Immune reconstitution
3. Discussion and future perspectives
3.5 Adoptive immunotherapy: current status and future perspectives
The three main technologies for the enrichment of clinical-grade antigen-specific T lymphocytes for the adoptive immunotherapy so far are:
(1) The adoptive transfer of in vitro expanded antigen-specific T cells with or without cloning [52, 133];
(2) The adoptive transfer of highly pure reversible pMHC multimer-isolated antigen-specific CD8+ CTLs (reversible pMHC streptamer technology from IBA TAGnology) sorted either directly from blood cells or after short-term in vitro stimulation [138];
(3) The adoptive transfer of isolated IFN-γ secreting antigen-specific cells (cytokine capture system technology (CliniMACS from Miltenyi Biotec), including CD8+ and CD4+ T cells, after short-term in vitro stimulation [102, 196, 197].
These techniques are successfully used in adoptive immunotherapy for the effective and fast treatment of HSCT- and SOT-related complications such as malignant tumors and infectious disease. Adoptive transfer of antigen-specific T lymphocytes offers the possibility to induce a beneficial GvI, GvL or GvT effect with reduced GvHD [198].
In the first approach, antigen-specific T cells can be expanded by repetitive antigen stimulation of in vitro cultured T cells with or without cloning [133]. This leads to antigen-specific CD8+ and/or CD4+ T cells depending on the antigen used. This technique has the disadvantage of a long-term and expensive in vitro cultivation before adoptive transfer. In contrast, the reversible pMHC streptamer and the cytokine capture system technology listed below offer the advantages of easy and fast methods that can readily be standardized with various malignant and infectious antigens for antigen-specific cellular immunotherapy approaches [133]. Because these described techniques are quite new, only a few studies are published about the enrichment of clinical-grade antigen-specific T cells [75, 95, 102, 134, 138, 171, 190], but the results are promising. Studies demonstrated a comparable safety of these infusions, while the products of the pMHC streptamer technology and the cytokine
capture technology had an excellent toxicity profile [102, 132, 134, 138]. Antigen-specific CD8+ CTLs isolated by the reversible pMHC multimer technology have a higher purity to CD8+ CTLs and CD4+ T helper cells isolated with the cytokine secretion system [102, 134, 138]. Moreover, the optimal or at least the minimal T-cell dose for the adoptive transfer in order to obtain desirable therapeutic effects, are still not know [52]. These few published studies only indicate an approximately value of the clinical relevant antigen-specific T-cell dose/infusion [102, 132, 134, 138]. The therapeutic effects of a variety of cell doses for the adoptive transfer have been reported for different treatments as followed:
(1) virus-specific
0.2x105 – 1x105 CMV-specific T-cell lines/kg, administered in a single infusion [52, 199];
4x107– 3x108 EBV-specific T cells/m2, administered in 1 or 2 infusions [52, 200];
5x106 – 1x108 multivirus-reactive cell line/m2, administered in a single infusion [52, 201];
(2) tumor-specific
0.11– 13.1x108 melanoma-specific T cells/infusion, administered in at least 3 infusions [52, 202];
2.3x1010– 13.7x1010 melanoma-specific T cells/infusion [52, 203];
~5x1010 ex vivo selected and expanded autologous tumor-infiltrating lymphocytes (TILs) isolated from metastatic melanoma patients/infusion [52, 204].
In conclusion, the enormous progress in understanding T-cell biology and physiology, combined with novel technologies for generation, detection, expansion, and isolation of antigen-specific T cells have made the adoptive transfer effective for clinical application with highly promising perspectives [52]. This doctoral thesis provides more insight into the generation and selection of antigen-specific T lymphocytes, while the established strategies developed in this study can be used in both basic and clinical immunology. In the future, the greatest challenges are the technology design and improvements as well as the control of clinical trials to find the optimal conditions (e.g., selection of cell dose/infusion, purities of infused T cells, selection of cell subpopulations) for a successful in vivo expansion associated with a long-lasting immunity after adoptive transfer [102].
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