CTLA-4 genotype and relapse incidence in patients with acute myeloid leukemia in first complete remission after induction chemotherapy

Article (PDF Available)inLeukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 23(3):486-91 · March 2009with22 Reads
DOI: 10.1038/leu.2008.339 · Source: PubMed
Abstract
The recently described single-nucleotide polymorphism CT60, located in the 3'-untranslated region of the CTLA4 (cytotoxic T-lymphocyte antigen 4 ) gene, has been associated with susceptibility to several autoimmune diseases and has also been shown to be involved in immune responses following allogeneic stem cell transplantation (SCT). However, the contribution of the CTLA4 genotype to the control of minimal residual disease in patients with acute myeloid leukemia (AML) has yet to be explored. We investigated the association between the CTLA4 CT60 A/G genotype and the incidence of leukemic relapse in 143 adult patients with AML in first complete remission after the same chemotherapy protocol (CETLAM LAM'03). The CT60 AA genotype was associated with a higher rate of leukemic relapse (56.4 vs 35.6%, P=0.004; hazard ratio (HR)=2.64, 95% confidence interval (CI)=1.36-5.14) and lower overall survival at 3 years (39.4 vs 68.4%, P=0.004; HR=2.80, 95% CI=1.39-5.64). This is the first study to report an association between polymorphisms at CTLA-4 and AML relapse.

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ORIGINAL ARTICLE
CTLA-4 genotype and relapse incidence in patients with acute myeloid leukemia in first
complete remission after induction chemotherapy
APe
´rez-Garcı´a
1
, S Brunet
2
, JJ Berlanga
1
, M Tormo
3
, J Nomdedeu
2
, R Guardia
1
, JM Ribera
1
, I Heras
4
, A Llorente
5
, M Hoyos
2
,
J Esteve
6
, J Besalduch
7
, J Bueno
8
, J Sierra
2
, D Gallardo
1
, ‘Grupo cooperativo para el estudio y tratamiento de las leucemias agudas
y mielodisplasias’ (CETLAM)
1
Hematology Department, Institut Catala
`d’Oncologia, Girona, L’Hospitalet and Badalona, Spain;
2
Hematology Department,
Hospital de la Santa Creu I Sant Pau, Barcelona, Spain;
3
Hematology Department, Hospital Clı´nico, Valencia, Spain;
4
Hematology Department, Hospital Morales Meseguer, Murcia, Spain;
5
Hematology Department, Hospital Joan XXIII, Tarragona,
Spain;
6
Hematology Department, Hospital Clı´nic, Barcelona, Spain;
7
Hematology Department, Hospital Son Dureta, Palma de
Mallorca, Spain and
8
Hematology Department, Hospital Vall d’Hebro
´n, Barcelona, Spain
The recently described single-nucleotide polymorphism CT60,
located in the 30-untranslated region of the CTLA4 (cytotoxic
T-lymphocyte antigen 4 ) gene, has been associated with
susceptibility to several autoimmune diseases and has also
been shown to be involved in immune responses following
allogeneic stem cell transplantation (SCT). However, the
contribution of the CTLA4 genotype to the control of minimal
residual disease in patients with acute myeloid leukemia (AML)
has yet to be explored. We investigated the association
between the CTLA4 CT60 A/G genotype and the incidence
of leukemic relapse in 143 adult patients with AML in first
complete remission after the same chemotherapy protocol
(CETLAM LAM’03). The CT60 AA genotype was associated with
a higher rate of leukemic relapse (56.4 vs 35.6%, P¼0.004;
hazard ratio (HR) ¼2.64, 95% confidence interval (CI) ¼1.36–
5.14) and lower overall survival at 3 years (39.4 vs 68.4%,
P¼0.004; HR ¼2.80, 95% CI ¼1.39–5.64). This is the first study
to report an association between polymorphisms at CTLA-4
and AML relapse.
Leukemia (2009) 23, 486–491; doi:10.1038/leu.2008.339;
published online 18 December 2008
Keywords: CTLA-4; acute myeloid leukemia; relapse
Introduction
The cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a homologous
molecule of CD28 that plays a critical role in the control of
T-cell activation. CTLA-4 has greater affinity and avidity for
B7 than does CD28, and its translocation to the cell surface
after T-cell activation results in a negative signal, which is
responsible for T-cell inactivation.
