Long term disease-free survival in acute leukemia patients recovering with increased gammadelta T cells after partially mismatched related donor bone marrow transplantation

Article (PDF Available)inBone Marrow Transplantation 39(12):751-7 · June 2007with30 Reads
DOI: 10.1038/sj.bmt.1705650 · Source: PubMed
Allogeneic stem cell transplantation (ASCT) has improved leukemia-free survival (LFS) in many but not all patients with acute leukemia. This is an eight-year follow-up to our previous study showing a survival advantage to patients with an increased gammadelta T cells following ASCT. gammadelta T cell levels were collected prospectively in 153 patients (acute lymphoblastic leukemia (ALL) n = 77; acute myelogenous leukemia (AML) n = 76) undergoing partially mismatched related donor ASCT. Median age was 22 years (1-59), and 62% of the patients were in relapse at transplant. Patient-donor human leukocyte antigen (HLA) disparity of three antigens was 37% in the graft-versus-host disease (GvHD) and 29% in the rejection directions. All patients received a partially T cell-depleted graft using T10B9 (n = 46) or OKT3 (n = 107). Five years LFS and overall survival (OS) of patients with increased gammadelta compared to those with normal/decreased numbers were 54.4 vs 19.1%; P < 0.0003, and 70.8 vs 19.6% P < 0.0001, respectively, with no difference in GvHD (P = 0.96). In a Cox multivariate analysis, normal/decreased gammadelta (hazard ratio (HR) 4.26, P = 0.0002) and sex mismatch (HR 1.45 P=0.049) were associated with inferior LFS. In conclusion, gammadelta T cells may facilitate a graft-versus-leukemia (GvL) effect, without causing GvHD. Further evaluations of this effect may lead to specific immunotherapy for patients with refractory leukemia.
Long term disease-free survival in acute leukemia patients recovering with
increased cd T cells after partially mismatched related donor bone marrow
KT Godder
, PJ Henslee-Downey
, J Mehta
, BS Park
, K-Y Chiang
, S Abhyankar
LS Lamb
South Carolina Cancer Center, Columbia, SC, USA;
Pediatric Hematology/Oncology, Children’s Medical Center, VCU Health
Systems/MCV Hospitals and Physicians, Richmond, VA, USA;
The Robert H Lurie Comprehensive Cancer Center, North Western
University, Chicago, IL, USA;
Biostatistics Shared Resource, Cancer Institute, Oregon Health and Science University, Portland,
Aflac Cancer Center, Children’s Health/Care of Atlanta at Emory University, Atlanta, GA, USA;
Kansas City BMT
Program, Kansas City, KS, USA and
University of Alabama at Birmingham, Birmingham, AL, USA
Allogeneic stem cell transplantation (ASCT) has im-
proved leukemia-free survival (LFS) in many but not all
patients with acute leukemia. This is an eight-year follow-
up to our previous study showing a survival advantage to
patients with an increased cd T cells following ASCT. cd
T cell levels were collected prospectively in 153 patients
(acute lymphoblastic leukemia (ALL) n ¼ 77; acute my-
elogenous leukemia (AML) n ¼ 76) undergoing partially
mismatched related donor ASCT. Median age was 22
years (1–59), and 62% of the patients were in relapse at
transplant. Patient–donor human leukocyte antigen (HLA)
disparity of three antigens was 37% in the graft-versus-
host disease (GvHD) and 29% in the rejection directions.
All patients received a partially T cell-depleted graft using
T10B9 (n ¼ 46) or OKT3 (n ¼ 107). Five years LFS and
overall survival (OS) of patients with increased cd
compared to those with normal/decreased numbers were
54.4 vs 19.1%; Po0.0003, and 70.8 vs 19.6% Po0.0001,
respectively, with no difference in GvHD (P ¼ 0.96). In a
Cox multivariate analysis, normal/decreased cd (hazard
ratio (HR) 4.26, P ¼ 0.0002) and sex mismatch (HR 1.45
P ¼ 0.049) were associated with inferior LFS. In conclu-
sion, cd T cells may facilitate a graft-versus-leukemia
(GvL) effect, without causing GvHD. Further evaluations
of this effect may lead to specific immunotherapy for
patients with refractory leukemia.
