T cells are functionally not impaired in AML: increased PD-1 expression is only seen at time of relapse and correlates with a shift towards the memory T cell compartment

Schnorfeil, Frauke; Lichtenegger, Felix S.; Emmerig, Katharina; Schlueter, Miriam; Neitz, Julia; Draenert, Rika; Hiddemann, Wolfgang; Subklewe, Marion

doi:10.1186/s13045-015-0189-2

Cited by 128 publications

(132 citation statements)

References 60 publications

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“…26 In addition, patients at diagnosis show similar expression profiles of inhibitory molecules (PD-1, 2B4, TIM-3, Lag-3, and CD160) compared with healthy donors, thus lack of T-cell responsiveness as a result of negative immune checkpoint molecules is less likely. 27,28 Furthermore, the proliferative capacity of residual T cells in chemotherapy-induced cytopenic AML patients was preserved and higher than that observed in ALL. 29 Finally, in relapsed patients after allogeneic stem cell transplantation, both PD-1 and 2B4 expression on T cells was higher and associated with a shift toward a differentiated T-effector memory phenotype.…”

Section: Discussionmentioning

confidence: 94%

“…29 Finally, in relapsed patients after allogeneic stem cell transplantation, both PD-1 and 2B4 expression on T cells was higher and associated with a shift toward a differentiated T-effector memory phenotype. 28 Overall, these observations suggest that intervention with a T cell redirecting therapeutic at early diagnosis or in combination with chemotherapy is a rational approach.…”

Section: Discussionmentioning

confidence: 99%

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An anti-CD3/anti–CLL-1 bispecific antibody for the treatment of acute myeloid leukemia

Leong¹,

Sukumaran²,

Hristopoulos³

et al. 2017

Blood

137

128

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• Bispecific antibodies binding CD3 and CLL-1 deplete CLL-1 1 target cells in animal models.• An appropriately engineered CLL-1/CD3 bispecific antibody could be effective in treating AML.Acute myeloid leukemia (AML) is a major unmet medical need. Most patients have poor long-term survival, and treatment has not significantly changed in 40 years. Recently, bispecific antibodies that redirect the cytotoxic activity of effector T cells by binding to CD3, the signaling component of the T-cell receptor, and a tumor target have shown clinical activity. Notably, blinatumomab is approved to treat relapsed/refractory acute lymphoid leukemia. Here we describe the design, discovery, pharmacologic activity, pharmacokinetics, and safety of a CD3 T cell-dependent bispecific (TDB) full-length human IgG1 therapeutic antibody targeting CLL-1 that could potentially be used in humans to treat AML. CLL-1 is prevalent in AML and, unlike other targets such as CD33 and CD123, is not expressed on hematopoietic stem cells providing potential hematopoietic recovery. We selected a high-affinity monkey cross-reactive anti-CLL-1 arm and tested several anti-CD3 arms that varied in affinity, and determined that the high-affinity CD3 arms were up to 100-fold more potent in vitro. However, in mouse models, the efficacy differences were less pronounced, probably because of prolonged exposure to TDB found with lower-affinity CD3 TDBs. In monkeys, assessment of safety and target cell depletion by the highand low-affinity TDBs revealed that only the low-affinity CD3/CLL1 TDB was well tolerated and able to deplete target cells. Our data suggest that an appropriately engineered CLL-1 TDB could be effective in the treatment of AML. (Blood. 2017;129(5):609-618)

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

An anti-CD3/anti–CLL-1 bispecific antibody for the treatment of acute myeloid leukemia

Leong¹,

Sukumaran²,

Hristopoulos³

et al. 2017

Blood

137

128

View full text Add to dashboard Cite

show abstract

“…Inhibitory pathways, including programmed cell death protein 1 (PD-1), T-cell immunoglobulin domain, and mucin domain 3 (TIM-3), 2B4, CD160, B-and T-lymphocyte attenuator (BTLA), and lymphocyte-activation gene 3 (LAG-3), contribute to the development of T-cell exhaustion (14)(15)(16)(17)(18)(19)(20). Several studies, including ours, have demonstrated an involvement of inhibitory pathways in AML progression (21)(22)(23)(24)(25). Strategies for blocking immune suppression are attractive due to their relatively simple administration and the resulting increased T-cell activity and enhanced tumor killing.…”

Section: Introductionmentioning

confidence: 80%

T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell Exhaustion and Poor Clinical Outcome in AML Patients

