Chronic lymphocytic leukemia B cells are highly sensitive to infection by herpes simplex virus-1 via herpesvirus-entry-mediator A

Eling, David J.; Johnson, Paul A.; Sharma, Sanjai; Tufaro, Frank; Kipps, Thomas J.

doi:10.1038/sj.gt.3301241

Cited by 31 publications

(21 citation statements)

References 29 publications

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“…In contrast to our observation of uniformly high expression of all three Hve genes in ALL cells, CLL cells were reported to express high levels of HveA but not HveC. 28 Thus, high expression of HveA and HveC predisposes ALL cells as ideal targets for HSV-1-based gene transfer strategies.…”

Section: Discussioncontrasting

confidence: 93%

“…3 In accordance with high level expression of all three Hve receptors, we have now extended this observation to HSV-1-derived amplicon vectors. It has previously been reported that HSV-1-derived recombinant 28 or HSV-1 amplicon vectors 5 effectively transduce human B cells obtained from patients with chronic lymphocytic leukemia (CLL). In contrast to our observation of uniformly high expression of all three Hve genes in ALL cells, CLL cells were reported to express high levels of HveA but not HveC.…”

Section: Discussionmentioning

confidence: 99%

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Herpes simplex virus type-1 amplicon vectors for vaccine generation in acute lymphoblastic leukemia

et al. 2005

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For leukemia vaccine generation, high-efficiency gene transfer is required to express immunomodulatory molecules that stimulate potent antileukemic immune responses. In this context, herpes simplex virus type-1 (HSV-1)-derived vectors have proven to be a promising tool for genetic modification of lymphoblastic leukemia cells. Yet, vector-associated viral protein expression might inadvertently modulate vaccine efficacy facilitating both immune evasion and immune stimulation. To explore the issue of immune-stimulation versus immune-suppression in immature lymphoblastic leukemia cells, two types of HSV-1 amplicon vectors, helper virus-dependent and helper virus-free that express the immunomodulatory molecules CD70 and IL-2, were compared with regard to their vector-associated immunomodulatory potential. We first established that lymphoblastic cell lines and primary acute lymphoblastic leukemia (ALL) cells express HSV receptor genes. Lymphoblastic cell lines were transduced with high efficiency, and in primary ALL cells high gene transfer rates of 47715 and 42714% were obtained with helper virus-dependent and -free HSV-1 amplicon vectors, respectively. The efficacy of the two amplicon vectors to induce antineoplastic responses was assessed in a vaccine setting in mice with pre-existing highly malignant lymphoblastic disease. Treatment of mice with vaccine cells transgenically expressing CD70+IL2 significantly suppressed lymphoblastic cell proliferation and improved survival. Of note, when helper virus-dependent HSV-1 amplicon vectors were used for vaccine preparation, the high immunogenic potential of the vector itself, in the absence of transgenic CD70+IL2 expression, seemed to be sufficient to mediate protection comparable to the antineoplastic response achieved by expression of immunomodulatory molecules. Thus for vaccine generation in B lymphoblastic leukemia, the immunogenic potential of HSV-1 helper virus-dependent amplicon vectors does provide additional benefit to the high transduction efficiency of HSV-1-derived vectors.

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Section: Discussioncontrasting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Herpes simplex virus type-1 amplicon vectors for vaccine generation in acute lymphoblastic leukemia

et al. 2005

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“…We and others had previously shown that HVEM was expressed in lymphoid malignancies, particularly on leukemias of B origin, with high intensity in all the CLL and all the mantle cell lymphomas (MCL) tested, and often observed in acute lymphoblastic leukemias [29,30]. As shown in Fig.…”

Section: Expression Of Hvem and Lt-br On Hematopoietic Malignanciesmentioning

confidence: 92%

A role for HVEM, but not lymphotoxin‐β receptor, in LIGHT‐induced tumor cell death and chemokine production

