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1.
Leukemia ; 32(2): 402-412, 2018 02.
Article in English | MEDLINE | ID: mdl-28951562

ABSTRACT

Current clinical outcomes using chimeric-antigen receptors (CARs) against multiple myeloma show promise in the eradication of bulk disease. However, these anti-BCMA (CD269) CARs observe relapse as a common phenomenon after treatment due to the reemergence of either antigen-positive or -negative cells. Hence, the development of improvements in CAR design to target antigen loss and increase effector cell persistency represents a critical need. Here, we report on the anti-tumor activity of a CAR T-cell possessing two complete and independent CAR receptors against the multiple myeloma antigens BCMA and CS1. We determined that the resulting compound CAR (cCAR) T-cell possesses consistent, potent and directed cytotoxicity against each target antigen population. Using multiple mouse models of myeloma and mixed cell populations, we are further able to show superior in vivo survival by directed cytotoxicity against multiple populations compared to a single-expressing CAR T-cell. These findings indicate that compound targeting of BCMA and CS1 on myeloma cells can potentially be an effective strategy for augmenting the response against myeloma bulk disease and for initiation of broader coverage CAR therapy.


Subject(s)
Multiple Myeloma/immunology , Receptors, Chimeric Antigen/immunology , Animals , B-Cell Maturation Antigen/immunology , Cell Line, Tumor , Cytotoxicity, Immunologic/immunology , Humans , K562 Cells , Male , Mice , Mice, Inbred NOD , Neoplasm Recurrence, Local/immunology , Receptors, Antigen, T-Cell/immunology , Signaling Lymphocytic Activation Molecule Family/immunology , T-Lymphocytes/immunology , Xenograft Model Antitumor Assays/methods
2.
Oncogene ; 36(35): 4997-5005, 2017 08 31.
Article in English | MEDLINE | ID: mdl-28459465

ABSTRACT

Inturned (INTU), a cilia and planar polarity effector, performs prominent ciliogenic functions during morphogenesis, such as in the skin. INTU is expressed in adult tissues but its role in tissue maintenance is unknown. Here, we report that the expression of the INTU gene is aberrantly elevated in human basal cell carcinoma (BCC), coinciding with increased primary cilia formation and activated hedgehog (Hh) signaling. Disrupting Intu in an oncogenic mutant Smo (SmoM2)-driven BCC mouse model prevented the formation of BCC through suppressing primary cilia formation and Hh signaling, suggesting that Intu performs a permissive role during BCC formation. INTU is essential for intraflagellar transport A complex assembly during ciliogenesis. To further determine whether Intu is directly involved in the activation of Hh signaling downstream of ciliogenesis, we examined the Hh signaling pathway in mouse embryonic fibroblasts, which readily responds to the Hh pathway activation. Depleting Intu blocked Smo agonist-induced Hh pathway activation, whereas the expression of Gli2ΔN, a constitutively active Gli2, restored Hh pathway activation in Intu-deficient cells, suggesting that INTU functions upstream of Gli2 activation. In contrast, overexpressing Intu did not promote ciliogenesis or Hh signaling. Taken together, data obtained from this study suggest that INTU is indispensable during BCC tumorigenesis and that its aberrant upregulation is likely a prerequisite for primary cilia formation during Hh-dependent tumorigenesis.


Subject(s)
Carcinoma, Basal Cell/metabolism , Cilia/metabolism , Cilia/pathology , Hedgehog Proteins/metabolism , Membrane Proteins/genetics , Skin Neoplasms/metabolism , Animals , Carcinoma, Basal Cell/genetics , Carcinoma, Basal Cell/pathology , Cells, Cultured , Disease Models, Animal , Female , Hedgehog Proteins/genetics , Humans , Male , Membrane Proteins/biosynthesis , Membrane Proteins/metabolism , Mice , Mice, Transgenic , Signal Transduction , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Transfection
3.
Leukemia ; 31(10): 2151-2160, 2017 10.
Article in English | MEDLINE | ID: mdl-28074066

