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Next Article 
Blood, Vol. 92 No. 5 (September 1), 1998:
pp. 1471-1490
REVIEW ARTICLE
Immune Reconstitution and Immunotherapy After Autologous Hematopoietic
Stem Cell Transplantation
By
Thierry Guillaume,
Daniel B. Rubinstein, and
Michel Symann
From the Laboratory of Experimental Oncology and Hematology,
University of Louvain, Brussels, Belgium; and the Section of
Hematology/Oncology, Boston University School of Medicine, Boston, MA.
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INTRODUCTION |
APPROXIMATELY 10,000 autologous
hematopoietic stem cell (HSC) transplants are performed
worldwide each year for malignant diseases.1 Results of
randomized trials in recent years suggest that high-dose chemotherapy
followed by infusion of autologous HSCs can offer prolonged
disease-free survival in hematologic malignancies including
non-Hodgkin's lymphoma in relapse,2 acute myelogenous
leukemia,3 and multiple myeloma.4
Similarly encouraging results have been seen in the
treatment of solid tumors.5,6
After transplantation, reconstitution of bone marrow (BM) consists of
two distinct phenomena, numerical recovery of BM cellular elements on
the one hand and functional recovery of cellular interactions on the
other.
Although reappearance of neutrophils and platelets is often considered
the endpoint of hematologic recovery after intensive chemotherapy and
stem cell transplantation, this ignores the second arm of BM recovery,
that of immunological reconstitution. In fact, functional recovery of
lymphoid and immune effector cells occurs very gradually, and
reconstitution of normal humoral and cellular immunity may take a year
or more.
Immune reconstitution involves several components of the immune
response. These include (1) reappearance of functional B cells, (2)
thymic and extra-thymic T-cell development, (3) reconstitution of
effector cells including cytotoxic T cells and natural killer (NK)
cells, and (4) efficient antigen presentation to reconstitute the
pretransplantation immune repertoire. This restoration of immune
function is not merely experimental. It may have direct clinical
implications: Immediately after the administration of intensive
cytotoxic drugs, minimal tumor burden is presumed to be present,
providing potentially ideal circumstances to eliminate residual disease
altogether by immunotherapeutic means. In this review, several
strategies that could lead to enhancement of cellular immune function
to take particular advantage of posttransplantation minimal residual
disease will be discussed. In addition, the potential to accelerate
immune reconstitution and the effect that might have in the therapy of
malignant disease will be considered.
Although there are similarities in immune reconstitution after allo-BM
transplantation (BMT)7,8 and autologous HSCs, allo-BMT
involves graft-versus-host disease (GVHD) and the use of
immunosuppressive therapy to control it, both of which interfere in the
early developmental stages of immune reconstitution. Autologous HSC
transplantation that entails neither GVHD nor immunosuppressive drugs
presents more direct insight into the factors involved in immune
reconstitution after grafting.
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B CELLS |
B-Cell Regeneration and Ig VH Gene Expression
Normal B-cell differentiation is accompanied by a set of preprogrammed
steps of Ig gene rearrangement and by successive acquisition and loss
of differentiation level-specific surface molecules.9 In
both its Ig gene rearrangements and in phenotypic expression, B-cell
recovery after transplantation appears to recapitulate normal B-cell
ontogeny.10 The relative and absolute numbers of
circulating cells expressing CD19 and CD20, two markers of mature B
cells, are decreased during the first 3 months following transplantation.11,12 Thereafter, the numbers of such cells increase to a plateau at 6 to 9 months. CD23 (the low-affinity receptor
for the Fc portion of IgE) and CD38 (the ecto-enzyme of nicotinamide
(NAD) glycohydrolase that acts as an adhesion/homing receptor and is involved in intracellular calcium homeostasis) are
strongly expressed on the circulating B cells of neonates and B cells
from cord blood, whereas in adults, CD23+ CD38+
B cells are a minor subset. During the first year postengraftment, the
majority of circulating B cells carry the CD23+,
CD38+ undifferentiated phenotype.12
Furthermore, as in neonates, the percentage of mIgM+ and
mIgD+ B cells is high in autologous transplant recipients.
Taken together, this suggests that the majority of posttransplantation
circulating B cells are poorly differentiated.
Consistent with the notion that autologous BMT (ABMT)
ontology follows developmental ontogeny, ABMT recipients have a
significant increase in the B-cell precursor marker CD10 in the BM as
early as 1 month after grafting which persists for at least 1 year and precedes repopulation of the peripheral blood mature B cells by 1 to 2 months.13 CD10 (also known as CALLA) is a highly conserved neural endopeptidase transiently expressed on early B progenitors before the appearance of heavy µ chain in the cytoplasm and is re-expressed after activation by antigen. Nevertheless, the
phenotype of circulating B cells posttransplantation differs from BM B
cells because CD10 is expressed on only a negligible fraction of
peripheral B cells.10
In recipients of CD19+ cell-depleted BM, the
immunophenotypic features of the resulting BM B-cell precursor
populations are similar to those of fetal liver or fetal BM-derived
B-cell precursors. As in normal fetal development, the expression of
CD10 and CD19 antigens in posttransplantation BM appears to precede
expression of other antigens characteristic of normal B-cell
ontogeny.14 As might be expected, in patients who received
ABMT for B-cell malignancies purged with anti-B-cell monoclonal
antibodies (MoAbs), B-cell recovery is further delayed; at 3 months,
only 50% of engrafted patients attain normal percentages of
CD20+ B cells.15
Ig gene rearrangements after ABMT, like phenotypic markers, suggest
retracing of B-cell ontogeny. Posttransplant Ig gene rearrangements are
consistent with wide B-cell polyclonality rather than a narrow oligo or
restricted clonality.13 However, Ig VH gene
family usage does differ from the normal adult distribution during the first 3 months after both allo-BMT and ABMT.16 Following
allo-BMT, the VH repertoire resembles that expressed by the
early normal fetal BM with a relative increase in the VH2,
VH4, VH5, and VH6 gene families.
After ABMT, the same general pattern is observed with a decreased
expression of the largest family VH3, offset by a relative
increase of the much smaller VH4 and VH5
families.16 This preferential expression of these small
VH gene families mimics the pattern seen during normal
B-cell ontogeny.17
By 90 days after BMT, VH3 and VH4 gene usage is
indistinguishable from that of normal adults, suggesting that the Ig
repertoire may have normalized by then.16 However, even
after attaining adult level of VH gene family usage, the
rearranged VH genes exhibit much less somatic mutations in
BMT recipients than seen in rearrangements of normal
adults.18 This may point to a block in antigen-selected affinity maturation of antibody and/or a maturation arrest in B-cell differentiation after Ig V gene rearrangement and may have implications in failures to attain high-specific, high-affinity antibodies in posttransplant vaccinations.
