title: Cancer immunotherapy utilizing gene-modified T cells: From the bench to the clinic.
abstract: The immune system plays a critical role in the elimination and suppression of pathogens. Although the endogenous immune system is capable of immune surveillance resulting in the elimination of cancer cells, tumor cells have developed a variety of mechanisms to escape immune recognition often resulting in tumor outgrowth. The presence of immune infiltrate in tumors has been correlated with a good prognosis following treatment (Sato et al., 2005; Loi et al., 2013; Clemente et al., 1996; Galon et al., 2006). As such, immune cells such as T cells, have been harnessed in order to target cancer. Tumor reactive lymphocytes, called tumor-infiltrating lymphocytes (TILs) have been isolated and expanded from the tumor and reinfused back into patients for the treatment of melanoma. The promise of adoptive immunotherapy utilizing TILs as a robust treatment for cancer has been highlighted in patients with advanced melanoma with greater than 50% of patients responding to treatment (Dudley et al., 2005). Although TIL therapy has shown promising results in melanoma patients, it has proved difficult to translate this approach to other cancers, given that the numbers of TILs that can be isolated are generally low. To broaden this therapy for other cancers, T cells have been genetically modified to endow them with tumor reactivity using either a T cell receptor (TCR) (Parkhurst et al., 2009, 2011; Chinnasamy et al., 2011) or a chimeric antigen receptor (CAR) (Grupp et al., 2013; Park et al., 2007). This review will outline the origins and development of adoptive immunotherapy utilizing TILs leading to genetic modification strategies to redirect T cells to cancer. Potential hurdles and novel strategies will be discussed for realizing the full potential of adoptive immunotherapy becoming a standard of care treatment for cancer.
authors.affiliation: Cancer Immunology Research Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Connie P M
authors.initials: CP
authors.lastname: Duong
authors.affiliation: Cancer Immunology Research Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Carmen S M
authors.initials: CS
authors.lastname: Yong
authors.affiliation: Cancer Immunology Research Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia; Department of Immunology, Monash University, Clayton, Australia.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kershaw
authors.affiliation: Cancer Immunology Research Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: clare.slaney@petermac.org.
authors.forename: Clare Y
authors.initials: CY
authors.lastname: Slaney
authors.affiliation: Cancer Immunology Research Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia; Department of Immunology, Monash University, Clayton, Australia. Electronic address: phil.darcy@petermac.org.
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
mesh_terms: D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods* / Q000639:trends; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D018448:Models, Immunological; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D019076:Transgenes / Q000235:genetics / Q000276:immunology*; D057170:Translational Research, Biomedical / Q000379:methods / Q000639:trends; D016896:Treatment Outcome
chemical_list: D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins
keywords: Adoptive immunotherapy; Chimeric antigen receptor; T cell receptor; Tumor infiltrating lymphocytes