Bone Marrow Transplantation (2007) 39, 751–757;
doi:10.1038/sj.bmt.1705650; published online 23 April 2007
hematopoietic stem cell transplantation; gd T
cells; acute leukemia; mismatched related donor
Allogeneic hematopoietic stem cell transplantation (HSCT)
has improved disease-free survival in patients with refrac-
tory acute leukemia, or those at a high risk of relapse. Over
the past several years, it became apparent that the donor
graft, in addition to its role in replacement of the ablated
hematopoietic system, elicits an immunotherapeutic benefit
(graft-versus-leukemia effect (GvL)). The role of T cells as
mediators of GvL was recognized when T cell depletion of
hematopoietic grafts was found to be associated with an
increased risk of relapsed disease, especially in patients with
chronic myeloid leukemia.
Subsequently, donor leuko-
cyte infusion (DLI) therapy (containing primarily T cells)
was found to induce a long-term remission in early relapse
CML patients.
Less frequent response to DLI has been
seen in patients with advanced stage CML or those with
acute leukemia.
The extent of response to DLI may
depend on the type of leukemia, its replication rate,
whether it expresses leukemia-specific target antigens and
on recognition and killing of minor and/or major
mismatched histocompatibility antigens.
nately, GvL is often linked with graft-versus-host disease
(GvHD), as demonstrated by a number of studies showing
a decreased relapse rate in patients who developed acute or
chronic GvHD.
Various T cell subset selection methods
have been applied to DLI in an attempt to separate the
GvL effect from GvHD. Despite these attempts, the risk of
GvHD remains an obstacle to successful DLI therapy,
prompting a substantial amount of investigative work that
has focused on the search for allogeneic cellular immu-
notherapy that would minimize the risk of GvHD while
providing effective protection against or therapy for post
HSCT leukemic relapse.
Gamma/delta (gd) T cells may provide an ideal source of
T cell immunotherapy for leukemia, as they exhibit biologic
characteristics consistent with innate immune recognition,
thereby allowing them to respond to malignancy without
recognition of alloantigens that could result in GvHD.
Received 22 March 2006; revised and accepted 1 February 2007;
published online 23 April 2007
Correspondence: Dr KT Godder, Pediatric Hematology/Oncology,
Children’s Medical Center, VCU Health Systems/MCV Hospitals and
Physicians, PO Box 980121, Richmond, VA 23298-0121, USA.
E-mail: kgodder@vcu.edu
Bone Marrow Transplantation (2007) 39, 751–757
& 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00
Unlike ab T cells, which recognize specific processed
peptide antigens presented on major histocompatibility
complex (MHC) molecules by antigen-presenting cells, gd T
cells directly recognize and respond to a variety of MHC-
like stress-induced self antigens expressed by malignant
Thus, gd T cells can recognize malignant cells
through less specific mechanisms that require no prior
antigen exposure or priming, a function that is shared by
other innate immune cells such as macrophages and natural
killer (NK) cells.
Preliminary observations from our group have shown
that patients who develop increased numbers of donor-
derived circulating gd T cells following haploidentical or
partially mismatched HSCT experienced a significant
leukemia-free survival (LFS) and overall survival (OS)
This report is up to 8 years, follow-up of these
and additional patients, and a comparative analysis of
concomitantly treated patients who received the same
transplant protocols in our institution and recovered with
normal/low levels of gd T cells.
Patient selection
Data were collected prospectively on all consecutive acute
leukemia patients who received partially mismatched
related donor (PMRD) HSCT between February 1993
and December 1999 at the Division of Transplantation
Medicine of the South Carolina Cancer Center. All patients
and donors provided written informed consent, and all
research was conducted under institutional review board-
approved protocols.