Origin of Posttransplant B Cells
After ABMT or autologous peripheral blood stem cell transplantation
(ABSCT), B cells regenerate from several sources: (1) B cells of the
transplant recipient which survived the pretransplantation chemotherapeutic intensification treatment; such cells may be seeded in
the BM, lymph nodes, or spleen; (2) B cells present in the graft; (3)
hematopoietic stem cell progenitors in the transplant that
differentiate after grafting in the recipient; and (4) residual recipient stem cells. Because allogeneically transplanted cells can be
readily traced, allo-BMT provides direct insight into the origin of B
cells in the transplant recipient. Transfer of humoral immunity has
been documented from donor to recipient, including immunity to tetanus,
varicella, diphteria, influenza virus, cytomegalovirus, hepatitis B
virus, and human immunodeficiency virus,19-23 suggesting that functional B cells are passively transferred by transplantation. The corollary of adoptive transfer of immunity is that active immunization of BM donors might serve to reduce the incidence of
infection in recipients of allo-BMT and that immunization before intensification might likewise be considered in ABMT and ABSCT recipients. Immunization of ABMT patients before BM harvests with either protein vaccines such as tetanus toxoid or conjugated
carbohydrate vaccines such as haemophilus influenzae can enhance early
recovery of specific antibody.24
Transfer of humoral immunity suggests that differentiated
antigen-selected B cells in the graft are a significant source of posttransplantation B cells. The ontogeny data presented in the preceding section indicated that stem cells differentiating into Ig
expressing B cells represent a significant part of the
posttransplantation B-cell population. In addition, findings from
B-cell-purged transplants indicate that both recipient and donor stem
cells contribute to the posttransplantation B-cell
population.15
B-Cell Function
Deficiencies in humoral responsiveness in HSC recipients is attributed
to both decreased T-cell help and to intrinsic B-cell defects.25-27 Serum Ig levels remain low
during the first 3 months after ABMT during the same period in which
the numbers of circulating B cells is reduced11,28 and
B-cell proliferative response to the T-cell-independent antigen
Staphylococcus aureus Cowan strain I (SAC)
blunted.12 While IgM production in response to pokeweed mitogen and SAC normalize at 3 months, IgG production is suppressed for
12 to 24 months in most patients.12 This delay in Ig
production parallels the pattern seen in B-cell ontogeny, and may
reflect the failure of posttransplant B cells to receive or respond to T-cell factors involved in isotype switching.
In patients receiving B-cell-purged BM for B-cell hematologic
malignancies, responsiveness to the normally proliferative effects of
cross-linking anti-Ig antibody is significantly lower than that of
normal controls at 3 and 6 months.15 As in engraftment of
unpurged marrow, recovery of in vivo B-cell function demonstrates a
selective defect with normal serum levels of IgM returning at 6 months,
IgG at 12 months, and IgA after 2 years, reflecting a recapitulation of
normal B-cell development.15
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T CELLS |
BM-derived hematopoietic stem cells in the normal process of
differentiation home to the thymus, the major site of T-cell differentiation. However, the thymus is not the only site of T-cell development. T-cell differentiation also occurs through extrathymic pathways in the gut mucosa, in the liver,29 and, at least
in the case of murine T-cell development, in the BM as
well.30 The contribution of these extrathymic sites may
play a role in posttransplant immune reconstitution.
Reconstitution of T-Cell Subsets
Surface markers have proven to be critically useful in characterizing T
lymphocytes and their functional subsets. Nevertheless, however useful
in our understanding of lymphoid ontogeny, phenotypic subtyping
identified to date doubtlessly represents only a part of the overall
T-cell functional repertoire. Evidence for the as-yet limited nature of
our T-cell characterization is the fact that phenotypic shifts in
posttransplantation T cells do not necessary result in immune
dysfunction. This must be borne in mind when discussing T-cell
phenotypes and their correlation to immune reconstitution after stem
cell transplantation.
T-Cell Subsets After ABMT
After ABMT, the relative number of CD3+ cells is
significantly decreased compared with those of normal controls during
the first month postgrafting, returning to normal levels within 3 months.31 In addition, a decrease in the relative and
absolute numbers of CD4+ cells in the peripheral blood is
commonly seen and can persist for a year or more.31-33 In
contrast, the relative and absolute number of CD8+ cells
reconstitutes fairly rapidly resulting in an inverted CD4/CD8 ratio in
the months following autologous transplantation.31-33
The observation of an inverse correlation between the size of the
thymus and the level of the CD4+ cells in the peripheral
blood after high-dose chemotherapy supports the notion that helper
T-cell development depends on residual thymic function.34
In addition, thymic epithelium has been shown to play a more important
role in helper T-cell development than in differentiation of the
suppressor T cell.35 The inverted CD4/CD8 ratio seen after
transplantation is consistent with such a schema. Thymic involution
starts as early as 1 year of age, continues at a rate of approximately
3% per year until middle age and thereafter decreases to less than 1%
per year.36 The fact that CD8+ T-cell
reconstitution appears not to be significantly impaired by age-related
involution of the thymus suggests that thymic-independent pathways
primarily contribute to its regeneration.37 A predominance of CD28 and CD57+ cells among the
CD8+ subset has been observed following chemotherapy that
may persist up to 9 months.37 The absence of CD28
expression is similar to that seen in extrathymically derived
CD8+ cells.38
Functional subsets of CD4+ and CD8+ T-cell
populations have been studied after ABMT and can be distinguished on
the basis of the expression of CD45 isoforms (CD45RA, CD45RO).
CD45RO+ T cells respond in vitro to recall antigens and
correspond to "memory cells" while CD45RA+ T cells
correspond to naïve cells recently issued from the thymus. During the first 3 months following ABMT, the number of
CD45RA+ lymphocytes is decreased, but returns to normal
levels by 1 year posttransplantation.31,39 The
CD4+CD45RA+ subset is profoundly reduced and
may take up to 2 years to recover. In contrast, the
CD8+CD45RA+ population normalizes within the
first month after ABMT.