1–3
The human CTLA-4 gene is located on 2q33, in a suscepti-
bility region for autoimmune diseases. Several single-nucleotide
polymorphisms have been described within the CTLA-4 gene.
Among these single-nucleotide polymorphisms, the most
studied have been þ49A/G in exon 1, which leads to an
alanine-to-threonine amino-acid substitution at codon 17 in the
leader peptide, and CT60, located in the 30-untranslated region
of the gene. The G allele of þ49A/G and the CT60 G allele
have been reported to increase susceptibility to several
autoimmune diseases
4,5
but it has also been related to
a decrease in graft-versus-host disease after allogeneic trans-
plantation.
6
Moreover, certain CTLA-4 polymorphisms have
been reported to be more prevalent in patients with renal cancer
or sporadic breast cancer,
7
suggesting that increased expression
of CTLA-4 would be associated with a decreased ability of the
immune system to detect and eliminate tumor-associated
antigens. However, little is known about the relationship
between the CTLA-4 genotype and the incidence of cancer
relapse once complete remission has been obtained through
chemotherapy.
Although acute myeloid leukemia (AML) can be cured after
standard chemotherapy and stem cell transplantation (SCT),
relapse after the first complete remission remains one of the
main causes of mortality. Here, we attempt to determine
whether the CTLA-4 gene polymorphism CT60 influences the
clinical outcome of patients with AML after obtaining the first
complete remission through standard induction chemotherapy.
Patients and methods
Patients
Participants included in this analysis were 198 adult patients
younger than 60 years. They all had primary AML and were
enrolled and treated in 19 Spanish institutions involved in the
prospective LAM’03 trial of the ‘Grupo Cooperativo para el
Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias’
(CETLAM). This study was opened for accrual in August 2003
and is still recruiting patients. The corresponding institutional
review boards approved the study and all patients signed an
informed consent form before entering the study. Inclusion
criteria were as follows: age between 18 and 60 years, diagnosis
of AML according to the French-American-British classification,
no history of myelodysplasia or previous cytotoxic drugs or
radiation and absence of severe concomitant disease. Patients
with acute promyelocytic leukemia were excluded and treated
in a separate trial.
In short, induction chemotherapy consisted of idarubicin
12 mg/m
2
intravenously (days 1, 3, 5), cytarabine 500 mg/m
2
/
12 h intravenously over 2 h (days 1, 3, 5, 7) and etoposide
(VP-16) 100 mg/m
2
intravenously (days 1, 2, 3); intensification
included cytarabine 500 mg/m
2
/12 h intravenously (days 1–6)
and mitoxantrone 12 mg/m
2
intravenously (days 4–6). Priming
Received 1 September 2008; revised 9 October 2008; accepted 7
November 2008; published online 18 December 2008
Correspondence: Dr D Gallardo, Clinical Hematology Department,
Institut Catala
`d’Oncologia, Hospital Josep Trueta, Institut d’Investi-
gacio
´Biome
`dica de Girona Josep Trueta, Avda. Franc¸a s/n, Girona
17007, Spain.
E-mail: 27532dgg@comb.es
The list of participant centres and current group members appears in
Appendix 1.
Leukemia (2009) 23, 486–491
&2009 Macmillan Publishers Limited All rights reserved 0887-6924/09 $32.00
www.nature.com/leu
with granulocyte-colony-stimulating factor was done during both
induction and intensification chemotherapy. Subsequent treat-
ment was as follows: patients with good prognosis cytogenetics
(defined as the presence of inversion 16, t(16;16) or t(8;21))
received cytarabine 3 g/m
2
/12 h intravenously (days 1, 3, 5);
patients with normal cytogenetics (in 20 metaphases), without
MLL rearrangement, FLT3-ITD negative and requiring only one
course of induction chemotherapy to achieve complete remission
were assigned to receive an autologous peripheral blood
transplantation as the post-remission strategy. The remaining
patients (that is, patients with cytogenetic abnormalities other
than t(8;21) or inv(16), FLT3-ITD positive, those without
valuable mitoses or those with normal karyotype requiring two
cycles to achieve complete remission) were allocated to
allogenic SCT or autologous transplantation according to human
leukocyte antigen-identical sibling donor availability.
