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358 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 359

allograft before transplantation is associated with a substantial increase on preclinical models, the common effector cells that could potentially
in the occurrence of graft rejection. 125,126 With modern conditioning mediate a clinical GVT effect include (1) CD8+ cytotoxic T lympho-
regimens, rates of allograft rejection are low (typically <5 percent) for cytes that recognize tumor-associated antigens in context of class I
patients who have received previous chemotherapy, which weakens major histocompatibility complex (MHC) antigens; (2) CD4+ T cells
their immune response to the allograft. In contrast, graft rejection in that recognize tumor-associated antigens in context of class II MHC
seen more often in patients who have not received cytotoxic chemo- antigens and mediate their effects via Th1 cytokines such as interferon
therapy before allogeneic HCT (for instance, some patients with mye- (IFN)-γ and IL-2, upregulating expression of class I MHC antigens and
loproliferative neoplasms) or those with nonmalignant diseases such as promoting expansion and activation of CD8+ cytotoxic T lymphocytes;
aplastic anemia, thalassemia, or sickle cell disease, who are often highly and (3) NK cells that recognize stress ligands and cells lacking MHC
sensitized against donor antigens by virtue of being heavily transfused expression. 135–141 The impact of NK cells seems especially pronounced in
before allogeneic HCT. HLA-haploidentical or mismatched allotransplantation. 104,142
A major question continues to be whether the subset of T cells that
Graft-Versus-Tumor Effects induce GVHD is the same population of T cells responsible for the GVT
The dominant mechanism of cancer eradication following allogeneic effect. One of the central aims of research in allogeneic HCT is to sep-
HCT is the immunologic recognition and destruction of residual host arate the beneficial GVT effects from deleterious GVHD. Clinical evi-
tumor cells by donor-derived immune cells. This phenomenon, termed dence suggests that, in principle, the two should be separable, as some
the GVT effect, has been conclusively demonstrated and represents one patients experience an apparent GVT effect in the absence of apparent
143
of the most significant biologic findings of the past half-century, with GVHD. Although numerous approaches have succeeded in separat-
implications well beyond the transplantation setting. The existence of ing GVT effects from GVHD in preclinical and animal models, none
GVT effects is supported by the following lines of evidence: of these approaches have yet been translated successfully to widespread
clinical use. One approach supported by preclinical models involves the
• Tumor relapse is lower after allogeneic than after syngeneic HCT: The use of T , and recent studies in the HLA-haploidentical setting are
144
reg
appreciation of alloreactive GVT effects stemmed from the observa- supportive of this concept. 145,146
tion that recipients of genotypically identical (syngeneic) grafts had
significantly higher rates of disease relapse than did patients who
received grafts from HLA-identical siblings. 127,128 TRANSPLANT PREPARATIVE REGIMENS
• Tumor relapse is higher in recipients of T-cell–depleted grafts: Further
support for the allogeneic GVT effect came from studies of T-cell The transplant preparative regimens used in HCT must accomplish
depletion of the graft. T-cell depletion was performed in the expec- two goals. Because the majority of autologous and allogeneic HCT are
129
tation that it would reduce the risk of GVHD. However, the later performed in individuals with cancer, these regimens were designed,
observation that these patients had a much higher risk of disease at least initially, to maximize tumor cytoreduction and disease eradi-
recurrence as well as graft rejection was unanticipated. These results cation. In the case of allogeneic HCT, the regimen must be sufficiently
linked GVHD with GVT effects, and supported the concept that immunosuppressive to overcome host rejection of the graft. In autol-
patients who developed some degree of alloreactivity, as manifested ogous HCT, where efficacy depends on exploiting the dose–response
by clinically apparent GVHD, had a reduced risk of disease relapse. curve, high-dose conditioning regimens are universally used. In con-
• Donor lymphocyte infusions can induce remission: Perhaps the most trast, in allogeneic HCT much or all of the clinical benefit derives from
definitive evidence for the existence of GVT effects came from the donor alloimmunity, enabling the use of RIC designed to facilitate
application of donor lymphocyte infusions (DLIs). In the early donor engraftment with minimal toxicity.
1990s, Kolb and others demonstrated that patients with relapsed
malignancies after allogeneic HCT could, in some cases, be returned TOTAL-BODY IRRADIATION
to complete remission by the simple infusion of donor-derived lym- TBI has been a primary component of many autologous and alloge-
phocytes. 130–132 With increasing experience, it became clear that some neic HCT preparative regimens since the inception of the field. TBI has
diseases (such as chronic myelogenous leukemia [CML]) respond excellent activity against a variety of hematolymphoid malignancies, has
very well to DLI whereas others (for instance, acute lymphoblastic pronounced immunosuppressive properties, and is able to treat sanc-
leukemia [ALL]) are much less responsive. Long-term followup of tuary sites like the testicles and the central nervous system. Aside from
patients successfully treated with DLIs revealed that responders had one very early study of high-dose TBI alone, most preparative regimens
remarkably durable remissions and excellent outcomes. These combine TBI with cytotoxic agents such as CY. Dose-finding studies
132
observations definitively established the GVT effect as a biologic suggest that higher TBI doses are associated with a lower risk of relapse
entity capable of controlling an otherwise lethal condition such as with dose escalation as high as 15.75 Gy, but doses above 12 Gy are asso-
leukemia. ciated with higher risks of GVHD and TRM, which offset the reduced
risk of relapse. Currently, most high-dose TBI-based conditioning
147
Targets and Effector Cells in Graft-Versus-Tumor Reactions regimens use a dose between 12 and 13.2 Gy. Long-term concerns with
The biology of the GVT effect remains incompletely understood. A TBI-based regimens include the development of cataracts and hypothy-
number of immunologic targets recognized by donor immune effec- roidism, impairment of growth and development in children, and sec-
tor cells have been proposed, including alloantigens (such as major or ondary malignancies. 148–150
minor histocompatibility antigens depending upon donor–recipient Hyperfractionated TBI, in which relatively small dose fractions are
genetic differences), lineage-specific antigens, and malignancy-specific given two to three times a day over a few days, minimizes leukemia
antigens such as products of chromosomal translocations. Donor T cells regrowth and reduces lung and gastrointestinal toxicity, allowing higher
clearly play a key role in GVT, and there is emerging evidence that NK TBI doses to be administered safely. Several clinical studies confirm
cells are also responsible for tumor cell control, especially in the set- decreased overall lung toxicity with fractionation. 151,152 Excellent results
ting of T-cell-depleted HLA-haploidentical HCT. Humoral immunity are also reported with the combination of fractionated TBI and VP-16
133
has also been implicated as playing a role in the GVT effect. Based (etoposide), particularly promising results in patients with ALL. 153,154
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