Patients were excluded if they had a secondary malig-
nancy (including secondary acute myelogenous leukemia
(AML)), were beyond first transplant or received a non-
total- body-irradiation containing regimen. To reduce
selection bias, only patients surviving beyond 59 days post
transplantation, were included in the analysis. In addition,
patients were evaluable for increased gd T cells only after
day þ 59 owing to incomplete T-cell recovery before that
Laboratory studies
Blasts were extensively characterized by morphologic
examination, flow cytometry and cytogenetics. Whole
peripheral blood was collected from donor and recipient
before HSCT and from the recipient on days þ 60, þ 100,
þ 180, þ 270, þ 365 post transplant and annually there-
after. Aliquots of 100 ml were labeled with flourochrome-
conjugated antibodies specific for lymphocytes and T cell
subsets (CD3, CD4, CD8, CD19, CD16/56, CD45,
TCR-gd and Vd1–Vd3), and prepared using a commercially
available erythrocyte-lysis procedure. Acquisition and
analysis were performed using a FACS Calibur flow
cytometer and CellQuest Pro acquisition and analysis
software (BD Biosciences, San Jose, CA, USA). Cell
subpopulations in the lymphocyte CD45/side scatter gate
were quantitated and expressed as a percentage of the total
lymphocyte population. The gd T cells were calculated as
a percentage of the total lysed whole blood lymphocyte
count (CD45/SSC gating followed by determination of gd
T cells as a percentage of lymphocytes) and a Beckman–
Coulter ACT-2 hematology analyzer for absolute lymphocyte
count (percent gd lymphocytes absolute lymphocyte count).
Patients were included in the increased gd group if they
had a total of 1.75 10
gd T cells/ml of whole blood at two
consecutive regularly scheduled lymphocyte phenotyping
measurements within the first year post bone marrow
transplantation (post BMT) (days þ 60, þ 100, þ 180,
þ 270 and þ 365). The definition of increased gd T cells
was based on data from 498% of 201 healthy allogeneic
donors from our center, and on the calculation of 5% (gd T
cells) of total lymphocyte 4 10
Conditioning regimens and GvHD prophylaxis
Patients’ conditioning therapy and GvHD prophylaxis had
been previously described.
Table 1 shows the char-
acteristics of patients recovering with high vs normal/low
levels of gd T cells. The marrow was depleted of T cells
using the monoclonal antibodies T10B9 (1993–1994) or
OKT3 (1995–1999) as described previously.
Acute and
chronic GvHD were diagnosed and staged based on
standard criteria, and treated with combination immuno-
suppressive therapy.
Statistical analysis
Altogether, we evaluated 14 potential risk factors for event-
free survival and overall survival including age (as contin-
uous, stratified by median and by decade), gender, race
(Caucasian vs other), disease (acute lymphoblastic leuke-
mia (ALL) vs AML), disease status (remission vs relapse),
pre-transplant cytomegalovirus (CMV) serology of recipi-
ent (positive vs negative), CMV serology of donor (positive
vs negative), donor relationship (sibling vs other) and age
(o28 vs X28 years), sex mismatch, T cell-depleting agent
(OKT3 vs other), human leukocyte antigen (HLA)
mismatch in the graft-versus-host direction (o3 vs 3) and
in the rejection direction (o3 vs 3) and gd status (high vs
normal/low). Kaplan–Meier curves were conducted for
time to OS and LFS for gd T cell status (high and normal/
low) and primary disease (AML and ALL), and compared
by log-rank test. P-values less than 0.05 were considered to
indicate statistical significance. The Cox proportional
hazard model was used to estimate the relative risk of
individual risk factors, with confidence interval (CI) of
95%. The effect of gd status (elevated or not) and potential
factors were analyzed using stepwise Cox proportional–
hazard model, with a value of P ¼ 0.05 necessary to enter
into the model. Cumulative incidence was calculated as per
and the IBMTR/ABMTR Statisticians Manual. All
analyses were performed with SAS software (version 8.1).
From 1993 to 1999, of 201 patients with acute leukemia
who underwent PMRD HSCT, 153 (ALL n ¼ 77; AML
n ¼ 76) survived to day þ 59 and were included in the
analysis. Of these, 18 patients (ALL n ¼ 14, AML n ¼ 4)
Long-term LFS with increased cd T cells post stem cell transplantation
KT Godder et al
Bone Marrow Transplantation
recovered with an increased gd T cell number. The
remaining 135 patients recovered with a normal or
decreased level of gd T cells. Median day to development
of elevated gd T cells was 140 days, whereas median day to
survival in the low gd group was 193 days. Median follow-
up of the survivors was 1771 days.