ABSTRACT

The outlook for T-cell malignancies remain poor due to the lack of effective therapeutic options. Chimeric antigen receptor (CAR) immunotherapy has recently shown promise in clinical trials for B-cell malignancies, however, designing CARs for T-cell based disease remain a challenge due to the shared surface antigen pool between normal and malignant T-cells. Normal T-cells express CD5 but NK (natural killer) cells do not, positioning NK cells as attractive cytotoxicity cells for CD5CAR design. Additionally, CD5 is highly expressed in T-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphomas (PTCLs). Here, we report a robust anti-CD5 CAR (CD5CAR) transduced into a human NK cell line NK-92 that can undergo stable expansion ex vivo. We found that CD5CAR NK-92 cells possessed consistent, specific, and potent anti-tumor activity against a variety of T-cell leukemia and lymphoma cell lines as well as primary tumor cells. Furthermore, we were able to demonstrate significant inhibition and control of disease progression in xenograft mouse models of T-ALL. The data suggest that CAR redirected targeting for T-cell malignancies using NK cells may be a viable method for new and complementary therapeutic approaches that could improve the current outcome for patients.


Subject(s)
Antigens, Neoplasm/immunology , CD5 Antigens/immunology , Immunotherapy, Adoptive/methods , Killer Cells, Natural/immunology , Lymphoma, T-Cell, Peripheral/therapy , Molecular Targeted Therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Recombinant Fusion Proteins/immunology , 4-1BB Ligand/genetics , 4-1BB Ligand/immunology , Animals , CD28 Antigens/immunology , CD3 Complex/genetics , CD3 Complex/immunology , CD8 Antigens/immunology , Cell Line, Tumor , Coculture Techniques , Cytotoxicity, Immunologic , Humans , Killer Cells, Natural/transplantation , Lymphoma, T-Cell, Peripheral/pathology , Mice , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Salvage Therapy , Single-Chain Antibodies/genetics , Single-Chain Antibodies/immunology , Transduction, Genetic , Tumor Necrosis Factor Receptor Superfamily, Member 9/immunology , Xenograft Model Antitumor Assays
4.
Br J Cancer ; 98(11): 1803-9, 2008 Jun 03.
Article in English | MEDLINE | ID: mdl-18506185

ABSTRACT

The present study determines if (1) basal protein levels of nitric oxide (NO) synthases (eNOS, iNOS, and nNOS) are different in cisplatin-sensitive (OV2008) and counterpart cisplatin-resistant (C13(*)) human ovarian cancer cells, (2) cisplatin alters NOS levels, (3) NO donor causes apoptosis and p53 upregulation, (4) NO donor sensitizes C13(*) cells to cisplatin via p53 upregulation (determined by p53 siRNA gene-knockdown), and (5) inhibition of endogenous NOS alters cisplatin-induced apoptosis. Basal iNOS levels were higher in OV2008 cells than in C13(*) cells. Cisplatin upregulated iNOS, but dramatically reduced eNOS and nNOS, in OV2008 cells only. Failure of cisplatin to upregulate iNOS and downregulate eNOS/nNOS in cisplatin-resistant C13(*) cells may be an aetiological factor in the development of resistance. The NO donor S-nitroso-N-acetylpenicillamine (SNAP) increased p53 protein levels and induced apoptosis in both cell types, and enhanced cisplatin-induced apoptosis in C13(*) cells in a p53-dependent manner (i.e., enhancement blocked by p53 siRNA). Specific iNOS inhibitor 1400W partially blocked cisplatin-induced apoptosis in OV2008 cells. In cisplatin-resistant C13(*) cells, blocking all NOSs with N(G)-amino-L-arginine dramatically changed these cells from cisplatin-resistant to cisplatin-sensitive, greatly potentiating cisplatin-induced apoptosis. The data suggest important roles for the three NOSs in regulating chemoresistance to cisplatin in ovarian cancer cells.


Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Nitric Oxide Synthase/analysis , Ovarian Neoplasms/drug therapy , Tumor Suppressor Protein p53/physiology , Apoptosis/drug effects , Cell Line, Tumor , Drug Resistance, Neoplasm , Female , Humans , Nitric Oxide Donors/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/physiology , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/pathology , RNA, Small Interfering/pharmacology , S-Nitroso-N-Acetylpenicillamine/pharmacology
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