Complete remission was defined as the presence of less than
5% of blast cells in a bone marrow smear after the first or second
course of induction therapy. Patients with a reduction of less
than 50% in marrow leukemia cells after the first course and
those who did not achieve a complete remission after two
courses were considered as refractory and were excluded.
CTLA-4 genotyping
DNA was obtained from peripheral blood or bone marrow
samples by standard procedures. PCR-restriction fragment
length polymorphism (PCR-RFLP) was used to genotype the
CTLA-4 CT60 single-nucleotide polymorphism. The primers
used were: forward 50-CACCACTATTTGGGATATACC-30,
reverse 50-AGCTCTATATTTCAGGAAGGC-30. PCRs were per-
formed with 100 ng DNA, as previously described,
6
and 3 mlof
the amplified products were digested for 1 h at 37 1C with 1 U of
NcoI (New England Biolabs, Beverly, MA, USA) in a total
reaction volume of 10 ml. The digestion products were resolved
in 3% agarose gels stained with ethidium bromide. Patients were
stratified into two groups according to their CT60 genotype:
patients homozygous for the CT60 A allele and patients carrying
at least one G allele (AG or GG).
Statistical analysis
Homogeneity between the CT60 AA and the CT60 AG/GG cohorts
was calculated using the w
2
-test for qualitative variables and the
Student’s t-test for continuous variables. Overall survival (OS)
and disease-free survival (DFS) were calculated by means of the
Kaplan–Meier method with comparison of curves using the log-rank
test. Statistical incidence estimates were used to determine the
cumulative incidence of relapse and non-relapse mortality depend-
ing on the CT60 genotype. Death in complete remission was
considered a competing risk in the analysis of relapse incidence. For
non-relapse mortality, relapse was the competing risk.
Multivariate Cox regression models using a forward stepwise
procedure with the likelihood ratio criterion (inclusion/
exclusion criteria: Pp0.05/P40.10, respectively) were applied
to analyze the combined effects of CTLA-4 CT60 polymorphism
and other factors on OS and relapse. All variables in the
univariate analysis with a P-value at or below 0.2 were included
in the multivariate analysis.
Results
CT60 genotype distribution
After receiving standard induction chemotherapy, 143 out of
198 patients obtained complete remission (72.2%). Twenty-six
patients (13.1%) showed chemoresistance and 25 (12.6%) died
due to complications during the treatment. Four cases could
not be evaluated for remission. When considering only those
patients achieving complete remission, we were able to obtain
the CT60 genotype in 138 cases: 39 patients (28.2%) were
homozygous for the CT60 A allele, whereas 99 (71.8%) were
carriers of at least one G allele (CT60 AG/GG). These genotype
frequencies were similar in the patients who did not enter
remission and are comparable to those previously described in
healthy stem cell donors.
Table 1 shows the comparison of these two groups as regards
the clinical characteristics of the patients. No significant
differences were detected with respect to age, French-Amer-
ican-British subtype, cytogenetics according to the Medical
Research Council criteria or FLT3 internal tandem duplication
(FLT3-ITD), number of cycles needed to obtain complete
remission or type of stem cell transplant received.
Overall survival
An increased OS at 3 years was observed for patients with the
CT60 AG/GG genotype when compared with the cohort of
patients homozygous for the CT60 A allele (68.4 vs 39.4%;
P¼0.013) (Figure 1). This association was maintained in the
Table 1 Clinical characteristics of the patients according to their
CTLA4 CT60 genotype
CT60 AA
(n¼39)
CT60 AG/
GG (n¼99)
P-value
Age (median-range) 42 (21–58) 46 (18–60) 0.599
Sex
Male 25 (64.1%) 54 (54.5%)
Female 14 (35.9%) 45 (45.5%) 0.307
FAB
M0 2 (5.1%) 3 (3.0%)
M1 9 (23.1%) 20 (20.2%)
M2 11 (28.2%) 26 (26.3%)
M4 8 (20.5%) 25 (25.3%)
M5 7 (17.9%) 16 (16.2%)
M6 1 (2.6%) 4 (4.0%)
Not classified 1 (2.6%) 5 (5.1%) 0.601
Cytogenetics
MRC good prognosis 3 (7.7%) 13 (13.1%)
MRC intermediate 28 (71.8%) 61 (61.6%)
MRC bad prognosis 5 (12.8%) 11 (11.1%)
No metaphases 3 (7.7%) 14 (14.1%) 0.536
FLT-3
Germinal 26 (66.6%) 71 (71.7%)
ITD 10 (25.6%) 20 (20.2%)
Missing 3 (7.7%) 8 (8.1%) 0.488
Cycles to CR1
One cycle 32 (82.1%) 83 (83.8%)
Two cycles 7 (17.9%) 16 (16.2%) 0.800
Stem cell transplantation
Autologous 14 (35.9%) 32 (32.3%)
Allogeneic 14 (35.9%) 30 (30.4%)
Syngeneic 2 (5.1%) 0 (0%)
Not performed 9 (23.1%) 37 (37.4%) 0.133
Abbreviations: CR, complete remission; FAB, French-American-British;
MRC, Medical Research Council.
