The Role of Immune Checkpoint Molecules for Relapse After Allogeneic Hematopoietic Cell Transplantation

Stickel, Natalie; Ruess, Dietrich Alexander; Kesselring, Rebecca; Zeiser, Robert

doi:10.3389/fimmu.2021.634435

Cited by 30 publications

(24 citation statements)

References 90 publications

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“…In the last few decades, immunotherapy has emerged as the fourth pillar following surgery, radiation/chemotherapy and targeted therapy for solid tumor and leukemia therapy. One of the most effective immunotherapies includes resolving T cell dysfunction with immune checkpoint (IC) inhibitors (ICIs), such as programmed death receptor-1 (PD-1) and its ligand (PD-L1), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and T cell immunoglobulin mucin-3 (Tim-3) (1)(2)(3)(4)(5). IC proteins are co-inhibitory receptors that distributed on the surface of several immune cells.…”

Section: Introductionmentioning

confidence: 99%

PD-1 and TIGIT Are Highly Co-Expressed on CD8+ T Cells in AML Patient Bone Marrow

Xu¹,

Yao²,

Zeng³

et al. 2021

Front. Oncol.

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Despite the great success of immune-checkpoint inhibitor (ICI) treatment for multiple cancers, evidence for the clinical use of ICIs in acute myeloid leukemia (AML) remains inadequate. Further exploration of the causes of immune evasion in the bone marrow (BM) environment, the primary leukemia site, and peripheral blood (PB) and understanding how T cells are affected by AML induction chemotherapy or the influence of age may help to select patients who may benefit from ICI treatment. In this study, we comprehensively compared the distribution of PD-1 and TIGIT, two of the most well-studied IC proteins, in PB and BM T cells from AML patients at the stages of initial diagnosis, complete remission (CR), and relapse-refractory (R/R) disease after chemotherapy. Our results show that PD-1 was generally expressed higher in PB and BM T cells from de novo (DN) and R/R patients, while it was partially recovered in CR patients. The expression of TIGIT was increased in the BM of CD8+ T cells from DN and R/R patients, but it did not recover with CR. In addition, according to age correlation analysis, we found that elderly AML patients possess an even higher percentage of PD-1 and TIGIT single-positive CD8+ T cells in PB and BM, which indicate greater impairment of T cell function in elderly patients. In addition, we found that both DN and R/R patients accumulate a higher frequency of PD-1+ and TIGIT+ CD8+ T cells in BM than in corresponding PB, indicating that a more immunosuppressive microenvironment in leukemia BM may promote disease progression. Collectively, our study may help guide the combined use of anti-PD-1 and anti-TIGIT antibodies for treating elderly AML patients and pave the way for the exploration of strategies for reviving the immunosuppressive BM microenvironment to improve the survival of AML patients.

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Section: Introductionmentioning

confidence: 99%

PD-1 and TIGIT Are Highly Co-Expressed on CD8+ T Cells in AML Patient Bone Marrow

Xu¹,

Yao²,

Zeng³

et al. 2021

Front. Oncol.

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“…A meta-analysis of 24 articles evaluated the benefit of checkpoint inhibitors before or after allo-HSCT in different hematological malignancies and revealed that adding checkpoint blockers before or after allo-HSCT leads to higher rate of chronic, acute and hyperacute GVHD. T cells with low expression of PD-1 persist for 10 months or more leading to a higher risk of GVHD [99]. Several studies, especially in cHL, showed that PD-1 inhibitors are highly efficient in the relapsed setting, after allo-HSCT, at the cost of a higher rate of GVHD [96,98,100].…”

Section: Results In Amlmentioning

confidence: 99%

Is There a Place for PD-1-PD-L Blockade in Acute Myeloid Leukemia?

