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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    • "Another approach to enhance in vivo T-cell persistence involves the application of virus-specific T cells which are genetically modified to express CAR. Murphy et al. have demonstrated the increased persistence of CAR-specific influenza virus T cells in mice with breast cancer (Murphy et al. 2007). In another experiment, improved persistence of CAR-specific Epstein Barr virus (EBV) T cells against GD2 was observed in patients with neuroblastoma (Pule et al. 2008). "
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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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    • "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). "

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