Frequencies of patient, donor and transplant character-
istics are detailed in Table 1. Among 153 acute leukemia
patients, median age was 22 years (1–59) and most patients
(62%) were in relapse at transplant. Major HLA disparity
was A, B and DR loci mismatched in 37% of patients
(graft-versus-host direction) and 29% of donors (rejection
direction). Donors’ median age was 27 (4–67) years and
46% donor–recipient pairs were sex mismatched. All
patients received partially T cell-depleted grafts, prepared
with T10B9 anti-ab (n ¼ 46) or OKT3 pan-T cell (n ¼ 107)
monoclonal antibody. Patients who recovered with in-
creased number of circulating gd T cells were, in general,
younger, more likely to be male and more often carried the
diagnosis of ALL. Also, their donors were younger. No
other characteristic differed between patients with in-
creased vs normal/low gd T cell count. It is of interest that
although patients who recovered with an increased gd T cell
count did not receive a substantial higher dose of T cell
dose in their grafts (median 52 500 vs 48 000 T cells/kg),
they were more likely to receive T10B9 (anti-ab antibody)-
depleted grafts than OKT3 (pan T cell antibody)-depleted
grafts (15 vs 10%).
Leukemia-free-survival and overall survival
Patients with ALL and AML were analyzed together as no
significant differences were seen between disease outcomes
(data not shown). Patients who recovered with an increased
number of gd had a better LFS compared to those who
recovered with normal/low numbers, resulting in a 5-year
LFS of 54.4 vs 19.1%, P ¼ 0.0003 (Figure 1a). Similarly,
Kaplan–Meier analysis of OS showed that patients
recovering with an increased gd T cell count had an
Table 1 Frequencies of patient, donor and transplant character-
istics comparing patients with high vs normal/low gd T cells following
bone marrow transplantation
Variable Increased gd,
N (%)
Normal/low gd,
N (%)
N ¼ 18 N ¼ 135
Patient characteristics
Age (years)
o10 9 (50) 32 (23)
X10 9 (50) 103 (76)
Male 14 (78) 81 (60)
Female 4 (22) 54 (40)
ALL (n ¼ 77) 14 (78) 63 (47)
AML (n ¼ 76) 4 (22) 72 (53)
Disease state
Remission 8 (44) 50 (37)
Relapse 10 (56) 85 (63)
Caucasian 14 (78) 97 (72)
Other 4 (22) 38 (28)
CMV recipient
Positive 11 (61) 73 (54)
Negative 7 (39) 62 (46)
Donor characteristics
Sibling 7 (39) 52 (39)
Other 11 (61) 83 (61)
Donor age (years)
o28 14 (78) 68 (50)
X28 4 (22) 67 (50)
Sex mismatch
Yes 10 (56) 61 (45)
No 8 (44) 74 (55)
HLA-antigen mismatch GvHD direction
o3 major loci 15 (83) 82 (61)
3 major loci 3 (17) 53 (39)
HLA-antigen mismatch rejection direction
o3 major loci 15 (83) 93 (69)
3 major loci 3 (17) 42 (31)
CMV donor
Positive 8 (44) 69 (51)
Negative 10 (56) 66 (49)
Transplant characteristics
Depleting agent
T10B9 (n ¼ 46) 7 (39) 39 (29)
OKT3 (n ¼ 107) 11 (61) 96 (71)
Abbreviations: ALL ¼ actute lymphoblastic leukemia; AML ¼ actute
myelogenous leukemia; CMV ¼ cytomegalovirus sero-positivity; GvHD ¼
graft-versus-host disease; HLA ¼ human leukocyte antigen.
Cum survival
Cum survival
Event free survival
 High
 High
 Low
 Low
Overal survival
Figure 1 Kaplan Meier curves of event-free survival (a) and overall
survival (b) of patients who recovered post PMRD-BMT with high vs low/
normal gd T-cells.