et al. 2009

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The TNF member LIGHT also known as TL4 or TNFSF14) can play a major role in cancer control via its two receptors; it induces tumor cell death through lymphotoxin-b receptor (LT-bR) and ligation to the herpes virus entry mediator (HVEM) amplifies the immune response. By studying the effect of LIGHT in the transcriptional profile of a lymphoid malignancy, we found that HVEM, but not LT-bR, stimulation induces a significant increase in the expression of chemokine genes such as IL-8, and an unexpected upregulation of apoptotic genes. This had functional consequences, since LIGHT, or HVEM mAb, thus far known to costimulate T-and B-cell activation, induced chronic lymphocytic leukemia cell death. Many of the mediators involved were identified here, with an apoptotic pathway as demonstrated by caspases activation, decrease in mitochondrial membrane potential, upregulation of the pro-apoptotic protein Bax, but also a role of TRAIL. Moreover, HVEM induced endogenous TNF-a production and TNF-a enhanced HVEM-mediated cell death. HVEM function was mainly dependent on LIGHT, since other ligands like HSV-glycoprotein D and B and T lymphocyte attenuator were essentially ineffective. In conclusion, we describe a novel, as yet unknown killing effect of LIGHT through HVEM on a lymphoid malignancy, and combined with induction of chemokine release this may represent an additional tool to boost cancer immunotherapy. 2502 IntroductionThe TNF and TNF receptor (TNFR) superfamilies have diverse and widespread physiological functions, including apoptosis, proliferation, differentiation, and immune system regulation. TNFR are schematically classified into two groups: those with a 80-amino acids death domain (DD) in the cytoplasmic region of the receptor, which signals cell death, and those without DD, which have been implicated in lymphoid cell proliferation and differentiation [1,2]. LIGHT also known as TL4 or TNFSF14) is a glycosylated, type II transmembrane protein of about 29 kDa, which can bind lymphotoxin-b receptor (LT-bR) and the herpes virus entry mediator (HVEM) both of which belong to the TNFR superfamily. HVEM is a type I transmembrane protein of 32 to 36 kDa, devoid of intracytoplasmic DD. To date, five ligands have been identified for HVEM. The first one is HSV glycoprotein D (HSV-gD), a structural component of the HSV envelope, essential for HSV entry into host cells [3]. Two of the ligands are members of the TNF superfamily: the trimeric lymphotoxin a (LTa3) and LIGHT [4]. Recently, it was also found that HVEM interacts with two immunoglobulin superfamily members B and T lymphocyte attenuator (BTLA) and CD160 [5][6][7]. HVEM is expressed in most immune cells such as monocytes, T and B lymphocytes, and natural killer cells whereas expression of LT-bR is restricted to stromal cells or non-lymphoid hematopoietic cells [8,9]. Functional differences between the two receptors of LIGHT have also been observed. LIGHT binding to HVEM confers mainly costimulatory effects; LIGHT has a potent, CD28-independent, co-stimulatory role in...

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“…Fundamentally, all gene therapy approaches must embody a requisite level of transduction to achieve an effective expression of the gene of interest. For MM, various vectors have been tested with various levels of efficacy reported (vesicular stomatitis virus glycoprotein pseudo-typed lentiviral vector, 7 herpes simplex virus, 54 fiber-modified Ad, 55,56 adeno-associated virus, 57 and measles virus 57 ). With respect to Ad vectors, DF3/ MUC-1 promoter-driven herpes simplex virus thymidine kinase expression vector has been applied to MM for ex vivo purging of MM cells.…”

Section: Il-6mentioning

confidence: 99%

Suppressor of cytokine signaling-1 expression by infectivity-enhanced adenoviral vector inhibits IL-6-dependent proliferation of multiple myeloma cells

et al. 2005

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Multiple myeloma (MM) accounts for 10% of hematological malignant disorders. Its refractory nature indicates the necessity of developing novel therapeutic modalities. Since interleukin 6 (IL-6) is one of the major growth factors for MM cells, we expressed suppressor of cytokine signaling-1 (SOCS-1), one of the blockades of IL-6 receptor downstream signaling, to suppress the proliferation of MM cells. Because MM cells are resistant to conventional adenoviral vector infection, we utilized infectivityenhanced adenoviral vectors with an RGD4C motif in the adenoviral fiber-knob region (RGD-modified vector). In infectivity analysis, RGD-modified vectors were superior to unmodified controls in the majority of the MM cell lines tested. The overexpression of SOCS-1 using infectivity-enhanced adenoviral vectors achieved growth suppression in IL-6-dependent MM cells, but not in the IL-6-independent cells. IL-6-induced STAT3 phosphorylation was suppressed in IL-6-dependent cells, indicating that the signal transduction cascade of the IL-6 receptor signaling was blocked. In aggregate, SOCS-1 overexpression with RGDmodified adenoviral vectors achieved the antiproliferative effect in IL-6-dependent MM cells. These results provide an initial proofof-principle of the anticancer effect of SOCS-1 expression vector as well as a promise for the future development of therapeutic modality for MM based on this vector.

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Chronic lymphocytic leukemia B cells are highly sensitive to infection by herpes simplex virus-1 via herpesvirus-entry-mediator A

Cited by 31 publications

References 29 publications

Herpes simplex virus type-1 amplicon vectors for vaccine generation in acute lymphoblastic leukemia

Herpes simplex virus type-1 amplicon vectors for vaccine generation in acute lymphoblastic leukemia

A role for HVEM, but not lymphotoxin‐β receptor, in LIGHT‐induced tumor cell death and chemokine production

Suppressor of cytokine signaling-1 expression by infectivity-enhanced adenoviral vector inhibits IL-6-dependent proliferation of multiple myeloma cells

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