Page 1852 - Hematology_ Basic Principles and Practice ( PDFDrive )

1648 Part X Transplantation

Further, in addition to delayed quantitative immune reconstitution lymphocytic leukemia [ClinicalTrials.gov: NCT01619761,
after DCBT, 86,134,135 there are delays in functional recovery of viral- NCT02280525] and other high-risk myeloid malignancies [Clinical-
136
specific T-cells for the first year posttransplantation. Therefore, Trials.gov: NCT01823198], and in conjunction with autologous
strategies to enhance immune recovery after CBT are critically needed. SCT for patients with multiple myeloma [ClinicalTrials.gov:
NCT01729091].
Adoptive immunotherapy using ex vivo expanded Tregs is another
ADOPTIVE IMMUNOTHERAPY area of investigation to prevent or treat GVHD. Brunstein et al
58
reported the results of a phase I clinical trial of CB derived ex vivo
Adoptive immunotherapy is an attractive strategy not only to enhance expanded Tregs from a third CB unit, which were infused in addition
antitumor responses but also to prevent GVHD and treat viral infec- to a double-unit CB grafts in 23 patients (median age 52 years) using
137
138
tions. (Table 107.5). Sun et al have reported the generation of Flu/Cy/TBI RIC regimen. The incidence of grade II–IV acute
+
139
CD4 EBV-specific cytotoxic lymphocytes from CB, and Park et al GVHD was significantly lower in the group that received Tregs
have generated CMV pp65-specific T cells from CB. The O’Reilly compared with historical controls (43% versus 61%, p = .05), but
group at MSKCC has investigated the alternative approach of using there were no differences in grade III–IV acute GVHD between the
third-party EBV-specific cytotoxic T lymphocytes (CTLs) to success- groups (17% versus 23%). The cumulative incidence of viral and
fully treat EBV-associated posttransplant lymphoma in two CBT fungal infections by day +100 in Treg treated patients (39%) was
recipients who failed tapering of immunosuppression and rituximab similar to controls (53%). Further, there were no differences in the
140
therapy. A group of investigators at the Baylor College of Medicine risks of relapse or mortality between the groups. Of note, the infused
has generated multivirus-specific T cells from CB lymphocytes to Tregs persisted in circulation for 2 weeks. The MDACC group
prevent and treat CMV, EBV, and adenovirus. 141,142 The preliminary recently demonstrated enhanced in vivo persistence of fucosylated CB
148
results of a phase I trial evaluating the efficacy of this approach in derived Tregs in a xenogenic GVHD mouse model. Moreover, the
eight patients showed it to be safe. No patient developed GVHD infusion of fucosylated Tregs was associated with improved clinical
from infusion of these cells. More strikingly, the CTLs were able to GVHD score as well as OS at day 30 compared with mice that
clear CMV reactivation within weeks of infusion in most of the received nonfucosylated Tregs (70% versus 23%, p < .0001). The
patients without the use of conventional treatment. Similarly, all clinical impact of this novel GVHD prophylaxis approach in CBT
patients with high EBV loads and almost every patient with adeno- recipients is of interest.
143
virus infection were able to clear the viruses. Furthermore, the same
group generated genetically modified CD19-chimeric receptor
antigen T-cells that not only possess an antitumor activity against FUTURE DIRECTIONS
B-cell ALL cells but are also active against EBV, CMV, and adenovi-
144
rus. This is a fascinating approach to treating viruses and disease CB is a promising alternative HSC source for use in the transplanta-
relapse with a single infused product. tion of patients with high-risk hematologic malignancies. CBT
The use of donor lymphocyte infusion to prevent or treat disease extends transplant access to patients from ethnic and racial minorities
relapse, which has been successfully used after PB or BM transplants, and those in need of urgent transplantation. Furthermore, survival
has been historically limited in the setting of CBT because of limita- after CBT has greatly improved because of larger CB inventory;
tion of cell dose. However, the advent of ex vivo expansion techniques possibly better unit quality; and improved conditioning regimens,
has now made this feasible and has created opportunities to develop grafts, and supportive care. Single-unit CBT has been shown to be
26
146
tumor specific CB CTLs. Ex vivo expanded CB NK cells have comparable with unrelated donor transplantation in children, and
demonstrated in vitro and in vivo antitumor effects. 145,147 Several early DCBT has had DFS comparable with the transplantation of adult
phase clinical trials are evaluating the safety and efficacy of prophy- donor HSC. 22,26,102,106–109 CBT should be considered as an immediate
lactic CB NK infusion in the setting of CBT for patients with chronic alternative in patients with high-risk hematologic malignancies who
are candidates for allogeneic HSC transplantation but lack a suitable
related donor.
Cellular Therapeutic Strategies to Mitigate Viral
TABLE Infections, Relapse, and Graft-Versus-Host Disease SUGGESTED READINGS
107.5
After Cord Blood Transplantation
Avery S, Shi W, Lubin M, et al: Influence of infused cell dose and HLA-match
Target Strategy Results on engraftment after double-unit cord blood allografts. Blood 117:3277,
Antiviral Multivirus specific CTLs Lysed antigen-pulsed 2011.
(CMV, EBV, and virus infected Ballen KK, Gluckman E, Broxmeyer HE: Umbilical cord blood transplanta-
adenovirus) 142 targets tion: the first 25 years and beyond. Blood 122(4):491–498, 2013.
Third-party EBV-specific 2 EBV PTLD patients Barker JN, Byam CE, Kernan NA, et al: Availability of cord blood extends
CTLs 140 achieved durable CR allogeneic hematopoietic stem cell transplant access to racial and ethnic
Antitumor IL-2 expansion of CB NK Cytolytic effect in vitro minorities. Biol Blood Marrow Transplant 16:1541, 2010.
cells 145 and in vivo against Barker JN, Byam C, Scaradavou A: How I treat: the selection and acquisition
leukemia cells of unrelated cord blood grafts. Blood 117:2332, 2011.
Barker JN, Doubrovina E, Sauter C, et al: Successful treatment of EBV-
Antitumor and CB-derived CTLs against In vitro antileukemic associated posttransplantation lymphoma after cord blood transplantation
antiviral CD19 and viruses (CMV, and antiviral effect using third-party EBV-specific cytotoxic T lymphocytes. Blood 116:5045,
EBV, adenovirus) 144 2010.
GVHD Infusion of ex vivo 23 patients accrued; Barker JN, Scaradavou A, Stevens CE: Combined effect of total nucleated
prevention expanded CB Treg 58 aGVHD incidence cell dose and HLA match on transplantation outcome in 1061 cord blood
decreased without recipients with hematologic malignancies. Blood 115:1843, 2010.
increase in relapse Barker JN, Weisdorf DJ, DeFor TE, et al: Transplantation of two partially
aGVHD, Acute graft-versus-host disease; CB, cord blood; CMV, HLA-matched umbilical cord blood units to enhance engraftment in
cytomegalovirus; CR, complete remission; CTL, cytotoxic T-cell lymphocyte; adults with hematologic malignancy. Blood 105:1343, 2005.
EBV, Epstein-Barr virus; GVHD, graft-versus-host disease; IL-2, interleukin-2; Bautista G, Cabrera JR, Regidor C, et al: Cord blood transplants supported
NK, natural killer; PTLD, posttransplant lymphoproliferative disease; Treg, by co-infusion of mobilized hematopoietic stem cells from a third-party
regulatory T cell.
donor. Bone Marrow Transplant 43:365, 2009.