Long-term LFS with increased cd T cells post stem cell transplantation
KT Godder et al
Bone Marrow Transplantation
improved 5-year survival over those who recovered with
normal or lower numbers (5-year OS: 70.8 vs 19.6%,
Po0.0001 by log-rank test, Figure 1b). To prevent the
possible selection bias of patients who survived longer,
another analysis limited to patients who survived beyond
day þ 140 (the median day of increased gd T cell recovery)
showed the same survival advantage in increased gd T cell
patients (5-year LFS and OS of increased compared to low/
normal gd T cell was 57.7 vs 30.9%, P ¼ 0.0082 and 70.8 vs
27.9%, P ¼ 0.0005, respectively).
In a Cox univariate analysis of LFS, two factors were found
to have a statistically significant association with a negative
outcome: normal/low gd T cells (P ¼ 0.0007) and donor
age X28 (P ¼ 0.018). In the Cox multivariate regression
analysis, normal/low level of gd T cells (P ¼ 0.0002) was
still significant, whereas donor age was not and mismatched
donor sex emerged with a borderline significance (P ¼ 0.049).
Overall, patients with a normal/low gd T cell count had 4.3
(95% CI 1.9–9.7) times greater risk of unfavorable LFS
compared to those who had increased gd after accounting for
the effect of the mismatched donor sex (Table 2). Similarly for
OS, in a univariate analysis, low/normal gd (P ¼ 0.0002),
donor age X28 (P ¼ 0.012) and patient age (continuous
P ¼ 0.039, 422 (median) P ¼ 0.028 and by decade P ¼ 0.023)
negatively affected survival, whereas in a multivariate
Cox regression, only normal/low gd Tcells(P ¼ 0.0002)
remained significant for poor survival. Patients with normal/
low gd had 6.7 (95% CI 2.4–18.1) times greater risk of death
than those who had increased gd T cells (Table 3).
It is of interest that despite infusion of a higher T cell dose
and recovery of gd T cells to a higher level, there was no
increase in the incidence of acute GvHD in the study group
(Figure 2).
Five of 18 patients in the increased gd T cell group relapsed
compared to 48 of 135 in the normal/low gd group
(P-value ¼ 0.65). Relapsed patients with increased gd
T cells were more likely to be salvaged (and hence the
difference between risk of relapse and LFS). Three of five
(60%) patients with increased gd T cells who relapsed after
transplant were surviving at the time of the analysis (all
received donor leukocyte infusion) compared to only one
survivor out of 48 relapsed patients in the normal/low gd
Cause of death
Patients with normal/low numbers of gd T cells died from
recurrent disease (n ¼ 49), graft failure (n ¼ 3), GvHD
(n ¼ 12), infection (n ¼ 18), secondary malignancy (n ¼ 8)
and other transplant-related toxicities (n ¼ 14). Patients
with an increased gd T cell count died from relapse (n ¼ 2),
chronic GvHD (n ¼ 1) and viral infection (n ¼ 1).
Our data demonstrate a long-term survival advantage in a
group of high-risk acute leukemia patients who recovered
with increased number of circulating gd T cells following
partially mismatched related HSCT, with no increased
Table 2 Analyses of factors affecting LFS in recipients of T-cell-
depleted grafts from partially mismatched related donors
(a) Univariate analysis
Variable P-value
Donor age (years)
o28 vs X28 0.018
gd number
High vs normal/low 0.0007
(b) Multivariate analysis
Risk factor Hazard ratio 95% CI P-value
Sex mismatch 1.45 1.002–2.01 0.049
Normal/low gd 4.26 1.87–9.71 0.0003
Abbreviations: CI ¼ confidence interval; LFS ¼ leukemia-free survival.
Table 3 Analysis of factors affecting OS in recipients of T-cell-
depleted grafts from partially mismatched related donors
(a) Univariate analysis
Variable P-value
Donor age o28
o28 vs X28 0.012
gd number
High vs normal/low 0.0002
(b) Multivariate analysis
Risk factor Hazard ratio 95% CI P-value
Normal/low gd 6.7 2.4–18.1 0.0002
Abbreviations: CI ¼ confidence interval; OS ¼ overall survival.
