Technical hurdles in a pilot clinical trial of combined B7-2 and GM-CSF immunogene therapy for glioblastomas and melanomas

Parney, Ian F.; Chang, Lung Ji; Farr-Jones, Maxine A.; Hao, Chunhai; Smylie, Michael; Petruk, Kenneth C.

doi:10.1007/s11060-005-9058-0

Cited by 39 publications

(36 citation statements)

References 35 publications

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“…No selection for tumor cell transfectants is necessary as is the case with retroviral vectors for which technical hurdles have been described. 21 In fact the efficiency of the retroviral vector approach was so low that from 116 malignant gliomas only three transfectants were successfully established and could be applied to the patients. 21 For comparison, in our glioblastoma study, 13 the efficiency of ATV-NDV tumor vaccine production (autologous cell cultures plus virus infection) was 90%.…”

Section: Discussionmentioning

confidence: 99%

“…22 Other data obtained by us (not shown here) revealed that NDFL (i) shows tumor selective replication as observed for NDV Ulster, 23 (ii) has a monocyclic replication cycle in tumor cells and (iii) produces noninfectious progeny virus similar to NDV Ulster. 21 The only difference between the two virus strains was that NDFL (rec(À)) had about three times higher cytotoxic effects on tumor cells as revealed by the Nicoletti assay. Such increased tumor cytotoxic effect may lead to an improvement of the immune response through uptake of apoptotic bodies and cross-presentation of tumor-associated antigens via host DCs.…”

Section: Discussionmentioning

confidence: 99%

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Recombinant Newcastle disease virus (NDV) with inserted gene coding for GM-CSF as a new vector for cancer immunogene therapy

Janke

Peeters²,

Leeuw

et al. 2007

Gene Ther

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Recombinant Newcastle disease virus (NDV) with inserted gene coding for GM-CSF as a new vector for cancer immunogene therapy

Janke

Peeters²,

Leeuw

et al. 2007

Gene Ther

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“…A clinical application of this approach, however, is generally impeded by technical hurdles and low transfection efficiencies. For instance, in one study, from 116 malignant gliomas only three patients could be vaccinated by a retrovirally transduced autologous tumor vaccine (35). For comparison, in our glioblastoma study, the efficiency of ATV-NDV production was 90% (26), which underlines the feasibility and reproducibility of our autologous tumor vaccine preparation.…”

Section: Discussionmentioning

confidence: 60%

An effective tumor vaccine optimized for costimulation via bispecific and trispecific fusion proteins

Aigner

Janke²,

Lulei³

et al. 2008

Int J Oncol

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Abstract. T cell costimulation has great therapeutic potential if it can be optimized and controlled. To achieve this, we engineered T cell-activating fusion proteins and immunocytokines that specifically attach to viral antigens of a virusinfected tumor vaccine. We employed the avian Newcastle Disease Virus because this agent is highly efficient for human tumor cell infection, and leads to introduction of viral hemagglutinin-neuraminidase (HN) molecules at the tumor cell surface. Here, we demonstrated the strong potentiation of the T cell stimulatory activity of such a vaccine upon attachment of bispecific or trispecific fusion proteins which bind with one arm to viral HN molecules of the vaccine, and with the other arm either to CD3 (signal 1), to CD28 (costimulatory signal 2a), or to interleukin-2 receptor (costimulatory signal 2b) on T cells. A vaccine with a combination of all three signals triggered the strongest activation of naïve human T cells, thereby inducing the most durable bystander antitumor activity in vitro. Adoptive transfer of such polyclonally activated cells into immunodeficient mice bearing human breast carcinoma caused tumor regression. Furthermore, tumor-reactive memory T cells from draining lymph nodes of carcinoma patients could be efficiently reactivated in a short-term ELISpot assay using an autologous tumor vaccine with optimized signals 1 and 2, but not with a similarly modified vaccine from an unrelated tumor cell line. Our data describe new bioactive molecules which in combination with an established virus-modified tumor vaccine greatly augments the antitumor activity of T cells from healthy donors and cancer patients. IntroductionThe strength of T cell stimulation is determined by numerous parameters including i) the concentration of major histocompatibility complex-restricted antigen on the surface of antigen-presenting cells (APCs) such as dendritic cells (DCs) and its affinity for the T cell receptor (TCR; determining the rate of TCR triggering) (1,2), ii) the presence or absence of costimulation (regulating the extent of signal amplification) (3,4), such as costimulation via CD28 which is the most prominent costimulatory receptor on T cells (5,6), and iii) the duration of the interactions between T cells and DCs (setting the duration of the signalling process) (7,8). A low-strength stimulation which may occur with tumor cells can have a negative effect leading to T cell unresponsiveness (anergy) (9), or apoptosis (10,11). However, CD28 engagement drives interleukin-2 (IL-2) production (12,13), a cytokine pivotal for T cell growth, survival and cytotoxicity (14).We have already reported on three recombinant, monomeric single chain Fv (scFv) fusion proteins (15-17). These specially designed molecules provide T cell activation signals by interacting either with the TCR-associated CD3 complex [signal 1, mediated by the bispecific (bs) fusion protein bsHN-CD3], or with the costimulatory molecule CD28 (signal 2a, mediated by bsHN-CD28), or with the IL-2 receptor (signal 2b, mediate...

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“…A pilot clinical trial of combined B7-2 and GM-CSF immunogene therapy for GBMs and melanomas has been reported. 40 In this trial, patients with recurrent malignant gliomas were vaccinated with irradiated autologous tumor cells transduced with the B7-2 and GM-CSF genes, using a retroviral vector. Although vaccine preparation was attempted using 116 samples of malignant glioma tissue, vaccine preparation was successful for only 5 GBM samples.…”

Section: Gm-csfmentioning

confidence: 99%

Cytokine Therapy

Ohno

Natsume

Wakabayashi

2012

Advances in Experimental Medicine and Biology

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Cytokines are a heterogeneous group of soluble small polypeptides or glycoproteins, which exert pleiotropic and redundant effects that promote growth, differentiation and activation of normal cells. Cytokines can have either pro- or anti-inflammatory activity and immunosuppressive activity, depending on the microenvironments. The tumor microenvironment consists of a variable combination of tumor cells, endothelial cells and infiltrating leukocytes, such as macrophages, T-lymphocytes, natural killer (NK) cells, B cells and antigen-presenting cells (APCs). Cytokine production acts as a means of communication in the tumor microenvironment. In this article, we review the cross-talk between cytokines in the tumor environment and the cytokine therapies that have been used till date for glioma treatment.

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Technical hurdles in a pilot clinical trial of combined B7-2 and GM-CSF immunogene therapy for glioblastomas and melanomas

Cited by 39 publications

References 35 publications

Recombinant Newcastle disease virus (NDV) with inserted gene coding for GM-CSF as a new vector for cancer immunogene therapy

Recombinant Newcastle disease virus (NDV) with inserted gene coding for GM-CSF as a new vector for cancer immunogene therapy

An effective tumor vaccine optimized for costimulation via bispecific and trispecific fusion proteins

Cytokine Therapy

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