T-Cell Subsets After ABSCT
Because peripheral blood stem cells (PBSC) contain a
larger proportion of more differentiated progenitor cells as well as terminally differentiated effector cells than BM, one might suppose that the kinetics of T-cell recovery may be accelerated following ABSCT
as compared with ABMT. The fraction of cells designated PBSC in fact
does contain large numbers of T cells. CD3+ cells may
represent more than 20% of peripheral cells collected after
granulocyte colony-stimulating factor (G-CSF) mobilization yielding
substantially more T cells (up to 1 log greater) than found in
BM.40,41
Immediately after transplantation of mobilized PBSC, total
CD3+ cell levels return to normal, CD4+ cell
levels remain below normal, and the number of CD8+ cells
increases resulting (depending on the study) in either severely42,43 or slightly44-47 reduced CD4/CD8
ratios. Overall, when CD4/CD8 and CD45RA/CD45RO ratios are examined,
recovery of T-cell subsets appears more promptly after ABSCT than after
ABMT.43,47,48 As noted however, here as in all similar
analyses, precise correlation of T-subset distribution to overall
T-cell function is uncertain.
T-Cell Repertoire (TCR)
Shifts in T-cell subsets as defined by TCR V gene expression have been
described early after both allo-BMT and ABMT.49-53 It is
not clear whether particular T-cell subsets as defined by V gene usage
are derived from T-cell precursors (either donor or recipient) or from
expansion of donor-derived mature T cells. A significant proportion of
patients shows increased usage of TCR  / during the early period
post-BMT. Within the TCR / subpopulation, there is a preferential
expression of the V9 and V2 genes as is seen during early fetal
life.54 This suggests that recapitulation of T-cell
ontogeny may occur early following BMT, analogous to that described for
B-cell regeneration.50,51 This early postengraftment predominance of V9+V2+ cells in the
periphery may subsequently be further increased by antigen-driven
expansion of the newly generated cells. An alternative
possibility exists that mature T cells are already present in
the BM graft, are expanded after contact with antigen, and do not
represent an ontologic recapitulation.
Origin of Posttransplant T Cells and the Role of Thymic and
Extrathymic Pathways
Examination of TCR leads to the question of T-cell origin. After ABMT
or ABSCT, T cells may reconstitute from at least four different
sources: (1) rare recipient T cells that survived the conditioning
regimen; these cells might be seeded in the BM, lymph nodes, or spleen;
(2) T cells present in the graft; (3) hematopoietic stem cell
progenitors of the graft that differentiate in the recipient; and (4)
residual recipient stem cells (Fig 1). Studies of TCR alluded to in the preceding section suggest that the quantity of T
cells present in the graft might influence the rapidity and the quality
of T-cell recovery. However, it remains unclear how much passively
transferred T lymphocytes will contribute to sustained cellular
immunity.
View larger version (10K):
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| Fig 1.
Origin of mature T cells in transplant recipients.
Derivation from transplanted stem cells and mature T cells contained in
the graft and derivation from surviving host T cells.
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In autologous grafting where the source of cells as either transplanted
or nontransplanted cannot be readily identified, data from gene marking
studies may help to trace the origin of T cells after transplantation.
Unfortunately, because gene transfer into BM cells is neither very
efficient nor very specific, gene transfer studies may not yet not give
a precise quantitative determination of the role of transplanted BM in
T-cell recovery. However that may be, following transplantation of
autologous BM that had been transduced with a retroviral vector
containing a neomycin resistance gene, T cells carrying the gene could
be detected by polymerase chain reaction (PCR) as early as 1 month and
remain detectable for at least 18 months.55 Nevertheless,
although the protocol of retroviral infection in the study cited was
intended to transfer the marker gene into stem cells only, one cannot
exclude that T cells from the graft had been transduced as well.
Data from allo-BMT are helpful in distinguishing the contribution of
grafted BM and T cells from that of postchemotherapy residual stem
cells or T cells. In most conditioning regimens used for allo-BMT,
recipient hematopoiesis is ablated. However, T cells can survive
conditioning regimens.56 Using PCR amplification of
minisatellite DNA regions, Roux et al57 were able to
determine the recipient or donor origin of T cells after allo-BMT.
Their data suggest that in recipients of T-cell-depleted
(TCD) BM, within the first year following transplantation,
the T-cell compartment has a mixed origin with T cells derived from
both transferred donor cells and surviving host T cells. In contrast,
when a patient was grafted with an unmanipulated BM, few or no
recipient T-cell clones are detected.
Another source of information is the transfer of antigen-specific
cellular immunity from the donor to the recipient. Reports indicate
that cellular immunity against varicella zoster virus and
tuberculin-purified protein derivative can be effectively transferred
from immune marrow donor to recipient.58,59 These findings
transposed to autologous transplantation suggest that T cells in the
graft can expand.
To study the relative contributions of peripheral lymphoid populations
and BM-derived precursors to T-cell regeneration after BMT and to
understand the role of the thymic function in the immune recovery,60 Mackall et al61 performed a
series of elegant experiments where they studied lethally irradiated
thymus-bearing and thymectomized mice that had received congenic lymph
node cells as a source of peripheral T-cell progenitors and syngeneic
T-cell-depleted BM. They showed that in hosts lacking thymic function,
the predominant reconstituting T cells were derived from peripheral
T-cell progenitors contained in the transplant which expanded in the
thymectomized recipients. In the presence of a functional thymus, the
expansion of peripheral T-cell progenitors is downregulated.
Furthermore, in thymectomized hosts, the majority of T lymphocytes did
not express the high-molecular-weight (HMW) CD45 isoform
which indicated normal maturation, while in thymus-bearing animals
there was an increase in the level of naive type cells.
There is evidence that thymic-independent T-cell regeneration occurs
primarily via expansion of peripheral T cells and is Ag driven because
significant expansion of CD4+ and CD8+
transgenic/TCR-bearing cells appears only in the presence of Ag
specific for the TCR.62 In humans, where thymic
regenerative capacity is compromised because of age- and
chemotherapy-related changes, it appears that a thymic-independent
pathway must predominate.60
The capacity of the thymic and extrathymic pathways to produce
CD4+ cells differed in thymectomized and thymus bearing
murine hosts.61 Lower numbers of CD4+ cells
were derived from TCD BM transplanted into thymectomized recipients
than when transplanted in thymus-bearing mice, while the percentage of
CD8+ cells did not differ significantly between the two
types of recipients. Although the BM is an inefficient source of
CD4+ cells in the absence of a functional thymus, the
peripheral lymphoid progenitor pathway appears capable of compensating,
resulting in adequate numbers of CD4+ cells in transplanted
thymectomized mice.
T-Cell Function
T-cell competence after stem cell transplantation can be gauged at
three distinct functional levels: cell proliferation, cytokine production, and lytic
capacity.
