen ◽  
Stefan K. Burgdorf ◽  
Jens R. Eriksen ◽  
Susanne Eiholm ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Lymph Nodes ◽  
Sentinel Node ◽  
Ex Vivo ◽  
Sentinel Node Mapping

scholarly journals Adoptively transferred ex vivo expanded γδ-T cells mediate in vivo antitumor activity in preclinical mouse models of breast cancer

2009 ◽  
Vol 122 (1) ◽  
pp. 135-144 ◽  
Author(s):  
Benjamin H. Beck ◽  
Hyung-Gyoon Kim ◽  
Hyunki Kim ◽  
Sharon Samuel ◽  
Zhiyong Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Antitumor Activity ◽  
Mouse Models ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
In Vivo Antitumor Activity

scholarly journals The SMAC mimetic LCL-161 displays antitumor activity in preclinical models of rituximab-resistant B-cell lymphoma

2018 ◽  
Vol 2 (23) ◽  
pp. 3516-3525 ◽  
Author(s):  
Kyle Runckel ◽  
Matthew J. Barth ◽  
Cory Mavis ◽  
Juan J. Gu ◽  
Francisco J. Hernandez-Ilizaliturri
Keyword(s):  
Antitumor Activity ◽  
Cell Lines ◽  
Antitumor Effect ◽  
Ex Vivo ◽  
B Cell Lymphoma ◽  
Sensitive Cell ◽  
In Vivo Models ◽  
Synergistic Enhancement

Abstract Clinical observations suggest the existence of shared resistance pathways between rituximab and chemotherapy agents. To explore the mechanisms of rituximab resistance, our group created rituximab-resistant cell lines (RRCLs), which display altered expression of several inhibitor of apoptosis (IAP) family proteins. Here, we provide evidence to support pharmacologically targeting IAPs in lymphoma with LCL-161, a small molecule mimetic of the second mitochondria-derived activator of caspases (SMAC). The antitumor effect of LCL-161 was determined using luminescent adenosine triphosphate assays, flow cytometry, SCID mouse xenografts, and ex vivo patient biopsy sample studies. In vitro exposure to LCL-161 also resulted in a dose-dependent decrease in IAP levels, along with synergistic enhancement of the antitumor effect of cytotoxic chemotherapy, in rituximab-sensitive cell lines and RRCLs. In addition, LCL-161 increased the cytotoxic effect of the proteasome inhibitor carfilzomib in ex vivo lymphoma patient samples. The combination of LCL-161 with the chemotherapy regimen rituximab, gemcitabine, and vinorelbine (RGV) improved in vivo survival compared with RGV alone in severe combined immunodeficient mice implanted with RRCLs but not in animals implanted with rituximab-sensitive cell lines. In summary, LCL-161 exhibits synergistic antitumor activity in both in vitro and in vivo models of resistant lymphoma. Our data support further preclinical investigation of LCL-161 as a novel antilymphoma agent.

Evaluating the Antitumor Activity of MLN9708 in a Disseminated Mouse Model of Double Transgenic iMyc Ca/Bcl-XL Plasma Cell Malignancy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3835-3835 ◽  
Author(s):  
Michael Fitzgerald ◽  
Yueying Cao ◽  
Bret Bannerman ◽  
Zhi Li ◽  
Olga Tayber ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Mouse Model ◽  
Lymph Nodes ◽  
Plasma Cell ◽  
Research Funding ◽  
Ex Vivo ◽  
Employment Equity ◽  
Equity Ownership