et al. 2021

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Checkpoint inhibitors were a major breakthrough in the field of oncology. In September 2014, based on the KEYNOTE-001 study, the Food and Drug Administration (FDA) approved pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, for advanced or unresectable melanoma. Up until now, seven PD-1/PD-ligand(L)-1 inhibitors are approved in various solid cancers and hundreds of clinical studies are currently ongoing. In hematology, PD-1 inhibitors nivolumab and pembrolizumab were approved for the treatment of relapsed/refractory (R/R) classic Hodgkin lymphoma, and later pembrolizumab was approved for R/R primary mediastinal large B-cell lymphoma. In acute myeloid leukemia (AML), the combination of hypomethylating agents and PD-1/PD-L1 inhibitors has shown promising results, worth of further investigation, while other combinations or single agent therapy have disappointing results. On the other hand, rather than in first line, these therapies could be useful in the consolidation or maintenance setting, for achieving minimal residual disease negativity. Furthermore, an interesting application could be the use of PD-1/PD-L1 inhibitors in the post allogeneic hematopoietic stem cell transplantation relapse. There are several reasons why checkpoint inhibitors are not very effective in treating AML, including the characteristics of the disease (systemic, rapidly progressive, and high tumor burden disease), low mutational burden, and dysregulation of the immune system. We here review the results of PD-1/PD-L1 inhibition in AML and discuss their potential future in the management of this disease.

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“…Loss of GVL effect is generally accountable to the relapse after allo-HSCT, which leads to tumor cells escaping from allogeneic immune response ( 12 , 35 ). With the clinical breakthrough of ICIs, boosting the GVL effect with ICIs post-allo-HSCT has become an appealing concept to treat relapse and improve prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…It is understandable that ICIs may potentially trigger uncontrollable immune breakthrough events, in particular severe GVHD, in the post-transplant setting ( 20 , 35 , 40 ). Therefore, the major obstacle with ICIs is to control the severity of GVHD while maintaining the GVL effect.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Preemptive Treatment With Low-Dose PD-1 Blockade and Azacitidine for Molecular Relapsed Acute Myeloid Leukemia With RUNX1-RUNX1T1 After Allogeneic Hematopoietic Stem Cell Transplantation

et al. 2022

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Acute myeloid leukemia (AML) patients who develop hematological relapse (HR) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) generally have dismal clinical outcomes. Measurable residual disease (MRD)-directed preemptive interventions are effective approaches to prevent disease progression and improve prognosis for molecular relapsed patients with warning signs of impending HR. In this situation, boosting the graft-vs-leukemia (GVL) effect with immune checkpoint inhibitors (ICIs) might be a promising prevention strategy, despite the potential for causing severe graft-vs-host disease (GVHD). In the present study, we reported for the first time an AML patient with RUNX1-RUNX1T1 who underwent preemptive treatment with the combined application of tislelizumab (an anti-PD-1 antibody) and azacitidine to avoid HR following allo-HSCT. On day +81, molecular relapse with MRD depicted by RUNX1-RUN1T1-positivity as well as mixed donor chimerism occurred in the patient. On day +95, with no signs of GVHD and an excellent eastern cooperative oncology group performance status (ECOG PS), the patient thus was administered with 100 mg of tislelizumab on day 1 and 100 mg of azacitidine on days 1-7. After the combination therapy, complete remission was successfully achieved with significant improvement in hematologic response, and the MRD marker RUNX1-RUNX1T1 turned negative, along with a complete donor chimerism in bone marrow. Meanwhile, the patient experienced moderate GVHD and immune-related adverse events (irAEs), successively involving the lung, liver, lower digestive tract and urinary system, which were well controlled by immunosuppressive therapies. As far as we know, this case is the first one to report the use of tislelizumab in combination with azacitidine to prevent post-transplant relapse in AML. In summary, the application of ICIs in MRD positive patients might be an attractive strategy for immune modulation in the future to reduce the incidence of HR in the post-transplant setting, but safer clinical application schedules need to be explored.

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The Role of Immune Checkpoint Molecules for Relapse After Allogeneic Hematopoietic Cell Transplantation

Cited by 30 publications

References 90 publications

PD-1 and TIGIT Are Highly Co-Expressed on CD8+ T Cells in AML Patient Bone Marrow

PD-1 and TIGIT Are Highly Co-Expressed on CD8+ T Cells in AML Patient Bone Marrow

Is There a Place for PD-1-PD-L Blockade in Acute Myeloid Leukemia?

Case Report: Preemptive Treatment With Low-Dose PD-1 Blockade and Azacitidine for Molecular Relapsed Acute Myeloid Leukemia With RUNX1-RUNX1T1 After Allogeneic Hematopoietic Stem Cell Transplantation

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