CTLA-4 genotype and AML relapse
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multivariate analysis, which identified the CTLA-4 CT60 AA
genotype as an independent risk factor for a worse OS
(P¼0.004; hazard ratio (HR) ¼2.80, 95% confidence interval
(CI) ¼1.39–5.64). Table 2 shows the results of the multivariate
analysis.
We also analyzed the impact of the CTLA-4 CT60 genotype
on OS considering only those patients with intermediate-risk
cytogenetics according to the Medical Research Council
criteria, which represented the majority of patients (n¼89).
This analysis revealed the same differences when considering
the whole series (CT60 AG/GG: 68.1% vs CT60 AA: 28.2%;
P¼0.005).
When considering the type of SCT, we found that patients
receiving an autologous transplant also had a better OS at
3 years when the CTLA-4 CT60 genotype was AG/GG (83.3 vs
53.4%; P¼0.048). This effect was not observed after allogeneic
transplant.
Relapse
We observed that patients with a CT60 AA genotype relapsed
more frequently than those with a CT60 AG/GG genotype (56.4
vs 35.6%; P¼0.003) (Figure 2). Multivariate analysis showed
that the CT60 AA genotype was an independent risk factor for
relapse (P¼0.004; HR ¼2.64, 95% CI ¼1.36–5.14). Table 2
also shows the multivariate analysis for relapse.
Patients receiving an autologous transplant also had a higher
relapse incidence when the CTLA-4 CT60 genotype was AA;
however, this difference did not reach statistical significance,
probably due to the limited number of cases (AA: 59.1% vs
AG/GG: 33.2%; P¼0.070).
Disease-free survival
As expected given the increased risk of relapse and worse OS,
DFS was affected by the CTLA-4 CT60 genotype. Patients with
the CT60 AA genotype had worse DFS than those with at least
one G allele (32.3 vs 53.9%; P¼0.004) (Figure 3).
Regarding those patients who received an autologous SCT,
the difference in DFS was similar, without reaching statistical
significance (39.2 vs 64.9%; P¼0.065).
Figure 1 Overall survival for patients obtaining first complete remission after standard induction chemotherapy according to their CTLA-4 CT60
genotype.
Table 2 Multivariate analysis for overall survival and leukemia
relapse
(A) Overall survival
FLT3-ITD P¼0.003
HR ¼3.07 (95% CI ¼1.48–6.36)
CT60 genotype (AG/GG) P: 0.004
HR ¼2.80 (95% CI ¼1.39–5.64)
One versus two cycles to obtain CR P¼0.024
HR ¼2.47 (95% CI ¼1.12–5.45)
Age older than 50 years P¼0.041
HR ¼2.11 (95% CI ¼1.03–4.34)
Cytogenetics (poor/intermediate/
poor prognosis)
P¼0.282
HR ¼1.46 (95% CI ¼0.68–3.13)
Peripheral blood leukocytes
450 10
9
/l
P¼0.699
HR ¼1.07 (95% CI ¼0.45–2.55)
(B) Relapse
FLT3-ITD P¼0.018
HR ¼2.38 (95% CI ¼1.16–4.88)
CT60 genotype (AG/GG) P: 0.004
HR ¼2.64 (95% CI ¼1.36–5.14)
Cytogenetics (poor/intermediate/
poor prognosis)
P¼0.088
HR ¼1.59 (95% CI ¼0.80–3.18)
One versus two cycles to obtain CR P¼0.097
HR ¼2.49 (95% CI ¼0.93–6.60)
Age older than 50 years P¼0.214
HR ¼1.85 (95% CI ¼0.89–3.84)
Peripheral blood leukocytes
450 10
9
/l
P¼0.718
HR ¼1.67 (95% CI ¼0.71–3.94)
Abbreviations: CR, complete remission; FLT3-ITD, FLT3 internal
tandem duplication; HR, hazard ratio.