T-Cell Proliferation
Using limiting dilution analysis, the frequency of mitogen-responsive T
cells in peripheral blood, including the frequency of
cytokine-secreting helper T cells, interleukin-2 (IL-2)
responding T cells, and cytotoxic T cells, was found to be low
after ABMT.63
Cayeux et al64 reported that isolated T cells at an early
post-ABMT stage (<2 months) had defective responses to normally proliferation-inducing MoAbs such as anti-CD3 or anti-CD2 even in the
presence of IL-2 affecting both CD4+ and CD8+
subsets. In response to anti-CD3 and IL-2, PB mononuclear cells (PBMC) from ABMT recipients proliferate but to a lesser
degree than in normal individuals.65 Sugita et
al66 found similar results: anti-CD3 alone or in
combination with anti-CD2, anti-CD26, or anti-CD29 could not induce
T-cell proliferation within 4 months after ABMT. However, T-cell
proliferation induced by anti-CD3 + anti-CD2 and by anti-CD3 + anti-CD26 reaches almost normal levels by 1 year. Just as in normal T
cells, coactivation with anti-CD28 MoAb can enhance the response in
some transplant patients, particularly in long-term recipients (above 6 months).67
In a mixed leukocyte reaction (MLR), accessory cells from
auto-transplanted recipients were unable to trigger normal levels of
proliferation of normal control T cells or to induce them to synthesize
IL-2.68,69 In addition, normal allogeneic accessory cells
failed to provide the necessary signals to activate transplant-derived T cells or induce them to produce IL-2 and proliferate. This deficiency could be corrected by addition of exogenous IL-2. The fact that recipient T cells do respond to IL-2 indicates that the IL-2 cell receptor is present on their surface and functional. These observations may indicate that during T-cell proliferation cell-to-cell contact does
not lead to T-cell activation but can induce IL-2
responsiveness.
T-cell proliferation is also impaired after autologous PBSC, but
recovery appears faster than that observed after ABMT.47 The depressed immune function might be partly related to the
suppressive effects caused by high numbers of monocytes present in
growth factor-mobilized PBSC.70,71 Although hematopoietic
engraftment after infusion of positively selected CD34+
cells appears similar to that observed after unselected PBSCT, no study
has compared the immune recovery after infusion of selected CD34+ cells and after PBSC or BM.
Cytolytic Function
Cytomegalovirus (CMV)-specific HLA-restricted CD8+
cytotoxic T cells (CTL) have been shown in the majority of patients
within the first 3 months after ABMT or APBSCT and are associated with protection from CMV infection.72 In contrast, specific CTL
response against Epstein-Barr virus (EBV) are impaired during the first 2 months after autologous stem cell transplantation.73
Further investigation of specific CTL activity are required in
developing of adjuvant vaccines in patients undergoing transplantation.
Lymphokine-activated killer (LAK)-like activity, that is
cells incubated with IL-2 capable of killing NK-resistant target cells,
is mediated primarily by CD16+CD3 cells
and to a lesser degree by CD16CD3+ cells
and appears 4 to 6 weeks after ABMT.74 LAK activity is not
observed after conventional chemotherapy not followed by
transplantation, but IL-2-responsive LAK precursor cells are rapidly
reconstituted after ABMT or ABSCT.75-77 Development of
IL-2-mediated cytotoxic activity may prove to be functionally
important for eradication of residual malignant cells in vivo.
Consistent with such a role is the finding that the cytotoxic activity
of PBMC after ABMT against NK-sensitive and NK-resistant target in
response to anti-CD3 and IL-2 is actually greater than that of normal
controls.67 IL-7 also induces significant LAK activity in
ABMT recipients to levels comparable to those obtained with IL-2,
suggesting that IL-7 may have an immunotherapeutic role alone or in
conjunction with IL-2.78 The potential therapeutic use of
cytokines in inducing cytotoxic activity is discussed under NK Cells.
Cytokine Production and T-Cell Responsiveness to Cytokines
In vitro-stimulated PBMC from recipients of ABMT have significant
defects in the production of a number of T-cell-derived cytokines
important in immune homeostasis, particularly IL-2, in the early
posttransplant period.64,79
The origin of the observed decreased cytokine production (notably IL-2)
and of the blunted T-cell proliferation can be ascribed to several
causes: subnormal levels of cytokine receptor expression, abnormal
accessory function, production of suppressive cytokines, or an
intrinsic T-cell defect. Insufficient IL-2 receptor cannot account for
the decreased proliferation since stimulation of posttransplant T cells
has been shown to induce the expression of the  chain of the IL-2
receptor.66,80,81 Normal accessory cells do not restore
normal production of IL-2 and, vice versa, patients'
accessory cells fail to activate normal T cells and induce IL-2
synthesis.68 However, the addition of exogenous IL-2 can at
least partially compensate the abnormal proliferative response.
Possibly signal transduction required for T-cell-non T-cell
interactions are in some way dysfunctional. These may entail the
interactions between CD40-CD40L, between CD4-MHC II, or between
B7-CD28.
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NK CELLS |
NK cells are defined as large granular lymphocytes capable of mediating
major histocompatability complex (MHC)-unrestricted cytolytic reactions
against tumor or virally infected cells and not expressing receptors
for antigen (ie, neither surface Ig or TCR). In addition, NK cells
characteristically have a
CD3CD16+CD56+ phenotype. NK
cells are among the first cells to recover after transplantation: in
contrast to B- and T-cell function, NK activity following both ABMT and
ABSCT reaches normal level within 1 month.46,48,80,82-84
IL-12, a 70-kD heterodimeric cytokine with pleiotropic
activities produced by antigen-presenting cells (APC),
stimulates the proliferation and cytotoxic activity of NK cells and
enhances generation of cytotoxic T cells.85 In addition, it
induces transcription and secretion of interferon- (IFN-) either
directly or in synergy with other inducers and promotes commitment of
naive T cells to the TH1 pathway resulting in the
production of TH1 cytokines including IL-2.85
As a result of these effects, IL-12 appears to have strong antitumor
and antimetastatic effects as shown in a murine model,86,87
with evidence suggesting a similar role in human malignancy.88 SAC stimulated PBMC derived from autologous
hematopoietic transplants show no decrease in the production of IL-12
as compared with control PBMC.89 However, this seemingly
normal in vitro production of IL-12 does not exclude the possibility
that in vivo IL-12 production remains abnormal. T cells play a role in
priming APC to produce IL-1290 and posttransplantation T
cells may be unable to carry out this function. Transplantation-derived
PBMC do not appear to have defective responsiveness to exogeneously provided IL-12 as evidenced by their degree of in vitro
proliferation and IL-12-mediated IL-2 production.89 In
addition, significant increases in NK and LAK activity are observed
with IL-12 alone or in combination with IL-2.91
The sum of these findings suggests that the recovery of NK cells seen
after ABMT and ABSCT is prompt both in quantity and in functional
quality. Maturation of NK cells can occur in the absence of a
functional thymus in mice and humans.92,93 This may account
for the prompt NK recovery. In the early posttransplant period, when
specific immunity is still recovering, NK cells may provide an
important defense against infections or tumor relapse. Expansion of NK
cells with growth factors immediately following transplantation might
therefore serve to increase host defenses. Such an immunotherapeutic
strategy is discussed below. However, despite our ability to accelerate
or potentiate cytotoxic cells, there is no direct evidence showing a
correlation between NK activity after transplantation and tumor
relapse.
