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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"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). "
[Show abstract][Hide abstract]ABSTRACT: The use of chimeric antigen receptor (CAR)-modified T cells is a promising approach for cancer immunotherapy. These genetically modified receptors contain an antigen-binding moiety, a hinge region, a transmembrane domain, and an intracellular costimulatory domain resulting in T-cell activation subsequent to antigen binding. Optimal tumor removal through CAR-modified T cells requires suitable target antigen selection, co-stimulatory signaling domain, and the ability of CAR T cells to traffic, persist, and retain antitumor function after adoptive transfer. There are several elements which can improve antitumor function of CAR T cells, including signaling, conditioning chemotherapy and irradiation, tumor burden of the disease, T-cell phenotype, and supplementary cytokine usage. This review outlines four generations of CAR. The pre-clinical and clinical studies showed that this technique has a great potential for treatment of solid and hematological malignancies. The main purpose of the current review is to focus on the pre-clinical and clinical developments of CAR-based immunotherapy.
"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. "
[Show abstract][Hide abstract]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.
Full-text · Article · Jul 2012 · Frontiers in Immunology
"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). "