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We found no differences in non-relapse mortality with respect
to the CTLA-4 CT60 genotype (CT60 AA: 5.8% vs CT60 AG/GG:
11.7%, P¼0.393).
Discussion
CTLA-4 is a key factor in regulating and maintaining self-
tolerance, providing a negative signal to the T cell and thus
limiting immune responses. Several polymorphisms within the
CTLA4 gene have been associated with an increased risk of
developing autoimmune diseases. The most widely studied of
these polymorphisms have been þ49 A/G, CT60, 318 C/T and
1722 C/T.
8,9
Specifically, the presence of a G allele in the
þ49 position or in the CT60 single-nucleotide polymorphism in
the 30-untranslated region has been identified as a risk factor for
developing coeliac disease, systemic lupus erythematosus,
multiple sclerosis, chronic inflammatory arthropathies, Sjo
¨gren’s
syndrome or autoimmune thyroiditis.
10–12
Figure 2 Relapse incidence after obtaining first complete remission with standard induction chemotherapy, depending on the CTLA-4 CT60
genotype.
Figure 3 Disease-free survival according to the CTLA-4 CT60 genotype.
CTLA-4 genotype and AML relapse
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Leukemia
Moreover, a high incidence of CTLA-4 CT60 AA and þ49 AA
genotypes has been reported in patients with renal cell cancer,
suggesting a role for the CTLA4 gene in tumor development.
13
In other words, the presence of a more tolerogenic CTLA4
genotype could represent a potential form of tumor immune
evasion. However, little is known regarding the impact of the
CTLA-4 genotype on the maintenance of cancer remission once
the treatment with chemotherapy has been successful.
The role of immunological surveillance as a mechanism to
control minimal residual disease is controversial in patients with
AML, because induction chemotherapy may impair the ability of
T lymphocytes to recognize tumor-associated antigens. More-
over, the previously described low level of expression of
costimulatory molecules on the surface of leukemic blasts may
also facilitate tumor escape from immune system action.
14
However, it has been reported that vaccination strategies using
leukemia-associated antigens, such as WT1 or PR1, may be
associated with the development of specific autologous cyto-
toxic T cells and with clinical responses, suggesting that the
autologous immune response is important in the control of
leukemic proliferation.
15
We found that AML patients with the
CTLA4 CT60 AA genotype have a higher relapse incidence after
obtaining a first complete remission with standard chemother-
apy, leading to worse OS. It therefore seems possible that the
presence of a ‘tolerogenic’ CTLA4 genotype is associated with a
lower ability of the immune system to detect and eliminate
residual leukemic cells.
The CT60 AA genotype has been reported to increase the
production of the soluble form of CTLA4, and we have
previously described an increased risk of graft-versus-host
disease and lower relapse rate after allogeneic SCT when the
donor’s CTLA4 CT60 genotype was homozygous for the A
allele.
6
These previous results seem to contradict not only
those of this study but also the more frequent observation of the
CT60 G genotype in patients with autoimmune diseases.
However, it should be considered that, in the context of an
allogeneic SCT, T lymphocytes from the donor may recognize a
broad spectrum of minor histocompatibility antigens, enhancing
the occurrence of immune reactions. Moreover, it has been
recently reported that the soluble form of CTLA4 (sCTLA4) is
able to suppress proliferation of autoreactive T-cell clones,
whereas abatacept (CTLA4-Ig) and belatacept (LEA29Y) are not.
In contrast, CTLA4Ig and LEA29Y, as opposed to sCTLA4, are
able to suppress naive alloreactive proliferation in a mixed
leukocyte reaction, indicating a differential role for sCTLA4,
CTLA4Ig and LEA29Y proteins in memory versus primary
immune responses.
16
The observation that immune inhibitory pathways through
CTLA-4 may influence leukemic relapse after obtaining com-
plete remission with standard chemotherapy is relevant because
the blockade of these inhibitory signals appears to be a
promising strategy for leukemia immunotherapy. Following this
rationale, two different fully-human anti-CTLA-4 antibodies
(ipilimumab and tremelimumab) have shown promising anti-
tumour activity in patients with advanced melanoma.