0 20406080
0 1
1 1
Cumulative incidence of GVHD
Figure 2 Cumulative incidence of acute GvHD in patients with high (1 1)
vs normal/low (0 1) gd T-cells.
Long-term LFS with increased cd T cells post stem cell transplantation
KT Godder et al
Bone Marrow Transplantation
incidence of acute GvHD, confirming and extending
previously published preliminary findings.
These patients
were four times more likely to survive disease-free
compared to patients who recovered with normal or lower
numbers of this specific T cell subset.
As activated gd T cells were shown to facilitate
we censored all patients before day
þ 59 (the earliest gd T cell population recovery), thereby
excluding patients who succumb to early transplant
mortality or non-engraftment, and decreasing the like-
lihood of a selective bias. Given the small number of
patients who recovered with increased gd T cells, there were
limitations to a more extensive and conclusive analysis.
Considering that patients were included if they developed
increased gd T cells at any time in the first year post
transplant, we may have selected patients who were fit for
repeated studies and had more chance to develop a high gd
T cells by virtue of their longer survival. To prevent such a
selective bias, we performed a subset analysis including
only those patients who survived beyond day þ 140 (the
median day of increased gd T cells), and still proved
survival advantage to patients with increased level of gd T
cell subset. Additionally, median survival of low/normal gd
patients was 193 days compared to median survival for the
high gd patients of 140 days, further excluding the
possibility of survival bias. Moreover, our study was
strengthened by a patient cohort treated in the same
institution, with standardized treatment protocols includ-
ing a partial T cell-depleted marrow from a haploidentical
donor, a uniform post transplant GvHD prophylaxis
regimen (cyclosporine, steroids and anti-thymocyte globu-
lin) and support care management.
Thereby, other
potential confounders of transplant outcomes, such as,
anti-infective, general practice care, graft manipulation for
T cell depletion, and GvHD prophylaxis and treatment,
were eliminated.
The low incidence of acute GvHD in patients recovering
with increased circulating gd T cells is not surprising
because these T cells do not recognize classical MHC-
associated antigens and are not expected to initiate GvHD.
Data from our laboratory and others indicate that gd T
cells do not require MHC class II for their maturation
proliferation in response to an allogeneic MHC disparity
and are not initiators of GvHD.
Moreover, Drobyski
showed that large doses of interleukin-2 (IL-2) expanded gd
T cells could be infused into lethally irradiated MHC-
disparate mice (C57BL/6 [H-2
]-B10.BR [H-2
] and
C57BL/6 [H-2
]-B6D2F1 [H-2
]) without causing
GvHD. Subsequent studies by Drobyski
showed that
although activated gd and naive ab T cells exacerbated
GvHD when infused together, delaying the infusion of ab T
cells by 2 weeks resulted in improved survival. These
findings are consistent with Ellison,
who noted that gd T
cells could be activated in the GvHD reaction but found no
evidence that GvHD was initiated by gd T cells.
In human studies, Schilbach
and Lamb
found that gd
T cells are not substantially activated in the in vitro
allogeneic mixed lymphocyte culture. Several post BMT
studies have shown transient increases in gd T cells
have not associated this finding with GvHD, although
found that gd T cells could be recruited to lesions
and activated by CD4 þ ab T cells. Kawanishi
273 recipients of T10B9 T cell-depleted bone marrow graft
(62 from HLA-matched sibling donors, 54 PMRD and 157
unrelated donors) and showed that the gd T cell dose was
not associated with the risk of acute or chronic GvHD.
Our next question was whether the improved LFS in our
study was related to an anti-leukemic effect of gd T cells.
Because of the small number of patients and the relatively
rare event, it was difficult to show differences in risk of
relapse between the increased and normal/low gd T cell
groups. Nevertheless, other studies have suggested a gd T
cell-mediated anti-leukemic effect. Using in vivo activated
gd T cells (with IL-2 and pamidronate), Wilhelm et al
observed anti-leukemic responses in three of 10 high-risk
patients. Laboratory studies from our group have shown
that co-culture of donor-derived gd T cells with recipient
ALL cells results in proliferation of predominantly Vd1 þ
cells and a time-dependent lysis. This effect was not noted
when gd T cells were incubated with third party mono-
nuclear cells.
