Generation and infusion of multi-antigen-specific T cells to prevent complications early after T-cell depleted allogeneic stem cell transplantation—a phase I/II study

Minor Histocompatibility Antigen-Specific T Cells

“…After separation, the HLA I-Streptamers can be dissociated from the positively selected cells by the addition of D-Biotin, allowing for rapid enrichment of unlabeled antigen-specific T cells under GMP conditions. However, in a clinical trial of Streptamerenriched multi-antigen-specific T cells to prevent complications early after T cell-depleted HCT, neither tumor associated antigen or minor H antigen-specific T cells could be confirmed in the majority of antigen-specific T cell products or after HCT, although EBV and CMV-specific T cells were readily detected in the products and sometimes after HCT (140). The greater success in isolating virus-specific T cells compared to minor H antigenor other tumor-associated antigen-specific T cells, may be due to the relatively high frequencies of virus-specific T cells in the repertoire of normal viral antigen-experienced donors.…”

“…Current hurdles to augmenting HCT grafts for hematopoieticrestricted minor H antigen-specific T cells include the relatively limited number of suitable target minor H antigens that have been discovered and characterized ( Table 1) and technical issues largely related to inadequate options for clinical-grade sorting of rare cells. Streptamer technology is being evaluated for isolating antigen-specific T cells (137)(138)(139)(140). The technology is based on the direct labeling of CD8 + T cells with HLA I-Streptamers composed of peptide-loaded HLA I-Strep-tag fusion proteins reversibly multimerized on magnetically labeled Strep-tactin.…”

“…The transferred memory T cells expanded after BMT and augmented GVL. This approach could be translated to humans by vaccinating donors months before HCT or intended post-HCT infusion and then specifically selecting the minor H antigen T cells using a immunomagnetic bead-based technique, such as Streptamer selection (137)(138)(139)(140) or the Miltenyi Biotec CliniMACs Cytokine Capture System (142,143). Alternatively, after donor vaccination with hematopoietic-restricted minor H antigens, donor T cells could be collected and depleted of naïve T cells to avoid GVHD (104), and the minor H antigen-specific T cell enriched memory T cells could be delivered with or following the stem cell graft.…”

T cell optimization for graft-versus-leukemia responses

“…We developed T cell immunotherapy employing donor Tm transduced with a lentiviral vector encoding a TCR specific for the hematopoietically restricted minor H antigen HA-1 (41) (Figure 3A), and are currently evaluating this approach in a phase I clinical trial for the treatment of post-HCT MRD or relapse (NCT03326921). Other approaches to augmenting HCT grafts for antileukemic activity include isolation of T cells targeting HA-1 and other LAAs using Streptamer technology to infuse very small numbers of unmanipulated antigen-specific T cells (44,45), or infusion of minor H antigen-specific T cell lines or clones (NCT03091933) (46, 47) (Figure 3B). Previously, Warren and colleagues infused T cell clones specific for minor H antigens into recipients of HLA-matched sibling donor HCT who developed post-HCT relapse ( 46) and observed complete remissions (CRs) in 5 of 7 patients.…”

T-cell receptor repertoire of cytomegalovirus-specific cytotoxic T-cells after allogeneic stem cell transplantation

“…Human leukocyte antigen (HLA)-specificity adds a further layer of complication to this problem. There have been recent attempts to use T-cell therapy to treat CMV and other viruses [29][30][31][32][33][34][35] . However, as TCRs are restricted by HLA-specificity, when planning to perform T-cell therapy with a third-party donor (TPD) rather than a stem cell donor, it is necessary to have a good understanding of the TCR repertoire specific to that HLA type.…”