17
According to our results, it would seem appropriate to test the
usefulness of these antibodies in maintaining AML complete
remission, at least in patients with high-risk leukemia and the
CTLA-4 CT60 AA genotype.
Conclusion
We conclude that CTLA-4 polymorphisms are involved in the
incidence of AML relapse after obtaining first complete remission
through standard chemotherapy, thus suggesting the ability of the
immune system to control minimal residual disease.
Acknowledgements
This study has been financed by Grant FIS PI050939 from the
Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III,
Ministerio de Sanidad y Consumo.
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Appendix 1
The centers and investigators contributing to the CETLAM study
were as follows: Institut Catala
`d’Oncologia (ICO) Hospital Josep
Trueta, Girona (David Gallardo, Ramo
´n Guardia, Cristalina
Ferna
´ndez); Hospital de la Santa Creu i Sant Pau, Barcelona
(Salut Brunet, Josep F Nomde
´deu, Montserrat Hoyos, Anna
Aventı´n, Jorge Sierra); Hospital Clı´nic, Barcelona (Jordi Esteve,
Mireia Camo
´s, Marı´a Rozman, Neus Villamor, Dolors Costa);
ICO Hospital Germans Trias i Pujol, Badalona (Josep M Ribera,
Isabel Granada, Albert Oriol); ICO/Duran i Reynals, L’Hospitalet
de Llobregat (Joan Berlanga, Rafael Duarte, Esther Alonso);
Hospital Vall d’Hebro
´n, Barcelona (Javier Bueno, Eva Sa
´nchez,
Teresa Vallespı´); Hospital del Mar, Barcelona (Carmen Pedro,
Lourdes Florensa, Francesc Soler); Clı´nica Teknon, Barcelona
(Pilar Vivancos); Hospital Juan Canalejo, A Corun
˜a (Pio Torres);
Hospital Clı´nico, Ma
´laga (M. Paz Queipo De Llano); Hospital
Clı´nico Universitario, Valencia (Mar Tormo); Hospital Son
Dureta, Palma (Joan Besalduch, Marta Barnue
´s); Hospital Son
Llatzer, Palma (Joan Bargay); Hospital Joan XXIII, Tarragona
(Andreu Llorente, Lourdes Escoda); Hospital Arnau de Vilanova,
Lleida (Antoni Garcı´a-Guin
˜o
´n); Hospital Verge de la Cinta,
Tortosa (Llorenc¸ Font); Hospital Mutua Terrassa, Terrassa (Josep
M Martı´-Tutusaus, Cristina Estany). The laboratory work has been
carried out at the Alloreactivity Unit, Laboratori de Recerca
Translacional, ICO (Arianne Pe
´rez-Garcı´a, David Gallardo).
CTLA-4 genotype and AML relapse
APe
´rez-Garcı
´aet al
491
Leukemia
    • "Abbreviations: CTLA-4: cytotoxic T lymphocyte antigen 4; PD-1: programmed death 1; MDSC: myeloid-derived suppressor cell. inferior 3-year overall survival (OS) in patients with AML, suggesting possible involvement of a " tolerogenic " CTLA-4 genotype that poorly controls minimal residual disease (MRD) [38] . The expression of CTLA- 4 varies in different lymphomas. "
    [Show abstract] [Hide abstract] ABSTRACT: Tumor cells utilize co-inhibitory molecules to avoid host immune destruction. Checkpoint blockade has emerged as a promising approach to treat cancer by restoring T cell effector function and breaking a tumor permissive microenvironment. Patients with hematological malignancies often have immune dysregulation, thus the role of checkpoint blockade in treatment of these neoplasms is particularly intriguing. In early trials, antibodies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) or the programmed death 1 (PD-1) signaling pathway have displayed significant efficacy with minimal toxicity in patients with relapsed and refractory hematological neoplasms. In this review, we provide evidence of dysregulation of CTLA-4 and PD-1/PD-Ls in the context of several major types of hematological neoplasms and summarize relevant clinical practice points for checkpoint blockade. The preclinical rationale and preliminary clinical data of potential combination approaches designed to optimize checkpoint antagonists are well presented.