The expanded gd T cell subtype in 490%
of our survivors was predominately Vd1 þ . Although the
biological implications of this finding are incompletely
understood, previous studies suggest both a depletion of
the Vd2 subset and activation and expansion of the Vd1
subset may be responsible for this.
Whether these findings are unique to T cell-depleted
grafts is not clear because there are very few publications
on immune reconstitution post HSCT that report on
recovery of the gd T cell subpopulation. In general, studies
on immune reconstitution post HSCT demonstrate no
significant qualitative differences between recipients of T
cell-depleted and recipients of unmodified grafts, although
immune reconstitution is relatively delayed in the T cell-
depleted group.
showed that a post BMT
absolute increase in gd T cells was significantly associated
with ab T cell depletion, as patients who received grafts that
were T cell depleted with OKT3, a pan T cell monoclonal
antibody, rarely showed an increase in gd T cells post BMT
(P ¼ 0.05). However, there was no difference in survival
between the two T cell depletion (TCD) regimens for
patients who developed increased gd T cells. Whether an
increased gd T cell represents a faster immune reconstitu-
tion and not a specific subset recovery is possible; however,
in earlier studies, we have shown that the lymphocyte
subsets recovery post PMRD HSCT follows a ‘normal’
recovery pattern.
Other than this report, only 2 small studies report on gd
T cell recovery post transplant; in the first, the authors
associated the increase in gd T cell with frequent serious
whereas in the other with acute GvHD.
patients with increased gd T cell recovery did not suffer
from frequent infections, including CMV reactivation, nor
did they have an increased incidence of GvHD. Possible
reasons for the differences between the studies may be
related to different graft manipulation and GvHD prophy-
Another interesting observation in our patients with
increased gd T cells was the prolonged survival post HSCT
relapse, as most patients were salvageable with post
transplant therapy (mostly DLI). This is in contrast to
patients with normal/low gd T cell counts who succumb
Long-term LFS with increased cd T cells post stem cell transplantation
KT Godder et al
Bone Marrow Transplantation
shortly after relapse. This observation, although in a small
group of patients, may be related to recommencement of
the surveillance role of donor-originated gd T cells.
This report extends our previously published findings
from a single institution showing an association between
increased gd T cells and LFS in PMRD-BMT patients. In
addition, we have summarized investigational laboratory
findings that confirm the capability of gd T cells to
recognize and kill leukemic cells. Taken together, adoptive
cellular therapy with gd T cells may provide a reasonable
approach to prevention of leukemic relapse in the
immediate post transplant period, when the immune system
is severely compromised, without additional risk of acute
This study was supported by NIH NCI R21 CA 76667 and
Leukemia and Lymphoma Society 6507. The study was
presented in part at the ASH meeting 2002 and ASCO meeting
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    • "Several studies have demonstrated a role for human γδ T cells in recognition of transformed cells. γδ T cells have been found with increased frequency in disease-free survivors of acute leukemia following allogeneic bone marrow transplantation [117,118]. In addition, adoptive transfer of ex vivo-expanded human γδ T cells in a mouse tumor model further supports the in vivo antitumor effects of γδ T cells. "
    [Show abstract] [Hide abstract] ABSTRACT: Excitement is growing for therapies that harness the power of patients' immune systems to combat their diseases. One approach to immunotherapy involves engineering patients' own T cells to express a chimeric antigen receptor (CAR), to treat advanced cancers, particularly those refractory to conventional therapeutic agents. Although these engineered immune cells have made remarkable strides in the treatment of patients with certain hematologic malignancies, success with solid tumors has been limited, probably due to immunosuppressive mechanisms in the tumor niche. In nearly all studies to date, T cells bearing αβ receptors have been used to generate CAR T cells. In this review, we highlight biological characteristics of γδ T cells that are distinct from those of αβ T cells, including homing to epithelial and mucosal tissues and unique functions such as direct antigen recognition, lack of alloreactivity, and ability to present antigens. We offer our perspective that these features make γδ T cells promising for use in cellular therapy against several types of solid tumors, including melanoma and gastrointestinal cancers. Engineered γδ T cells should be considered as a new platform for adoptive T cell cancer therapy for mucosal tumors.
