Page 1873 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 108 Graft-Versus-Host Disease and Graft-Versus-Leukemia Responses 1665

threatening, include adult respiratory distress syndrome, fluid reten- responses. Data also demonstrated that given sufficient time and a
tion, neurologic toxicity, cardiac, renal and/or hepatic failure, and low tumor burden, cross-presentation of TAAs and/or alloantigens by
disseminated intravascular coagulation. Some of these, particularly professional donor APCs can occur and may promote or sustain GVL
lung and cardiac dysfunction, can be rapid onset and severe, but are responses by maintaining or expanding alloreactive T cells after initial
typically reversible. Neurologic symptoms occurring in the context priming on host APCs. 91,426 This concept is consistent with clinical
of CRS are varied and may occur coincident with other symptoms GVL responses in CML in which the final stage of a GVL response
of CRS or may arise when the other symptoms of CRS are resolv- to CML may be the result of donor T cells responding not directly
414
ing. Magnetic resonance imaging often reveals no abnormalities. to the small number of CML stem cells or progenitors (which would
IL-6 appears to be the most relevant cytokine in CRS, although likely be undifferentiated and therefore poor APCs) but to tumor antigens
not the only cytokine involved. CRS may also be associated with cross-presented on professional donor APCs. Emerging data suggest
findings of macrophage activation syndrome/hemophagocytic lym- that enhancing such cross-presentation is sufficient to elicit effective
414
phohistiocytosis. In addition, rapid turnover of underlying GVL responses against acute or advanced leukemia. These data,
leukemia/tumor might lead to tumor lysis syndrome that may coin- however, suggest that GVL responses generated after low-intensity
cide or contribute to the severity of CRS. Appropriate supportive conditioning may not be as robust as those after full intensity HCT
care, steroids, and anti–IL-6, tociluzimab remain the current mainstay and highlight the need for a clearer understanding of the effects of
for management of CRS. Furthermore, whether CRS severity is the cytokine storm and lymphopenia generated danger signals on the
dependent on the type of T cell being engineered (central versus activation of APCs in mediating GVL.
effector versus naive versus bulk),or the type of vector and/or antigen Recent data showed that APC subsets could potentially be
being targeted remains unknown. modulated to enhance the GVL effect without aggravating GVHD.
+
Host-derived CD8α DCs were shown to be required for the induc-
tion of optimal GVT responses when Batf3 deficient mice were
Immunobiology of Graft-Versus-Leukemia Responses used as recipients in experimental allo-HCT. TLR3 stimulation
109
+
via poly I:C in host CD8α DCs, enhanced GVL responses without
Given the tight association of clinical GVHD and GVL, as well as exacerbating GVHD. However, cellular processes of regulating GVL
the common biologic principles governing these responses after responses in host APCs still remain unclear. The molecular mecha-
allogeneic HCT, it is important to discuss the similarities and distinc- nisms underpinning the role of host APC subsets in GVL are just
tions between them in the context of the three cellular phases of now being deciphered. It has been observed that absence of Ikaros
GVHD. 415 in host hematopoietic APCs exacerbates GVHD, but without con-
427
comitantly enhancing GVT responses in multiple models. The
role of donor-derived DCs in mediating GVL is also being explored.
Phase 1: Activation of Antigen-Presenting Cells Initial reports regarding this association demonstrated that donor
APCs are not required for GVL responses, but play an indispens-
The concept that tumor eradication after allogeneic HCT might not able role in GVHD in a MHC-matched, MiHA-mismatched BMT
require toxic chemoradiotherapy and could be achieved primarily by model. In order to present host TSAs, via donor APCs, to donor
+
the immunotherapeutic effect from the GVL responses has led to the CD8 T cells, donor APCs must have the capacity for cross-
clinical development of nonmyeloablative HCT for hematologic and presentation as they do not express both endogenous alloantigens
416
428
nonhematologic malignancies. Phase 1 is characterized by the and TSAs. Furthermore, additional studies are needed to deter-
development of the cytokine storm-generated danger signals from the mine which specific subsets of donor APCs play a critical role in
−
415
conditioning regimen and the subsequent activation of APCs. enhancing GVT responses. Reports suggest that donor CD11b
Experimental data suggested that the reduction in conditioning would APCs within the BM grafts consist mostly of pDC progenitors
attenuate the cytokine storm, lead to the development of mixed (pre-pDCs) and enhance the GVL activity of donor T cells by
donor-host chimerism, and confine the GVH response primarily to promoting differentiation into Th1/type 1 CTLs. Pre-pDCs also
secondary lymphoid organs, thus cause less severe GVHD without regulate GVH and GVT responses altering the balance between
impairing GVL responses. 417–419 However, nonmyeloablative HCT donor Tregs and inflammatory T cells by inducing indoleamine
has delayed the kinetics but did not reduce the overall incidence of 2,3-dioxygenase synthesis. 428
GVHD and a significant number of patients either failed to respond
21
or relapsed. Furthermore, recent murine and human studies have
suggested that homeostatic expansion of T cells in a lymphopenic Phase 2: Donor T-Cell Activation
environment induced by conditioning (as opposed to mere immuno-
suppression) improves the antitumor efficacy of adoptively transferred The core of GVL responses, as with GVHD, is also dependent on
syngeneic or autologous T cells by increasing the availability of space, the activation of appropriate numbers of T cells. The “second” signals
enhancing the memory responses, and reducing the competition for from professional APCs (or certain tumor cells that function as effec-
230
homeostatic cytokines (such as IL-7 and IL-15) for transferred T cells tive APCs) are critical for generating an effective GVL response.
while eliminating regulatory T cells. 420–422 Thus low-intensity HCT Several of the costimulatory pathways that modulate GVHD have
clearly demonstrates the principle of the GVL effect, but the roles of also been evaluated in mediating GVL responses. Blockade of CD28
the cytokine storm and homeostatic expansion of allogeneic T cells in costimulation preserved GVL responses but reduced GVHD in
429
shaping the intensity of GVL responses are not known. murine studies. However, when the tumor cells also expressed B7
425
Host and donor APCs are critical for the induction and severity molecules, such blockade reduced the GVL responses. Ex vivo
7
415
of GVHD. Activation of APCs is the key step in phase 1 of GVHD. blockade of CD40-CD40L interaction has been shown to reduce
Significant progress has been made in understanding the role of APCs GVHD by generating Tregs but still preserve GVL. By contrast,
140
in GVL. Recent experimental evidence has demonstrated a crucial blockade of the 4-1BB pathway reduced both GVHD and GVL.
role for professional host APCs in the induction of GVL responses The other costimulatory molecules (OX40 and ICOS) and the
mediated by donor T cells, even when the tumor cells showed some inhibitory molecules (CTLA-4 and PD-1) also modulate antitumor
features of APCs. 91,423 Tumors that merely express costimulatory responses. 141,142 A better understanding of the context (i.e., low
molecules may still be unable to stimulate an effective immune intensity or DLI) and the hierarchy of timing, duration, and extent
response because of their various “immunoediting” processes that of costimulatory requirements of donor T-cell subsets might allow for
424
cause ineffective antigen presentation. However, when the tumor balancing the intensity of GVL and GVHD responses. Clinical and
cell itself functions as a professional APC, as with CML, it can gener- experimental evidence suggest that donor T-cell numbers correlate
ate an effective GVL response. 425,426 By contrast, cancers such as acute with the severity of GVHD and GVL responses. TCD grafts had
leukemias that seldom differentiate into APCs generate poor GVL reduced GVHD but increased disease relapse, suggesting a role for