Article

Genetic Manipulation of Tumor-specific Cytotoxic T Lymphocytes to Restore Responsiveness to IL-7

Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital, Houston, Texas 77030, USA.
Molecular Therapy (Impact Factor: 6.43). 04/2009; 17(5):880-8. DOI: 10.1038/mt.2009.34
Source: PubMed

ABSTRACT Adoptive transfer of antigen-specific cytotoxic T lymphocytes (CTLs) can induce objective clinical responses in patients with malignant diseases. The option of providing a proliferative and survival advantage to adoptively transferred CTLs remains a challenge to improve their efficacy. Host lymphodepletion and administration of recombinant interleukin-2 (IL-2) are currently used to improve CTL survival and expansion after adoptive transfer, but these approaches are frequently associated with significant side effects and may increase proliferation of T regulatory cells. IL-7 is a crucial homeostatic cytokine that has been safely administered as a recombinant protein. However, while IL-7 induces robust expansion of naive and memory T lymphocytes, the lack of expression of the IL-7 receptor alpha chain (IL-7Ralpha) by CTLs precludes their response to this cytokine. We found that CTLs can be genetically modified to re-express IL-7Ralpha, and that this manipulation restores the response of these cells to IL-7 without apparent modification of their antigen specificity or dependency, and without changing their response to other common gamma (gammac) chain cytokines. This approach may allow selective expansion of CTLs without the unwanted effects associated with IL-2.

1 Follower
 · 
172 Views
  • Source
    • "In an alternative approach, adoptively transferred T cells may be further modified to specifically respond to a given cytokine, such as those that may be naturally present within the tumor microenvironment (Lo et al. 2008) or those that may be safely administered as an exogenous cytokine source (Vera et al. 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Harnessing the power of the immune system to target cancer has long been a goal of tumor immunologists. One avenue under investigation is the modification of T cells to express a chimeric antigen receptor (CAR). Expression of such a receptor enables T-cell specificity to be redirected against a chosen tumor antigen. Substantial research in this field has been carried out, incorporating a wide variety of malignancies and tumor-associated antigens. Ongoing investigations will ensure this area continues to expand at a rapid pace. This review will explain the evolution of CAR technology over the last two decades in addition to detailing the associated benefits and disadvantages. The outcome of recent phase I clinical trials and the impact that these have had upon the direction of future research in this field will also be addressed.
    Archivum Immunologiae et Therapiae Experimentalis 04/2010; 58(3):165-78. DOI:10.1007/s00005-010-0074-1 · 2.82 Impact Factor
  • Source
    • "Alternatively, the T cells may be modified to express a receptor for a cytokine that is present (or can be safely administered) in the environment but to which they may not otherwise be able to respond. For example, our group has modified activated antigen-specific T cells to express the IL-7 receptor (Vera et al., 2009), which is normally down-regulated on T cells once they have been stimulated by antigen. This modification restores the T cell's ability to respond to IL-7 that is available as a result of cytokine production in response to lymphodepletion of the host or from administration of the recombinant cytokine, which has been administered safely and without expansion of Tregs (Rosenberg et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adoptive transfer of T cells can enhance immune-mediated elimination of tumor cells and provides a specific, non-toxic cancer therapy. This approach has been effective in treating some hematologic and solid malignancies. In addition, the ability to genetically modify T cells to enhance their activity and persistence as well as overcome tumor immune evasion mechanisms has the potential to increase the success of these therapies in a wide range of tumors. In this review we discuss methods for gene transfer and specific modifications that have been made to T cells.
    Discovery medicine 04/2010; 9(47):297-303. · 3.50 Impact Factor
  • Source
    • "Administration of IL-7 accelerates immune reconstitution in murine models (Alpdogan et al., 2003) and the cytokine has been well tolerated in early-phase clinical trials, in which it produced polyclonal expansion of naive CD4 þ and CD8 þ T lymphocytes and no evident Treg expansion (Rosenberg et al., 2006; Sportes et al., 2008). IL-7 administration could enhance the expansion of adoptively transferred T cells if they physiologically reexpressed the IL-7 receptor a chain (Powell et al., 2005) or if such expression were forced by genetic manipulation (Vera et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: "T-body" or chimeric antigen receptor (CAR) technology, which combines the specificity of an antibody with the homing, tissue penetration, and target cell destruction of T cells, was first described in 1993. After many years of unmet promise, significant improvements in gene transfer, including the development of efficient retroviral vectors for transduction of human T cells, and better understanding of immunological pathways and immune cell interactions, are allowing this technology to reach a critical phase of evaluation, in which we will learn whether the approach can truly meet expectations. In this review we summarize the concept of CAR-based immunotherapy, describe the steps accomplished, and outline the future progress we need to make if this approach is truly to improve cancer immunotherapy.
    Human gene therapy 09/2009; 20(11):1229-39. DOI:10.1089/hum.2009.142 · 3.62 Impact Factor
Show more

Preview

Download
5 Downloads
Available from