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TRANSFER OF T- AND B-CELL-MEDIATED IMMUNITY |
The degree of T-cell incompetence after autologous transplantation is
difficult to gauge exactly in vitro. The capacity to mount an effective
immune response against foreign antigen better reflects the immune
status of transplant recipients than do in vitro tests. Information
garnered from allogeneic transplantation indicates that with the
passive transfer of allogeneic lymphocytes, transplantation recipients
show short-term production of antibodies against viral
pathogens.20,94 However, vaccination in the months after
transplantation does not always result in sustained protection. This
pattern of temporarily effective but nonsustainable protection suggests
that B lymphocytes derived from the donor, which generate specific
antibody in the short term, are transferred together with the
transplant, but that antigen-specific T cells necessary for ongoing
sustained protection must be regenerated anew since the transfer of T
cells functional against specific infections appears less
efficient.95-97 The reduced transfer of antigen-specific T
lymphocytes may be caused by an already impaired T-cell-mediated immunity before transplant in patients who have received significant prior chemotherapy.
ABMT patients have an overall increased risk of infections, including
CMV, influenza, herpes simplex virus, and varicella zoster
virus,98-100 although the incidence of infections and
severity are lower in ABMT than among allo-BMT
recipients.72,95,101 This disparity may be accountable by
the possibility that T-cell transfer from an allogeneic donor is
further compromised by GVHD prophylaxis. Lymphocyte proliferative
responses to herpes simplex virus and CMV in seropositive patients
return more rapidly in ABMT recipients than allo-BMT.72
Overall, the transfer of antigen-specific T cells is substantially less
efficient than the passive transfer of antibody-producing B lymphocytes
transfer. This has implications in designing infection-specific vaccines for administration before and after transplantation.
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STRATEGIES TO ENHANCE IMMUNE RESPONSIVENESS AFTER AUTOLOGOUS STEM
CELL GRAFTING |
The effectiveness of any cancer immunotherapy in limiting or
eliminating malignant cells is a function of the target tumor mass.
Even when therapeutically bolstered, immune mechanisms can be rendered
ineffective by the presence of overwhelming numbers of target malignant
cells. Because high-dose chemotherapy followed by ABMT or ABSCT results
in (or is presumed to result) in minimal burden of residual malignant
disease it provides a potentially ideal setting for immunotherapy.
Administration of Cytokines
Interleukin-2
It has been 15 years since the first demonstration that IL-2 activates
and promotes proliferation of murine and human NK cells in vitro
resulting in both a greater degree and wider spectrum of lytic
activity and initial preclinical studies had shown that systemic IL-2 had significant antitumor effects.102,103
This lead to clinical studies using IL-2 regimens with or without
adoptive transfer of in vitro activated LAK cells. After the
exhilarating results of the initial clinical trials involving high-dose
recombinant IL-2 and LAK cells,104 the true response rate
of IL-2 with or without the addition of LAK cells was found to be in
the range of 15% to 25% for renal cell carcinoma and
melanoma.105 Although a variety of tumors of different
histological types are sensitive to IL-2/LAK cell therapy, complete
eradication of tumor is rare. Nevertheless, because of the measurable
tumor regression seen in a significant minority of patients with
metastatic malignancies, a logical extension was to perform similar
trials of IL-2 after ABMT for hematologic malignancies. The rationale
for using IL-2 is based on the following: (1) preclinical data showing
that human hematologic malignant cells can be lysed in vitro by
IL-2-activated effector cells106-108; (2) IL-2-responsive
cells are present early following transplantation74-76; (3)
immunotherapy is likely to be more effective when minimal tumor burden
is present; and (4) chemotherapy-resistant cells can be lysed by
IL-2-activated NK and T cells. IL-2-based trials have included both
preclinical and clinical studies.
Preclinical studies.
Mice inoculated with a leukemic cell line were
administered intravenous cyclophosphamide and syngeneic BMT 24 hours
later. This was followed by either recombinant (r) IL-2 for 5 days
starting on day 1, 7, or 21 or by no further therapy.109
Mice not treated with IL-2 relapsed and died within 50 days
posttransplantation, whereas mice receiving IL-2 had long-term
disease-free survivals. The maximal antileukemic effect was observed in
mice receiving IL-2 3 weeks after BMT. The delayed maximal effect is
consistent with and likely results from the delay needed to first
achieve maximal lymphocyte reconstitution that can then respond to
IL-2.
Clinical studies.
Trials of continuous-infusion IL-2 administration after ABMT have been
performed primarily in hematologic malignancies,83,110-124 although several studies of its use following ABMT for solid tumors have also been performed.83,114,125
IL-2 administered after ABMT has significant immunomodulatory effects,
including an increase in circulating lymphocytes expressing CD3, CD4,
CD8, and the NK-associated markers CD16 and CD56 as well as an increase
in circulating NK and LAK activity.83,110,111,114,115,117 However, in one trial where IL-2 treatment was begun on the day after
transplantation for acute lymphoblastic leukemia (ALL), cells with the
NK phenotype and circulating NK activity were not enhanced.119 Nevertheless, the majority of IL-2-treated
patients showed strong cytotoxicity against an ALL cell line.
One of the primary drawbacks to the use of high-dose IL-2 is its
systemic toxicity. Fever, fatigue, diffuse rash, and varying degrees of
a capillary leak syndrome with weight gain and hypotension are
frequently observed in most of the studies using high doses of IL-2
(between 9 and 24 × 106/IU/m2/d). The
major hematopoietic toxicity of IL-2 after ABMT has been thrombocytopenia. Lymphocytosis, neutrophilia, and eosinophilia are
commonly reported as well. These effects may be caused by the induction
of secretion of other cytokines by IL-2.126
The conclusion drawn from these clinical trials is that although the
administration of IL-2 is complicated by significant side effects in at
least 30% of recipients, it remains a viable option for some patients.