    Full-text · Article · Nov 2015
    • "During the last several years, growing attention has been focused on polymorphisms in genes of the KIR family (Gagne et al. 2002;Giebel et al. 2009;Ludajic et al. 2009), as well as on cytokine and cytokine receptor genes (BoguniaKubik 2004;Dickinson and Holler 2008;Karabon et al. 2005;Markey et al. 2008). Given the importance of co-stimulatory pathways and attempts to use CTLA-4-Ig to prevent GvHD in animal models (Blazar et al. 1996;Ichiki et al. 2006 ), several published reports evaluated the association between donor CTLA-4 gene polymorphisms and outcome after hematopoietic stem cell transplantation (Bosch-Vizcaya et al. 2012;Iravani-Saadi et al. 2014;Mossallam and Samra 2013;Perez-Garcia et al. 2009;Piccioli et al. 2010). However, the results presented in these studies were inconsistent. "
    [Show abstract] [Hide abstract] ABSTRACT: T cell activation plays a crucial role in the development of acute graft versus host disease (aGvHD). Cytotoxic T cell antigen-4 (CTLA-4) is a co-inhibitory molecule that negatively regulates T cell activation, differentiation, and proliferation. Single-nucleotide polymorphisms (SNPs) in CTLA-4 gene may affect its function. Inconsistent observations have been reported regarding the associations of CTLA-4 SNPs with complications after hematopoietic stem cell transplantation (HSCT). Moreover, the majority of the observations were focused on the donors' SNPs. Recently, a few studies have shown that recipients' genetic variations in the CTLA-4 gene might influence HSCT results. The aim of our study was to determine the influence of the CTLA-4 gene polymorphisms of the donors and the recipients on the outcome of HSCT. Altogether, 312 donor-recipient pairs were genotyped for the CTLA-4c.49A>G (rs231775) and CT60G>A (rs3087243) SNPs using the TaqMan®SNP Genotyping Assays. In this study, it was shown that the recipients' CT60G>A[GG] genotype, the myeloablative conditioning regimen, and HSCT from an unrelated donor were independent aGvHD risk factors (odds ratio (OR) 2.63, 95 % confidence intervals (95 % CI) 1.45-4.59, p = 0.001; OR 2.68, 95 % CI 1.65-4.07, p = 0.00003; and OR 1.87, 95 % CI 1.02-3.24, p = 0.04, respectively). Moreover, haplotype analysis revealed that possessing allele A in both of the SNPs decreased the risk of aGvHD approximately 1.5-fold (RR 0.69, p = 0.008). Our data suggest that the CT60G>A[GG] genotype in the recipient has an impact on aGvHD development, especially in patients receiving transplants from unrelated donors together with the myeloablative conditioning regimen.
    Full-text · Article · May 2015
    • "-Dosing of cell subtypes -Enrichment or priming of alloreactive T cells -Optimal donor selection -Biological assessment of bi-directional alloreactivity NEACT conducive to host or donor-derived TAA-specific T cells generation and other tumor types [136] raises the possibility that CTLA-4 blockade itself may prevent AML relapse. AML relapse is more frequent with a particular genotype associated with increased production of soluble CTLA-4, which is thought to have an anti-proliferative effect on T cells [137]. Blocking or deletion of CTLA-4 promoted T cell-mediated rejection of AML cell lines that express one of its cognate ligands, CD80, in a pre-clinical model [138]. "
    [Show abstract] [Hide abstract] ABSTRACT: Human leukocyte antigen-mismatched leukocyte infusions outside of the context of transplantation are a promising strategy for acute myeloid leukemia. Recent studies using such non-engrafting alloreactive cellular therapy (NEACT) revealed that survival of elderly patients increased from 10% to 39% when NEACT was given following chemotherapy, and that durable complete remissions were achieved in about a third of patients with relapsed or chemorefractory disease. We review the clinical reports of different NEACT approaches to date and describe how although T-cell and NK alloreactivity could generate immediate anti-leukemic effects, long-term disease control may be achieved by stimulating recipient-derived T-cell responses against tumor-associated antigens. Other variables likely impacting NEACT such as the release of pro-inflammatory cytokines from donor-host bidirectional alloreactivity and the choice of chemotherapeutics as well as future avenues for improving NEACT, such as optimizing the cell dose and potential synergies with adjuvant pharmacologic immune check-point blockade, are discussed.
    Full-text · Article · Sep 2014
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