Page 1872 - Hematology_ Basic Principles and Practice ( PDFDrive )

1664 Part X Transplantation

Clinical Features of Graft-Versus-Leukemia Although these antigens are specific, most T-cell responses to these
antigens are limited because of the poor immunogenicity of these
Clinical evidence that the donor graft mediates an important anti- proteins, expression on normal cells, defects in the processing
leukemic effect comes from higher relapse rates for recipients of or presentation of tumor antigens, or production of factors that
syngeneic stem cells than for recipients of HLA-matched sibling disable T-cell responses. Thus clinical attempts to obtain high
380
grafts. These findings have also been confirmed in a multicenter specificity of T-cell responses have been offset with difficulties in
analysis of HCT recipients with acute myelogenous leukemia (AML) obtaining enough sensitivity and vice versa. Furthermore, given the
in first remission and subsequent retrospective analyses by the Inter- current concepts of stem cell origins of leukemia and cancers,
national Bone Marrow Transplant Registry (IBMTR). 381–383 The identification of the immunogenic proteins that are specifically
second IBMTR analysis also showed that the magnitude of this GVL expressed in the malignant stem cells and harnessing T-cell responses
effect is greater for patients with CML and AML and not statistically to those antigens will be needed for the optimal GVL effect to cure
significant for patients with acute lymphoblastic leukemia (ALL) in malignancy. 407,408
first remission. 384,385 In contrast to the TSAs or tumor-associated antigens (TAAs)
Several case reports of patients with relapse of leukemia after allo- discussed earlier, alloantigens are not subjected to tolerance mecha-
geneic HCT noted remissions of the malignancy either after abrupt nisms. Vaccination strategies with autologous T cells using TAAs or
409
withdrawal of immunosuppression or during a flare of acute TSAs have yielded disappointing clinical antitumor responses. By
GVHD. 386–389 Patients who develop GVHD after allogeneic HCT contrast, allogeneic HCT has met with remarkable GVL responses
experience relapse less frequently than similar patients who do not perhaps owing to recognition of minor alloantigens in addition to
410
develop clinical disease. GVHD is protective against relapse both for the TAAs. This concept has been demonstrated by recent murine
HCT recipients with advanced leukemia 390–392 and for patients who studies, which showed that alloantigen on the tumor cells is required
393
receive transplants in earlier stages of malignancy. Additional analy- for GVL responses and that the principal targets of GVL are the
ses also suggest that the magnitude of the GVL effect appears to be immunodominant allogeneic MiHAs rather than the TAAs. 60,91 Thus
disease and stage-specific. 392–394 Initial reports suggested that chronic T cells specific for MiHA antigens could provide for a potent GVL
392
GVHD was most protective against relapse, but other analyses effect. Significant progress has been made in the identification of
393
demonstrate that acute GVHD is also protective. Based on these MiHAs that are specifically expressed in the host hematopoietic
reports, newer trials of immunotherapy are designed to include cessa- tissues and therefore might allow for a GVL response without causing
53
tion of immunosuppressive therapy (without taper) to induce a GVL GVHD. Together, these results suggest that in addition to tumor-
reaction for patients whose malignancy has relapsed after HCT. Fur- specific proteins, expression of alloantigens and cognate interactions
thermore, Childs and colleagues demonstrated that the graft-versus- between donor T cells and the tumor tissues are required for the
tumor (GVT) effect also plays an important role in inducing remissions effective induction of the majority of GVL responses. However, T
from a nonhematologic malignancy, renal cell carcinoma. 395 cells specific for some MiHAs are also responsible for GVHD, and a
Another line of clinical evidence regarding the GVL effect of means of consistently separating the beneficial GVL effect from
allogeneic HCT and its tight linkage to GVHD comes from the GVHD has not yet been clinically achieved.
studies using T-cell depletion of the donor graft. Donor T cells
included in the stem cell graft are critical for acute GVHD, and T-cell
depletion by various strategies is one of the most successful means of Killer-Cell Immunoglobulin-Like
reducing the incidence and severity of GVHD after allogeneic Receptor Polymorphisms
HCT. 26,396–401 Unfortunately, although T-cell depletion results in less
treatment-related morbidity and mortality, improved overall survival The two competing models described earlier, the “mismatched
rates have not been reliably demonstrated. This failure is caused in ligand” and the “missing ligand” models for HLA-KIR allorecogni-
large part by a reciprocal increase in the subsequent relapse rate after tion, have been supported by clinical observations of GVL responses
T-cell depletion, as well as to graft failure and other complica- in different patient and transplant populations. 65,66 The former model
tions. 394,402,403 T-cell depletion increases relapse rates particularly in has been shown to separate GVL and GVHD responses in the context
CML. 393,394,404 This observation provides further strong, albeit indi- of TCD haploidentical HCT for AML. 46,67 Even though this model
rect, evidence that allogeneic donor T cells are important mediators is supported by elegant laboratory studies, it was found to be invalid
not only of GVHD, but also of the GVL properties of the allogeneic for ALL and also for AML after unrelated donor HCT with immu-
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stem cell graft. Finally, the most compelling evidence of donor T cells nosuppression. Recent retrospective clinical data suggest that
in mediating GVL comes from the observations made from donor GVHD and GVL can be separated by the “missing ligand” model in
lymphocyte infusions (discussed later). The induction of GVL is a CML/AML and myelodysplastic syndrome patients after TCD HLA
complex process. identical sibling HCT. 46,66,69 Further validation of either models by
clinical prospective studies and a better understanding of the balance
between the inhibitory and activating receptor-ligand interaction of
Genetic Basis the NK cells are needed to adequately exploit the interface between
HLA-KIR genetics to separate GVHD from GVL (see Chapter
The immunotherapeutic effect that occurs in the allo-BMT setting 102). 64,411
is primarily mediated by allogeneic donor T or NK cells directed
against the alloantigens shared by the recipient tumor and target
tissues and/or tumor-specific antigens (TSAs) that have the advan- Chimeric Antigen Receptor T Cells and Cytokine
tage of not being subjected to tolerance mechanisms by the host Release Syndrome
tumor. 56,405,406 Understanding of the exquisite specificity of T-cell
responses led to attempts to identify specific antigens that are Infusion of unselected CD19 specific CAR T cells is associated with
responsible for the GVL effect. Much of the focus has been on the a massive cytokine storm that causes severe toxicity, known as cyto-
identification of (1) certain oncogenic viral proteins (because these kine release syndrome (CRS). CRS is a nonantigen-specific toxicity
are absent in normal cells but expressed by transformed tumor cells that occurs as a result of high-level immune activation. 412,413 The
[certain Epstein-Barr virus peptides such as Epstein-Barr virus magnitude of immune activation typically required to mediate clini-
nuclear antigen-1, latent membrane protein {LMP}-1, LMP, LCL]), cal benefit using modern immunotherapies exceeds the levels of
(2) antigens that are expressed in a tissue-specific fashion (melanoma immune activation that occur in more natural settings. The symp-
specific proteins), and (3) proteins that are overexpressed in tumors tomatology and severity associated with CRS varies greatly and many
(WT1, proteinase 3, survivin, telomerase reverse transcriptase, features of CRS mimic infection. Thus fever is a hallmark, at times
CYPB1, and human epidermal growth factor receptor 2/neu). 53,56 temperatures exceeding 40.0°C. Other features, some potentially life