Abstract Abstract 3835 Poster Board III-771 Introduction The first generation proteasome inhibitor VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma (MM), a form of plasma cell malignancy (PCM). MLN9708 is our novel proteasome inhibitor that selectively and reversibly binds to, and potently inhibits the b5 site of the 20s proteasome in preclinical studies. We have recently demonstrated that MLN9708 significantly prolongs tumor-free survival of double transgenic iMycCa/Bcl-XL mice, a genetically-engineered mouse model of de novo PCM. Here we describe the in vivo evaluation of cell lines derived from double transgenic iMycCa/Bcl-XL mice and the antitumor activity of MLN9708 in a disseminated mouse model of iMycCa/Bcl-XL PCM. Materials MLN9708 immediately hydrolyzes to MLN2238, the biologically active form, upon exposure to aqueous solutions or plasma. MLN2238 was used for all preclinical studies described below. Double transgenic iMycCa/Bcl-XL mice develop de novo PCM, in which neoplastic plasma cell development is driven by the targeted expression of the oncoprotein Myc and anti-apoptotic Bcl-XL (J. Clin. Invest. 113:1763-1773, 2004). DP54 and DP42 are plasma cell tumor cell lines isolated from the bone marrow and lymph nodes, respectively, of syngeneic mice previously inoculated with iMycCa/Bcl-XL tumors (Cancer Res. 67:4069-4078, 2007). In vitro, DP54 and DP42 cells express both the Myc and Bcl-XL transgenes, various plasma cell and B-cell markers including CD38, CD138 and B220, and have gene expression profiles very similar to human MM. Methods Cell viability studies were performed to determine the antiproliferative effects of MLN2238 in DP54 and DP42 cells in vitro. To evaluate DP54 and DP42 cells in vivo, these cells were aseptically inoculated into the tail vein of NOD-SCID mice. Progressions of the resultant PCM were monitored and tumor burdens were evaluated by magnetic resonance imaging (MRI), ex vivo mCT imaging, and histopathology. Mouse plasma samples were collected at the end of the studies and levels of immunoglobulin were assessed. To establish a preclinical disseminated mouse model of iMycCa/Bcl-XL PCM, freshly dissociated DP54-Luc cells (constitutively expressing firefly luciferase under a mouse Ig-k promoter) were aseptically inoculated into the tail vein of NOD-SCID mice. Once tumor growth has been established, mice were randomized into treatment groups and then treated with vehicle, bortezomib (at 0.7mg/kg intravenously [IV] twice weekly [BIW]) or MLN2238 (at 11 mg/kg IV BIW) for 3 consecutive weeks. Tumor burden was measured by bioluminescent imaging. Results In vitro, both DP54 and DP42 cells were sensitive to MLN2238 treatment (LD50 values of 14 and 25 nM, respectively). In vivo, NOD-SCID mice rapidly succumbed to PCM after being inoculated with DP54 and DP42 cells (25 and 14 days post-inoculation, respectively), where the disease was accompanied by marked elevation of plasma immunoglobulins. MRI scans revealed the presence of multiple lesions and several abnormalities were found including: cranial deformation, bowel distortion, splenomegaly and renal edema. Tumor infiltrates, ranging from minor to extensive, were identified in multiple organ compartments (brain<kidney<liver<lymph nodes<spleen<bone marrow) by histopathological analysis. Ex vivo mCT imaging has also revealed signs of bone erosion in the cranial sagittal sutures. Dissemination of DP54-Luc cells after tail vein inoculations was detected by in vivo bioluminescent and confirmed by ex vivo imaging where luminescent tumor nodules were identified in the spleen, kidneys, liver, intestine, lymph nodes, spinal bone and cranium. To assess the antitumor activity of MLN2238, an efficacy study was performed using the DP54-Luc disseminated model. Tumor burden (bioluminescence), skeletal malformation (mCT) and overall survival after treatment with bortezomib and MLN2238 will be presented. Conclusion The DP54-Luc disseminated mouse model of double transgenic iMycCa/Bcl-XL PCM recapitulated several key features of human MM and provided real-time assessment of novel MM therapy preclinically. MLN9708 is currently in human clinical development for both hematological and solid tumor indications. Disclosures: Cao: Milllennium: Employment, Equity Ownership. Bannerman:Milllennium: Employment. Li:Milllennium: Employment. Bradley:Milllennium: Employment, Equity Ownership, Research Funding. Silverman:Milllennium: Employment. Janz:Milllennium: Research Funding. Van Ness:Milllennium: Research Funding. Kupperman:Milllennium: Employment. Manfredi:Milllennium: Employment. Lee:Milllennium: Employment, Equity Ownership.

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