Genetic engineering of T cells for adoptive immunotherapy

Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, 421 Curie Blvd-556 BRB II/III, Philadelphia, PA, 19104, USA.
Immunologic Research (Impact Factor: 3.1). 11/2008; 42(1-3):166-81. DOI: 10.1007/s12026-008-8057-6
Source: PubMed


To be effective for the treatment of cancer and infectious diseases, T cell adoptive immunotherapy requires large numbers of cells with abundant proliferative reserves and intact effector functions. We are achieving these goals using a gene therapy strategy wherein the desired characteristics are introduced into a starting cell population, primarily by high efficiency lentiviral vector-mediated transduction. Modified cells are then expanded using ex vivo expansion protocols designed to minimally alter the desired cellular phenotype. In this article, we focus on strategies to (1) dissect the signals controlling T cell proliferation; (2) render CD4 T cells resistant to HIV-1 infection; and (3) redirect CD8 T cell antigen specificity.

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Available from: Angela Mexas, Jun 18, 2014
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    • "Despite these findings, Th17 cells and ICOS ligation have yet to be exploited in the clinic (129). However, gene therapy now permits the opportunity to redirect Th17 cells (via TCR or CAR that recognize tumor antigen) for the potential treatment of a broader range of malignancies (130–135). This approach could circumvent the use of inefficacious differentiated T cells obtained from TIL (113, 136). "
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    Frontiers in Immunology 06/2014; 5:276. DOI:10.3389/fimmu.2014.00276
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    • "Since the holy grail of cancer immunotherapy is to stimulate tumor-specific T cells that will elicit a cytotoxic response with high specificity and minimal toxicity, adoptive transfer of TAA-specific T cells has gained popularity over the past few years (37, 38). Adoptive T-cell transfer involves the isolation of T lymphocytes from the patients and their reinfusion to treat disease. "
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    ABSTRACT: Despite recent advances in cancer treatment over the past 30 years, therapeutic options remain limited and do not always offer a cure for malignancy. Given that tumor-associated antigens (TAA) are, by definition, self-proteins, the need to productively engage autoreactive T cells remains at the heart of strategies for cancer immunotherapy. These have traditionally focused on the administration of autologous monocyte-derived dendritic cells (moDC) pulsed with TAA, or the ex vivo expansion and adoptive transfer of tumor-infiltrating lymphocytes (TIL) as a source of TAA-specific cytotoxic T cells (CTL). Although such approaches have shown some efficacy, success has been limited by the poor capacity of moDC to cross present exogenous TAA to the CD8(+) T-cell repertoire and the potential for exhaustion of CTL expanded ex vivo. Recent advances in induced pluripotency offer opportunities to generate patient-specific stem cell lines with the potential to differentiate in vitro into cell types whose properties may help address these issues. Here, we review recent success in the differentiation of NK cells from human induced pluripotent stem (iPS) cells as well as minor subsets of dendritic cells (DCs) with therapeutic potential, including CD141(+)XCR1(+) DC, capable of cross presenting TAA to naïve CD8(+) T cells. Furthermore, we review recent progress in the use of TIL as the starting material for the derivation of iPSC lines, thereby capturing their antigen specificity in a self-renewing stem cell line, from which potentially unlimited numbers of naïve TAA-specific T cells may be differentiated, free of the risks of exhaustion.
    Frontiers in Immunology 04/2014; 5:176. DOI:10.3389/fimmu.2014.00176
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    • "Significant effort has been put forth over the past few years to evaluate the potential to treat cancer via the adoptive transfer of T lymphocytes, both effector lymphocytes (CD8 and CD4) and regulatory (Treg) cells, manipulated ex-vivo to generate large numbers and in some cases to enhance their activity (see for examples [15-17]). Such efforts been enabled by enhanced understanding of T cell immunobiology, and facilitated by the development of approaches to expand and manipulate T cells ex vivo [18-20], methodologies to enable manufacture under Good Manufacturing Practice (GMP) [21-23], as well as genetic approaches to augment T cell specificity and function [24,25]. These developments have facilitated a broad range of clinical trials to evaluate the ability of T cell therapy-based strategies to target tumors. "
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