Most groups administer IL-2 once hematopoietic engrafment has been
achieved, generally 2 to 3 months after transplantation while
endogenously activated cells and IL-2-responsive immunocompetent precursors cells are present earlier in the posttransplant period. Immune modulation with marked time-dependent increases of NK cells (CD56bright+CD16+CD3) have
been achieved with low doses of IL-2 (2 to 4 × 105
IU/m2/d) administered for a period of 3 months without
significant toxicity.114,122,127 NK and LAK activities were
also found to be enhanced by low doses of IL-2.114
Furthermore, none of the studies including two randomized ones in acute
leukemia in adults have shown that the immunomodulatory effects of IL-2
were beneficial in terms of survival.120,124 It is probably
unlikely that IL-2 administered alone will be effective, but it may
find its place to expand or sustain in vivo NK or cytotoxic T cells
injected after transplantation.
Interleukin-7
As noted, T-cell precursors leaving the BM enter the thymus for
terminal differentiation. Data from cytokine-deficient mice (knockout
mice) suggest that with the exception of IL-7, cytokines can be removed
without significantly affecting intra-thymic
development.128,129 Mice lacking the IL-7 gene or a
functional IL-7 receptor gene have severe impairment of early
lymphocyte expansion.128,129 The severe lymphopenia seen in
IL-7-deficient mice is associated with normal distribution of T-cell
subsets and response to mitogens, suggesting that IL-7 acts on the
expansion and proliferation of T cells rather than on their
differentiation and function. These multiple effects of IL-7 on T-cell
development have led to preclinical studies in murine BMT.
Preclinical studies.
In a murine model of BMT, IL-7 administration accelerates both T- and
B-cell reconstitution by up to 2 to 4 weeks130 and both
CD4+ and CD8+ cell counts are found to be
expanded. Bolotin et al131 reported that in a syngeneic
murine BMT model, injections of IL-7 from day 5 to 18 induced an
increase in the cellularity of the thymus by 4 weeks, while the
proliferation of early thymic precursor cells was increased nearly
eightfold. In contrast, in mice not receiving IL-7, normal numbers of
thymocytes appeared only by week 8. Furthermore, in the IL-7-treated
mice, distribution of thymic subpopulations approximated those of
normal untransplanted mice. Abdul-Hai et al132 reported
similar findings of accelerated repopulation of the thymus with IL-7
injected for 10 days immediately after murine
transplantation. IL-7 also increased RAG-1 (recombination activator gene) expression in the thymus. Taken together, these data
suggest that IL-7 may find a therapeutic role in accelerating T-cell
reconstitution after autologous transplantation.
Incubation of HSC With Cytokines and Growth Factors
Preclinical Studies
Incubation of murine BM with IL-2 results in the generation of killer
cells with non-MHC-restricted cytotoxicity against tumor cells which
appears superior to the cytotoxicity of spleen LAK cells.133-135 Transplantation of IL-2-activated BM (ABM)
immediately followed by administration of systemic IL-2 reduces the
dissemination of established melanoma and sarcoma in mice more
effectively than transplantation with untreated BM with or without
systemic IL-2 alone.133,134 This suggests that priming with
IL-2 before ABMT induces an antitumor effect capable of eradicating
residual malignant disease. When IL-2 therapy is delayed for 1 or 2 weeks after transplantation with ABM, there is a progressive decrease
in the cure rate,136 suggesting that ABM cells cannot
maintain a prolonged cytotoxicity in vivo. The hematopoietic
regenerative capacity of IL-2-activated BM was preserved despite a
reduction in viable cell number.
As in the murine studies, in vitro incubation of human BM with IL-2
leads to the generation of cells with cytotoxicity against tumor cell
lines.137-141 In vitro activation of BM cells with IL-2 significantly enhances cytotoxicity against chemotherapy-resistant leukemic cells, suggesting that this approach might be useful to
eliminate drug-resistant minimal residual disease.142
Significantly, PBSC cultured in IL-2 for 24 hours retain adequate
potential for hematopoietic reconstitution.143
NK cells present potentially ideal instruments of immunotherapy. Large
scale ex vivo culture of PBSC enriched in monocytes and NK precursors
with IL-2 should yield sufficiently high numbers of activated NK cells
for clinical use.144,145 It remains to be seen whether
optimal regimens of ex vivo and in vivo IL-2 will result in enhanced
cytotoxicity against postchemotherapy/transplantation residual
malignancy.
Similar studies with granulocyte-macrophage colony-stimulating factor
(GM-CSF) indicate that as with IL-2, ex vivo activation of BM with
GM-CSF induces cytotoxicity against tumor cells.146 In the
case of GM-CSF, however, this is due to the proliferative effect of
GM-CSF on macrophages rather than on T cells. When combined with a
tumor-specific antibody, GM-CSF induces specific antibody-dependent cytotoxicity (ADCC) against tumor cells.146
Clinical Studies
Only limited studies of hematopoietic stem cells exposed to IL-2 have
been reported so far and these included small numbers of patients with
leukemia, breast cancer, and non-Hodgkin's
lymphoma.142,147-149 In the reported studies, BM was
maintained with IL-2 for a variety of schedules ranging from 24 hours
to 10 days. IL-2-activated BM successfully engrafts patients who had
previously received myeloablative chemotherapy. In most studies,
additional systemic IL-2 was administered intravenously after
transplantation with the expectation that IL-2 would maintain the NK
activity. Although in vitro cytotoxicity of IL-2-activated BM against
NK-sensitive cell lines was demonstrated, no studies showed any effect
against autologous tumor cells. From the preliminary data, it is not
yet possible to conclude whether this approach will be successful.
Induction of an Autoaggression Syndrome With Cyclosporine A
(CsA)
Preclinical Studies
CsA is a potent immunosuppressive agent that has been used for more
than 15 years to prevent GVHD in patients receiving allogeneic BMT.
