Antitumor activity of dual-specific T cells and influenza virus

Cancer Immunology Research Program, Peter MacCallum Cancer Centre, Melbourne, Australia.
Cancer Gene Therapy (Impact Factor: 2.42). 06/2007; 14(5):499-508. DOI: 10.1038/sj.cgt.7701034
Source: PubMed


Activation and expansion of T cells are important in disease resolution, but tumors do not usually satisfy these immune requirements. Therefore, we employed a novel strategy whereby dual-specific T cells were generated that could respond to both tumor and influenza virus, reasoning that immunization with influenza virus would activate and expand tumor-specific cells, and inhibit tumor growth. Dual-specific T cells were generated by gene modification of influenza virus-specific mouse T cells with a chimeric gene-encoding reactivity against the erbB2 tumor-associated antigen. Dual-specific T cells were demonstrated to respond against both tumor and influenza in vitro, and expanded in vitro in response to influenza to a much greater degree than in response to tumor cells. Following adoptive transfer and immunization of tumor-bearing mice with influenza virus, dual-specific T cells expanded greatly in numbers in the peritoneal cavity and spleen. This resulted in a significant increase in time of survival of mice. However, tumors were not eradicated, which may have been due to the observed poor penetration of tumor by T cells. This is the first demonstration that the potent immunogenic nature of an infectious agent can be utilized to directly impact on T-cell expansion and activity against tumor in vivo.

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Available from: Lorena Brown, May 21, 2014
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    • "Thus, the use of these cells represents an interesting possibility to prevent the mispairing of the naturally expressed TCR chains with the exogenous one (van der Veken et al., 2006). Bispecific T-cells represent another possible option (reviewed in Marr et al., 2012); for example, virus-specific cells (specific for EBV, CMV or Influenza) can be engineered to express an additional receptor to target tumor cells (Rossig et al., 2002; Murphy et al., 2007; Pule et al., 2008; van der Veken et al., 2009). The use of these cells may considerably reduce off-target effects as these cells have a defined specificity and can provide protection from latent viruses during the immunosuppressed phase prior to adoptive transfer. "
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    ABSTRACT: T-cells are central players in the immune response against both pathogens and cancer. Their specificity is solely dictated by the T-cell receptor (TCR) they clonally express. As such, the genetic modification of T lymphocytes using pathogen- or cancer-specific TCRs represents an appealing strategy to generate a desired immune response from peripheral blood lymphocytes. Moreover, notable objective clinical responses were observed in terminally ill cancer patients treated with TCR-gene modified cells in several clinical trials conducted recently. Nevertheless, several key aspects of this approach are the object of intensive research aimed at improving the reliability and efficacy of this strategy. Herein, we will survey recent studies in the field of TCR-gene transfer dealing with the improvement of this approach and its application for the treatment of malignant, autoimmune, and infectious diseases.
    Frontiers in Immunology 07/2012; 3(186):186. DOI:10.3389/fimmu.2012.00186
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    • "Several constructs have been designed to target three members of HER family HER2, HER3 and HER4, such as: scFv-CD3ζ (Altenschmidt et al., 1997), scFv-CD3γ (Li et al., 2008), scFv- CD28-CD3ζ (Moulder and Hortobagyi, 2008), heregulin-CD3ζ (Muniappan et al., 2000), ScFv-CD28-CD3ζ " infuluenza " (Dual-specific T cells were generated by gene modification of influenza virus-specific mouse T cells with a chimeric gene-encoding reactivity against the HER2) (Murphy et al., 2007). In a study intravenously administration of primary mouse T cells with CAR against HER2 post tumour inoculation caused the rejection of established metastatic breast carcinoma (Berry et al., 2009; Moulder and Hortobagyi, 2008). "
    Breast Cancer - Current and Alternative Therapeutic Modalities, 11/2011; , ISBN: 978-953-307-776-5
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    • "Adaptive cancer immunotherapy can cause stimulation of the immune system in different ways, thus leading to the prevention of cancerous cellular growth [1] [2] [3]. Regarding the important role of T cells in cellular immunity against tumors, various strategies have been applied to increase the performance and specific activation of T cells against tumors [4] [5] [6] [7]. The aim of T-cell engineering is modification of chimeric T-cell receptors (chTCRs), in order to achieve high chimeric antigen receptor (CAR) expression. "
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    ABSTRACT: Adaptive cell immunotherapy with the use of chimeric receptors leads to the best and most specific response against tumors. Chimeric receptors consist of a signaling fragment, extracellular spacer, costimulating domain, and an antibody. Antibodies cause immunogenicity; therefore, VHH is a good replacement for ScFv in chimeric receptors. Since peptide sequences have an influence on chimeric receptors, the effect of peptide domains on each other's conformation were investigated. CD3Zeta, CD28, VHH and CD8α, and FcgIIα are used as signaling moieties, costimulating domain, antibody, and spacers, respectively. To investigate the influence of the ligation of spacers on the conformational structure of VHH, models of VHH were constructed. Molecular dynamics simulation was run to study the influence of the presence of spacers on the conformational changes in the binding sites of VHH. Root mean square deviation and root mean square fluctuation of critical segments in the binding site showed no noticeable differences with those in the native VHH. Results from molecular docking revealed that the presence of spacer FcgIIα causes an increasing effect on VHH with MUC1 interaction. Each of the constructs was transformed into the Jurkat E6.1. Expression analysis and evaluation of their functions were examined. The results showed good expression and function.
    BioMed Research International 08/2011; 2011(1110-7243):578128. DOI:10.1155/2011/578128 · 2.71 Impact Factor
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