Kong

Zhu

Schell

et al. 2016

Clinical Cancer Research

231

233

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Purpose: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is a recently identified T-cell coinhibitory receptor. In this study, we aimed to determine the clinical impact of TIGIT in patients with acute myelogenous leukemia (AML) and dissect the role of TIGIT in the pathogenesis of leukemia progression.Experimental Design: TIGIT expression on T cells from peripheral blood collected from patients with AML was examined by flow cytometry. The correlation of TIGIT expression to clinical outcomes, including rate of complete remission and relapse post-allogeneic stem cell transplantation (alloSCT) in AML patients, was analyzed. Phenotypic and functional study (cytokine release, proliferation, killing, and apoptosis) of TIGIT-expressing T cells were performed. Using siRNA to silence TIGIT, we further elucidated the regulatory role of TIGIT in the T-cell immune response by dissecting the effect of TIGIT knockdown on cytokine release and apoptosis of T cells from AML patients.Results: TIGIT expression on CD8 þ T cells is elevated in AML patients and high-TIGIT correlates with primary refractory disease and leukemia relapse post-alloSCT. TIGIT þ CD8 þ T cells display phenotypic features of exhaustion and exhibit functional impairment manifested by low production of cytokines and high susceptibility to apoptosis. Importantly, their functional defects are reversed by TIGIT knockdown. Conclusions: TIGIT contributes to functional T-cell impairment and associates with poor clinical outcome in AML. Our study suggests that blockade of TIGIT to restore T-cell function and antitumor immunity may represent a novel effective leukemia therapeutic.

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“…These regulations could be the result of chronic stimulation leading to enhanced T cell exhaustion. The CMV status of the patients might play a role here, however, recent papers showed defects in T cell function irrespective of CMV serostatus [48, 49]. …”

Section: Discussionmentioning

confidence: 99%

T cells in multiple myeloma display features of exhaustion and senescence at the tumor site

Zelle‐Rieser¹,

Thangavadivel²,

Biedermann³

et al. 2016

J Hematol Oncol

228

214

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BackgroundMultiple myeloma is an incurable plasma cell malignancy that is mostly restricted to the bone marrow. Cancer-induced dysfunction of cytotoxic T cells at the tumor site may be responsible for immune evasion and therapeutical failure of immunotherapies. Therefore, enhanced knowledge about the actual status of T cells in myeloma bone marrow is urgently needed. Here, we assessed the expression of inhibitory molecules PD-1, CTLA-4, 2B4, CD160, senescence marker CD57, and CD28 on T cells of naive and treated myeloma patients in the bone marrow and peripheral blood and collected data on T cell subset distribution in both compartments. In addition, T cell function concerning proliferation and expression of T-bet, IL-2, IFNγ, and CD107a was investigated after in vitro stimulation by CD3/CD28. Finally, data was compared to healthy, age-matched donor T cells from both compartments.MethodsMulticolor flow cytometry was utilized for the analyses of surface molecules, intracellular staining of cytokines was also performed by flow cytometry, and proliferation was assessed by 3H-thymidine incorporation. Statistical analyses were performed utilizing unpaired T test and Mann-Whitney U test.ResultsWe observed enhanced T cell exhaustion and senescence especially at the tumor site. CD8+ T cells expressed several molecules associated with T cell exhaustion (PD-1, CTLA-4, 2B4, CD160) and T cell senescence (CD57, lack of CD28). This phenotype was associated with lower proliferative capacity and impaired function. Despite a high expression of the transcription factor T-bet, CD8+ T cells from the tumor site failed to produce IFNγ after CD3/CD28 in vitro restimulation and displayed a reduced ability to degranulate in response to T cell stimuli. Notably, the percentage of senescent CD57+CD28− CD8+ T cells was significantly lower in treated myeloma patients when compared to untreated patients.ConclusionsT cells from the bone marrow of myeloma patients were more severely impaired than peripheral T cells. While our data suggest that terminally differentiated cells are preferentially deleted by therapy, immune-checkpoint molecules were still present on T cells supporting the potential of checkpoint inhibitors to reactivate T cells in myeloma patients in combination therapies. However, additional avenues to restore anti-myeloma T cell responses are urgently needed.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0345-3) contains supplementary material, which is available to authorized users.

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T cells are functionally not impaired in AML: increased PD-1 expression is only seen at time of relapse and correlates with a shift towards the memory T cell compartment

Cited by 128 publications

References 60 publications

An anti-CD3/anti–CLL-1 bispecific antibody for the treatment of acute myeloid leukemia

An anti-CD3/anti–CLL-1 bispecific antibody for the treatment of acute myeloid leukemia

T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell Exhaustion and Poor Clinical Outcome in AML Patients

T cells in multiple myeloma display features of exhaustion and senescence at the tumor site

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