Paradoxically, however, the administration of CsA after syngeneic BMT
in rats can lead to the development of an autoimmune phenomenon that is
clinically and histologically similar to allogeneic GVHD with the
appearance of CD4+ and CD8+ effector cells
recognizing MHC class II antigens, including self.150,151 Lethally irradiated rats reconstituted with syngeneic BM and treated with CsA for 40 days develop a T-cell-dependent autoimmune syndrome 14 to 28 days after discontinuation of CsA treatment characterized by
erythroderma and dermatitis.150 The mechanism for induction of this autoimmune phenomenon remains unclear. It has been suggested that CsA induces modifications in the thymus, including medullary involution, loss of Hassal's corpuscles, and decreased expression of
MHC II antigens in the medulla,152 changes which interfere with intrathymic differentiation of T cells.150,151,153
CsA also appears to enhance the development of
autoreactive T lymphocytes by blocking their deletion in the
thymus.154 The role of the intact thymus in autoaggression
is indicated by the finding that syngeneic GVHD cannot be induced in
thymectomized animals.153 However, the inhibition of clonal
deletion in the thymus and the development of autoreactive T cells in
the periphery is insufficient by itself to induce the autoimmune
phenomenon. The ablation of the lympho-hematopoietic system with the
preparative regimens for transplantation (irradiation or cytotoxic
chemotherapy) is also apparently necessary to eliminate peripheral
regulatory mechanisms155,156 because infusion of spleen
cells from rats with autoreactive disease into normal rats does not
transfer the clinical syndrome. In addition, CsA treatment of
untransplanted rats does not induce an autoimmune syndrome.
The effector mechanisms of the CsA-induced autoimmune syndrome remain
unclear. Because CsA causes a marked decrease in the expression of MHC
class II antigens in the thymic medulla,157 developing T
cells in the thymus may fail to recognize these MHC determinants as
self. Therefore, MHC class II determinants might then turn out to be
the principal targets of autoreactivity. The T-cell receptor repertoire
of effector T lymphocytes appears restricted, suggesting that only a
limited number of class II MHC antigenic determinants may be
recognized, and administration of anti-MHC class II antibodies can
delay or prevent autoreactivity.158 Recently, the peptide
termed CLIP derived from the MHC class II invariant chain which
protects the MHC molecules from nonspecific binding of peptides was
found to be the target of autoreactive T cells.159
The autoreactive cells generated by CsA treatment after ABMT have been
found to have antitumor effect in vitro.160 Unfortunately, the cytotoxic capacity of these cells is directed against tumor cells
expressing the MHC II antigen, limiting the practical application of
the therapy. Moreover, CsA induces significant autoimmunity in some,
but not all, strains of rats and mice.161
In an attempt to widen the potential use of CsA, Charak et
al,162 using a murine strain that does not develop
autoimmune syndrome after CsA therapy, have shown that mice inoculated
with non-Ia-bearing tumors (B16 melanoma and C1498 leukemic cells) which received both IL-2 and CsA after BMT had a better survival than
mice receiving either IL-2 or CsA alone. However, no mice were cured.
The rationale for linking IL-2 and CsA was based on the finding that
CsA-generated T cells are highly responsive to IL-2 in
vitro.163 The effectiveness of this two-step mechanism is
borne out by the finding that the antitumor effect generated in mice
receiving IL-2 and CsA could be transferred into secondary tumor-bearing recipients.164
Clinical Studies
CsA can induce an autoimmune syndrome in patients with lymphoma, acute
myeloid leukemia, or breast cancer receiving ABMT.164-170 This syndrome is mainly confined to the skin (erythematous
maculopapular rash) without clinical evidence of visceral involvement.
In one report, the presence of cytotoxic T cells recognizing the
patient's own pretransplant lymphocytes or tumor cell lines that
expressed MHC class II determinants could be shown.164 No
analysis of cytotoxicity against autologous fresh tumor cells was
reported. The reason why clinical signs of autoaggression are located
in the skin remains unknown. This could be related to the presence of
Langerhans cells in the dermis or a high expression of MHC II in the
skin.
Because hematologic malignancies and some solid tumors express MHC
class II determinants, they too can presumably serve as the target of a
CsA-induced cytotoxic effect. Encouraging results have been reported in
a nonrandomized study for the treatment of 40 relapsed or refractory
intermediate grade non-Hodgkin's lymphoma treated with ABMT, CsA, and
IFN- in an attempt to further upregulate the expression of HLA
antigens. Thirteen percent of the patients were found to relapse after
a median follow-up of 24 months.170 This clinical outcome
compares favorably with the trial of ABMT alone in patients with
relapsing non-Hodgkin's lymphoma. However, carefully planned trials
comparing APSCT alone versus APBSCT with CsA are still lacking. CsA
with or without IFN- has been administered after high-dose
chemotherapy and ABMT in women with metastatic breast carcinoma, and
showed that the combined therapy had an acceptable level of
toxicity.166,167 However, no clinical benefits could be
shown.
In none of the clinical studies was HLA expression analyzed on primary
neoplastic tissue of patients entering the study nor was in vitro
evidence of an antitumor effects shown. Overall, it remains to be seen
whether there is consistent clinical benefit to the concept of inducing
an autoaggressive GVHD-like syndrome in autologous marrow recipients.
Adoptive Transfer of Ex Vivo-Expanded MHC Nonrestricted Effector
Cells
As described above, BM or PBSC can be incubated in vitro with cytokines
to induce the development of cytotoxic cells. A number of protocols
have been devised to select effector cells with cytotoxic activity from
PBMC.
Activated NK Cells: Clinical Studies
Initial enthusiasm for the therapeutic use of LAK came from its use in
preclinical and clinical studies against lymphoma and leukemia.171,172 In treating minimal residual malignant
disease, LAK cells might be expected to be most effective if they are
active against chemotherapy-resistant tumor cells which may have
survived pretransplantation high-dose chemotherapy regimens. In in
vitro studies, LAK cytotoxicity has been demonstrated against tumor cells surviving therapeutic concentrations of chemotherapeutic agents.173 This in vitro data led to pilot clinical trials
combining systemic administration of IL-2 followed by apheresis to
generate LAK cells after ABMT or ABSCT in lymphoma patients either in
relapse or resistant to primary chemotherapy and in acute leukemia with poor prognostic indicators.115,117
CD3CD56dim peripheral blood cells make
up a specific subset of NK cells. These cells are obtained from the
post-IL-2 leukapheresis product by adherence to plastic in the
presence of IL-2. Such activated NK cells can be expanded in culture
for 2 to 3 weeks with IL-2 in the presence of irradiated allogeneic
concanavalin A (conA)-preactivated mononuclear cells. The
injection of activated NK cells along with IL-2 to support the
antitumor activity of NK cells has been used immediately
posttransplantation in patients with lymphoma and no major toxicity has
been observed with this combination therapy.174
Such manipulations including those involving apheresis after IL-2,
expansion of NK cells, injection of IL-2 to support in vivo activity of
NK cells entail many practical difficulties and morbidities limiting
their applications to selected patients. In addition,
these initial phase I trials have been performed on too small a number
of patients to allow any conclusions regarding any potential benefit of
these approaches.
