Cell and Gene Therapies by Miguel-Angel Perales & Syed A. Abutalib & Catherine Bollard
Author:Miguel-Angel Perales & Syed A. Abutalib & Catherine Bollard
Language: eng
Format: epub
ISBN: 9783319543680
Publisher: Springer International Publishing
8.7 Generation of Virus-Specific T Cells from Virus-Naïve Donors
Initially, the generation of donor-derived virus-specific T cells had a prerequisite that the donor should be seropositive for the relevant virus in order to successfully isolate virus-specific memory T cells. Inevitably, this restricted the widespread application of the product to a subgroup of transplant recipients and was not a viable treatment option for those patients with seronegative donors. Cord-blood transplants are often considered to be virus-naïve grafts, and the number of cord-blood transplants being performed has been increasing (Passweg et al. 2012). Therefore, the potential of producing virus-specific T cells from naïve donors was explored (Savoldo et al. 2002; Park et al. 2006; Jedema et al. 2011).
The process of generating virus-specific T cells from naïve donors was previously reported for EBV-specific CTLs. A comparison was made between generating EBV-T cells from EBV-seronegative adults and children (Savoldo et al. 2002). Two methods of generation of EBV-CTLs were adopted depending on the type of cell used as an APC. One method used EBV-LCLs as APCs, whereas the other method used dendritic cells (DCs) loaded with EBV antigen. They found that using EBV-LCLs as APCS effectively generated EBV-T cells from all seronegative adult donors but not from any of the seronegative children. The EBV antigen-loaded DCs expanded EBV-T cells in only a minority of the children indicating that different approaches may be needed depending on whether the donor is child or adult.
With the advent of multi-virus-specific T cells, Hanley et al. (2009) have explored the possibility of generating mVSTs from virus-naïve donors. Using cord blood, they developed a protocol to generate single cultures of T cells from cord blood by transducing EBV-LCLs with an Ad5f35CMVpp65 adenoviral vector, which recognised viral epitopes only after 2 weeks of expansion. They discovered that the recognition of adenovirus epitopes was the same for adult donor-derived T cells but that the pattern of CMV epitopes recognised appeared different to those recognised by adult donor-derived VSTs. Furthermore, they reported that the generation of CMV-specific T cells from cord blood did not depend upon the CMV serostatus of the mother.
The safety of multi-virus-specific T cells generated from naïve donors and used prophylactically has been reported in three consecutive cord-blood transplant patients (Hanley et al. 2015). The cells were generated from 20% of cord blood units where the remaining 80% were used as the transplanted graft. They reported no infusion-related toxicity or GvHD development post-infusion but confirmed the previous reports that the CMV-specific T cells generated from virus-naïve donors were specific for atypical epitopes for the CMV pp65 peptide (Hanley et al. 2009). The development of strategies to produce multi-virus-specific T cells from peripheral blood has also been explored. In a study where 34 patients were given peripheral blood-derived trivirus-specific T cells and 8 patients were given cord blood-derived CTLs, none of the patients developed GvHD greater than grade 2 (Hanley et al. 2013). Eleven patients had CMV reactivation detected prior to the infusion, and 8 of 11 became negative for the infection within 7 days of the infusion.
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