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Adoptive immunotherapy is a promising approach for the treatment of cancer; however, autoimmunity against normal tissue can be a serious complication of this therapy. We hypothesized that T-cell cultures responding maximally only when engaging two antigens would be more specific for tumor cells, and less active against normal cells, as long as the tumor expressed both antigens, while normal cells expressed only one of the antigens. A model system was developed consisting of cell lines expressing either folate binding protein or erbB-2, representing 'normal' tissue, and cells expressing both antigens representing tumor tissue. Human T-cell cultures were produced using two chimeric antigen receptor vectors ('dual transduced'), or using a single chimeric antigen receptor vector (monospecific). Dual-transduced T cells responded less against 'normal' cells compared with tumor cells. This relatively simple procedure produced T-cell cultures that were as active against a tumor as the monospecific cultures used traditionally, but had lower activity against model normal cells.

Adoptive cellular immunotherapy involving transfer of tumor-reactive T cells has shown some notable antitumor responses in a minority of cancer patients. In particular, transfer of tumor-infiltrating lymphocytes has resulted in long-term objective responses in patients with advanced melanoma. However, the inability to isolate sufficient numbers of tumor-specific T cells from most malignancies has restricted the broad utility of this approach. An emerging approach to circumvent this limitation involves the genetic modification of effector cells with T cell receptor (TCR) transgenes or chimeric single-chain variable fragment (scFv) receptors that can specifically redirect T cells to tumor. There has been much progress in the design of TCR and scFv receptors to enhance the antigen-specific activation of effector cells and their trafficking and persistence in vivo. Considerable effort has been directed toward improving the safety of this approach and reducing the immunogenicity of the receptor. This review discusses the latest developments in the field of adoptive immunotherapy using genetically modified immune cells that have been transduced with either TCR or scFv receptor transgenes and used in preclinical and clinical settings as anticancer agents.

Enteroviruses CVA21, CVA21-DAFv, and EV1 are potentially potent oncolytic agents against human prostate cancer.

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