    Full-text · Article · Jul 2016
    • "Lamb and colleagues found that the five year leukemiafree survival (LFS) and OS of acute leukemia patients with increased γδ T cells after HSCT was significantly higher compared with those with normal/decreased γδ T cells. Meanwhile, this group also demonstrated in vitro that original donor γδ T cells are less likely to mediated GvHD effects [21][22][23]. Most recently, Vδ1 and Vδ2 T cell clones expanded in vivo have been demonstrated to efficiently lyse primary lymphoid and myeloid blasts in patients who received HLA-haploidentical transplantation (haplo-HSCT) [24][25][26][27]. "
    [Show abstract] [Hide abstract] ABSTRACT: The outcome for T-cell acute lymphoblastic leukemia (T-ALL) in relapse after hematopoietic stem cell transplantation (HSCT) is quite poor, while, both donor lymphocytes infusion (DLI) and adoptively infusion of γδ T cells in leukemia patients after HSCT have demonstrated good results in prolonging survival time of patients. Here, we reported a T-ALL case who experienced three relapses and received HSCT and DLI with an overall survival (OS) time lasting for more than seven years. Based on our previous identification of a leukemic and reactive clone in this patient, continual γδ T cell repertoire monitoring affirmed that the same Vδ5 leukemic clone existed in most samples from the patient, particularly including a sample taken at the time of the third T-ALL relapse, while it could not be detected in the donor sample. In addition, an identical Vδ4 monoclonal T cell that proliferated in the recipient for several years was confirmed to come from the donor graft, and its expression level significantly increased in third leukemia recurrence. These results indicate that clonally expanded Vδ4 T cells may represent a reconstituted γδ T cell repertoire after HSCT, which also hints to a relatively better outcome for this case. Based on this case study, we recommend DLI should be as a treatment strategy for patients who achieve CR or relapse from HSCT. Moreover, dynamically monitoring the TCR repertoire in patients who receive HSCT will benefit in supervising of malignant clone evolution and residue, identifying T cell clones mediate anti-infection, GvHD or GvL.
    Article · Jun 2016
    • "In a recent study, which integrated tumor gene expression profiles and overall survival data from nearly 18,000 patients, intra-tumoral gd T cell signatures emerged as the most significant favorable cancer-wide prognostic population, and at the molecular level, CD161 has been identified as the top favorable pan-cancer prognostic gene (Gentles et al., 2015 ). Both indirect and direct evidence for the anti-leukemic potential of gd T cells have also been obtained (Airoldi et al., 2015; Godder et al., 2007; Wilhelm et al., 2014). Inflammatory and immune responses are associated with the controlled or lytic release of nucleotides, particularly ATP (Idzko et al., 2014). "
    [Show abstract] [Hide abstract] ABSTRACT: In humans, Vγ9Vδ2 T cells respond to self and pathogen-associated, diphosphate-containing isoprenoids, also known as phosphoantigens (pAgs). However, activation and homeostasis of Vγ9Vδ2 T cells remain incompletely understood. Here, we show that pAgs induced expression of the ecto-ATPase CD39, which, however, not only hydrolyzed ATP but also abrogated the γδ T cell receptor (TCR) agonistic activity of self and microbial pAgs (C5 to C15). Only mevalonate-derived geranylgeranyl diphosphate (GGPP, C20) resisted CD39-mediated hydrolysis and acted as a regulator of CD39 expression and activity. GGPP enhanced macrophage differentiation in response to the tissue stress cytokine interleukin-15. In addition, GGPP-imprinted macrophage-like cells displayed increased capacity to produce IL-1β as well as the chemokine CCL2 and preferentially activated CD161-expressing CD4+ T cells in an innate-like manner. Our studies reveal a previously unrecognized immunoregulatory function of CD39 and highlight a particular role of GGPP among pAgs.
    Article · Jun 2016
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