Cytokine-Induced Killer Cells
A somewhat different therapeutically useful cytotoxic cell can be
obtained by in vitro exposure of PBMC to combinations of IFN-, IL-2,
and anti-CD3 monoclonal antibody. The resultant effector cell termed
cytokine-induced killer cells (CIK) bears a
CD3+CD56+ (but CD16)
phenotype and demonstrates non-MHC restricted
cytotoxicity.175,176 CIK cells have been found to be
substantially more cytotoxic in culture than LAK cells against cellular
targets and, like LAK cells, they are effective against
chemotherapy-resistant cell lines.177 Although ex vivo
generation of CIK cells is IL-2 dependent, in vivo use of CIK cells has
the advantage over LAK cells of not requiring additional systemic
administration of potentially toxic IL-2 to augment their antitumor
activity. In direct comparison, CIK cells have been shown to result in
greater regression of disseminated human lymphoma in severe combined
immunodeficient (SCID) mice than LAK cells.178,179 While a
significant minority of CIK-treated lymphoma-bearing SCID mice had
long-term survival, none of the LAK-treated mice
survived.178 Because of apparent efficient cytotoxicity and
limited systemic effects, expansion of CIK cells may find a place in
protocols of autologous transplantation.
Cytotoxic Cell Lines
Human cell lines with potent MHC nonrestricted cytotoxicity activity
against tumor cells have been reported. A cell line termed TALL-104
bearing the characteristic phenotype of cytotoxic cells has been
derived from a human acute T-lymphoblastic leukemia and maintained in
continuous culture in the presence of IL-2. TALL-104 cells show
cytotoxicity exclusively against tumors across species without
deleterious effects on normal tissues.179-181 After lethal irradiation, the cells are no longer leukemogenic when injected into
SCID mice, but retain their killer function. In murine models bearing
human tumors, administration of the human cytotoxic T-cell line had
effective antitumor effects when given at early stage of
disease.181
Additional NK cell lines have been established.182,183
Their capacity to lyse cells appears restricted however to certain tumor types, thereby limiting their potential use. Because cell lines
can be expanded continuously in culture, they constitute an unlimited
source of effector cells. They may ultimately find a therapeutic niche
after transplantation when minimal tumor disease is present and when
poorly reactive immunity permits the injection of unmatched allogeneic
cells.
Adoptive Transfer of Tumor-Specific MHC-Restricted Effector Cells
Adoptive cellular immunotherapy can be described as the transfer of
target-specific effector cells to treat malignant disease. Such an
approach entails the isolation and expansion of effector CD4+ and CD8+ T cells with specific reactivity
for tumor cells from the host or other donor. In addition, adoptive
immunotherapy requires that such cells survive in vivo for a sufficient
amount of time to eradicate the tumor.184 This approach
could be combined with injection of autologous stem cells.
It is currently feasible to grow T cells to large numbers in vitro by
stimulating with antigen and by the addition of cytokines such as
IL-2.185 As a result, T-cell therapy has been evaluated as
a means to restore protective immunity against CMV following allo-BMT.
CD8+ cytotoxic T-cell clones specific for CMV isolated from
the blood of BM donors and grown in vitro have been infused to the
recipients of allogeneic BM transplants to prevent CMV
pneumonia.186 Adoptive transfer of antigen-sensitized T
cells may in theory be evaluated in the treatment of malignant
diseases. However, adoptive transfer of specific immunity is only
possible when specific target tumor antigen(s) are identified and
antitumor antigen-specific T cells are expanded. For most tumors
currently treatable by high-dose chemotherapy and autologous
transplantation, tumor-specific antigens are to date not known.
Ideal tumor antigens should be expressed exclusively or at least
preferentially by tumors cells. In the emerging concept of tumor-specific cytotoxicity the context of tumor antigen presentation is no less important than the antigen itself. Once processed, the
tumor-related antigen is presented on tumor cells as peptides bound to
the HLA molecules. For clinical use then, this HLA restriction must
also be identified. The antigen must further be shown to induce T-cell
cytolytic responses in vitro and in vivo against tumor cells.
Ig expressed by B-cell malignancies are unique in that they can be
distinguished from those expressed by normal B cells. The idiotype
resulting from the combination of the variable regions of Ig heavy and
light chain therefore represents the best example of a tumor-specific
antigen. A number of hematologic malignancies are associated with
mutations or translocations that result in expression of cellular
oncogenic or chimeric proteins that play a role in malignant
transformations and are present only on malignant cells
(Table 1). These antigens
presented in MHC molecules might induce a T-cell response which may
potentially be expanded for clinical use. Prospective candidates for
eliciting such a response are two leukemic-associated neoantigens.
Chronic myelogenous leukemia (CML) and acute promyelogenous leukemia
(APL) are characterized by recurrent translocations leading to the
formation of fusion proteins, p210 bcr-abl and promyelocytic
leukemia/retinoic acid receptor- (PML/RAR) in CML and APL,
respectively. In the case of p210, peptides have been derived from the
fusion sequences and have been analyzed for consensus anchor residues
for binding to a given HLA molecules. However, if a proliferation
response can be obtained, a cytolytic response has mainly been
performed using as target cell lines or normal PBMC bearing appropriate HLA type and loaded with peptides.207-210 Few
data are available using fresh leukemic cells as target of cytolytic T
cells. In addition, difficulties in obtaining peptide-specific CTL from PBMC of patients with CML in chronic phase suggest that these T cells
may frequently be unresponsive to bcr-abl peptides.211 The
demonstration of the presence of the processed peptides on the surface
of fresh CML cells needs to be confirmed to validate such an approach.
Therefore, search for new tumor antigens in addition to the Ig idiotype
are needed.
View this table:
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Table 1.
Mutated Oncogenes, Tumor-Suppressor Gene Products,
Overexpressed Oncogene-Encoded Proteins, and Tissue-Specific
Differentiation Proteins That Might be Candidates to Induce T-Cell
Immunity in Malignant Diseases Treated With Autologous
Transplantation
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An identical need for tumor-specific cell-surface antigens exists in
the immunotherapy of solid tumors. Tumor-specific antigens and
CTL-specific responses to these antigens have been most successfully shown for melanoma.212 Unfortunately, antigens uniquely or
preferentially expressed by solid tumors currently treatable by
high-dose chemotherapy and autologous stem cell support have not been
so extensively described as those for melanoma and are now the object
of active investigation.212 Solid-tumor-associated
antigens might be oncogenic proteins that are mutated and overex |
Introduction
References