Page 1874 - Hematology_ Basic Principles and Practice ( PDFDrive )

1666 Part X Transplantation

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T-cell numbers in GVL responses as well. Clinical attempts to clinical HCT when the GVL responses might not be entirely depen-
separate GVHD and GVL by regulating allogeneic T-cell dose have dent on CD8 T cells.
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met with limited success. For example, administration of 1 × 10 T
cells/kg after HLA-matched sibling transplantation did not mediate T-Cell Migration
GVL effects and yet was associated with a measurable incidence of It is conceivable that manipulation of these interactions to focus the
GVHD. Thus infusion of the correct numbers of donor T-cell effec- alloimmune response to lymphohematopoietic tissues would enhance
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tors is crucial for GVL responses. This has been demonstrated by GVL responses but not GVHD. For example, blockade of the CCR9
durable responses that are observed in CML and other malignancies ligand TECK or CCR5 and CCL17 may prevent the migration of
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after DLI (see later), despite the experimental evidence that host donor T cells to GI tract and skin respectively, but preserve GVL.
APCs stimulate a stronger GVL response than do donor APCs. 91,426 Pharmacologic manipulation with the immunosuppressive agent
This could be because, clinically, DLI is almost always given without FTY720 has recently provided the proof in principle for this
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immunosuppression to an individual who has not developed GVHD approach. Given the redundancy, strategies to modulate the che-
either from the chemical immunosuppression or physical removal of mokine biology for separation of GVHD and GVL will require
donor T cells from the allograft. This lack of immunosuppression greater understanding of these networks in modulating the migration
after DLI increases the likelihood of a GVH response, and DLI is not only of specific T-cell subsets but also of the other immune cells
almost always associated with clinical GVHD. The delivery of in the context of different conditioning regimens.
additional allogeneic effector cells in DLI also increases the effector:
target ratio compared with the time of initial HCT. The latter is also
clinically demonstrated by a more effective GVL response to DLI Phase 3: Effector Phase of Graft-Versus-Leukemia
against minimal residual disease (BCR-ABL positivity by PCR)
compared with the response against high leukemic burden (e.g., blast The effector arm of GVL is also characterized primarily by the
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crisis) in CML patients. Thus DLI provides the proof, in principle, antigen-specific cellular components and less by the inflammatory
for the concepts that sufficient T-cell numbers and appropriate components of alloresponse. Experimental data demonstrate that
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antigen presentation are required for both GVHD and an effective neutralization of IL-1α reduced GVHD but preserved GVL. By
GVL response. contrast, donor TNF-α secretion contributes to both GVHD and
GVL effects, and in some cases, antagonism of TNF-α reduced
T-Cell Subsets GVHD and GVL responses. 437–439 Nonetheless, antagonism of non-
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Most experimental studies have implicated donor CD8 T cells as the specific inflammatory effectors (such as either IL-1 or TNF-α)
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primary mediators of GVL, but there are no clinical data for CD8 - appears to regulate GVHD to a greater extent than GVL responses
mediated GVL responses in the absence of CD4 T cells. 56,236,426 after experimental allogeneic HCT. 439
Moreover, some clinical data suggest a role for greater CD4-mediated Several lines of experimental and clinical data demonstrate that
GVL responses without an increase in GVHD after allogeneic HCT antigen-specific donor T-cell subsets and NK cells are the key effec-
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and DLI. 423,431–434 But it is unclear whether CD4 T-cell initiated tors of GVL. The cytotoxic pathways that are operative in the NK
GVL responses occur in the absence of generation of MiHA specific and T cell–mediated antitumor responses have been well character-
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CD8 T cells. Given the critical requirement of alloantigens for most ized. Fas ligand-mediated CTL of tumor targets is used by both NK
GVL responses, the specific requirement of CD4 and/or CD8 T cells and T (mostly Th1) cells, but most murine experiments with FasL-
for GVL and GVHD is likely to be determined by the expression of deficient donor T cells suggested that FasL is a key effector molecule
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the relevant immunodominant MiHAs and/or TAAs. Therefore it is for causing GVHD but not GVL. However, one study found that
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unlikely that GVHD and GVL responses can be separated under all FasL is required for CD4 -mediated GVL against myeloid leuke-
circumstances merely by depletion of either subset of alloreactive T mia. 440,441 By contrast, even though perforin-mediated CTL pathways
cells. However, experimental data suggest it might be possible to are also used by T (mostly Th2) and NK cells, experimental data with
separate GVHD and GVL when certain donor T-cell subsets are perforin-deficient donor T cells demonstrated a loss of GVL with a
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either depleted or infused (DLI) at an appropriate interval after diminution in the severity of GVHD. In some other experimental
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transplant. But the optimal time interval, if any, after clinical HCT models, perforin was required only for GVL but not for GVHD.
is yet to be determined. Recent data showed that TRAIL-mediated CTL had no effect on
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Because of recent identification and understanding of the role of GVHD severity but was required for optimal GVL. Therefore
various T-cell subsets in mediating immune responses, depletion of strategies that increase donor T cell TRAIL expression or enhance the
specific T-cell subsets to separate GVHD and GVL remains an area susceptibility of tumors to TRAIL-mediated CTL (such as histone
of active investigation. For example, recent experimental data suggest deacetylase inhibitors) may promote a robust GVL effect without
that CD62L expressing naive T cells home to secondary lymph nodes exacerbating GVHD. 442–444 Thus significant progress has been made
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and are critical for initiating GVHD. By contrast, CD62L-negative in recent understanding of the CTL pathways used by donor T cells
effector memory T cells with enhanced reactivity to recall antigens for GVL responses, but the role and context of use of these pathways
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mediated GVL responses with minimal GVHD. An important by donor NK and NKT cells after allogeneic HCT are not known.
caveat to these data is the fact that the lack of a priori knowledge of It is likely that effector cells responsible for the GVL and GVHD
the repertoire of human memory T cells would make it difficult to effects of HCT will similarly be responsible for the GVL effect associ-
predict whether these cells might cross-react only with TAAs or with ated with DLI, although this assumption has not been formally
the recipient’s alloantigens. Using CD62L status alone as a determi- proven. The administration of select subsets of donor mononuclear
nant of GVHD potential can also have other unintended conse- cell fractions is the ideal setting in which to dissect the cellular
quences; recent studies have demonstrated that its expression is mechanisms responsible for GVL induction and strategies that delay
critical for the regulation of GVHD by Tregs (see later). Moreover, the infusion of these various cellular subsets will help define the
it is not known whether the behavior of human memory T cells paral- mechanisms and enhance the efficacy of DLI.
lels that of murine memory T cells in their migratory, functional, and
cytolytic capabilities. Although Tregs reduce antitumor immunity in
murine models and in human subjects, experimental data suggest that Immunobiology of Cytokine Release Syndrome After
administration of donor-type Tregs, either at the time of HCT or Chimeric Antigen Receptor T-Cell Therapy
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when delayed, reduced GVHD but preserved CD8 -mediated
perforin-dependent GVL responses. 435,436 Similar preservation of CRS has been typically reported with mAb infusions, such as anti-
experimental GVL was also observed by harnessing donor NKT cell CD3 (OKT3), and the CD28 superagonist etc. 445,446 In recent years
function with granulocyte colony stimulating factor analogues. 178,179 it has been increasingly appreciated as the major acute toxicity from
However, it remains unclear whether these observations are valid after infusion of CAR T cells and bispecific antibodies for leukemia. 447,448