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Review
. 2008;42(1-3):182-96.
doi: 10.1007/s12026-008-8070-9.

Adoptive immunotherapy: good habits instilled at youth have long-term benefits

Chrystal M Paulos  1 , Megan M Suhoski, Gabriela Plesa, Tianying Jiang, Samik Basu, Tatiana N Golovina, Shuguang Jiang, Nicole A Aqui, Daniel J Powell Jr, Bruce L Levine, Richard G Carroll, James L Riley, Carl H June
Affiliations
Review

Adoptive immunotherapy: good habits instilled at youth have long-term benefits

Chrystal M Paulos et al. Immunol Res. 2008.

Abstract

Many recent advances in basic cell biology and immunology are a harbinger of progress in adoptive cell therapy (ACT) including (1) the finding that host lymphodepletion enhances engraftment and efficacy, (2) the recognition that in vitro T cell functions may not correlate with in vivo efficacy, and (3) the development of advanced ex vivo culture methods to expand lymphocytes to therapeutically effective numbers. In this article, we focus on the development of artificial antigen presenting cells (aAPCs) in our laboratory and their applicability to augment ACT protocols. We also describe how aAPCs can be used to broaden ACT to treat patients with a wide variety of cancers, chronic infectious diseases, and autoimmune manifestations.

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Figures

Fig. 1
Fig. 1
Essential factors for augmenting adoptive immunotherapy. It is now clear that successful cell therapy needs to encompass at least three important factors: (1) proper preconditioning of the patient prior to ACT (i.e. surgery or various lymphodepleting preparative regimens), (2) the selection of the right cell type for programming and engineering (stem, cord blood cell, peripheral blood T cells), as well as the correct differentiation state of the cell, and (3) development of effective ex vivo culture strategies (cytokines, beads, or artificial APCs) that expand lymphocytes to unique T cell subsets
Fig. 2
Fig. 2
Adoptive cell transfer strategy. Input cells are isolated by apheresis for example, or tumor digestion (not shown), purified, and stimulated with an artificial antigen presenting cell (aAPC). The desired phenotype can be engineered into the cells, predominantly through high efficiency lentiviral vector-mediated transduction. The cells are then rapidly expanded and subject to both in vitro and in vivo functional assays prior to infusion into the patient
Fig. 3
Fig. 3
The evolving artificial antigen presenting cell (aAPC). Due to the limitation of autologous DC to reproducibly expanding large numbers of quality human T cells, various types of aAPCs were developed over the past decades to improve the yield of lymphocytes obtained from patients for ACT therapy. The first generation of aAPCs consisted of antibodies to CD3 and CD28 covalently bound to paramagnetic beads. More recently, the use of cell-based aAPCs has been explored. The first generation of K562 cell-based aAPCs was produced using plasmid transfection and antibiotic selection. The most recent generation of K562-based aAPCs has been constructed by lentiviral vector mediated-transduction. High titer lentiviral vectors permit the introduction of numerous (up to 7) costimulatory molecules or soluble immunomodulators
Fig. 4
Fig. 4
Development of artificial APCs that program human CD4 T cells to a Treg, Th17, Th1 or Th2 phenotype. Naïve CD4 T cells can be polarized by modulating cytokines, costimulatory molecules or signaling pathways such as mTOR using rapamycin. Bead-based aAPCs promote the expansion of the polarized CD4 T cells. With the exception of Tregs, the ability of K562 cells to promote expansion of functional, polarized Th1, Th2, and Th17 cells remain largely unexplored
Fig. 5
Fig. 5
Cord blood or precursor stem T cells: Greater potential for adoptive cellular transfer? Because cord blood T cells and stem cell precursor T cells are more naïve in phenotype and function compared to peripheral T cells, future adoptive transfer protocols may exploit their larger reserves of proliferative potential to enhance treatment outcome and promote life long immunosurveillance
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