scholarly journals Targeting Immune Signaling Checkpoints in Acute Myeloid Leukemia

2019 ◽  
Vol 8 (2) ◽  
pp. 236 ◽  
Author(s):  
Krzysztof Giannopoulos
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Negative Control ◽  
Immune Checkpoints ◽  
Hematopoietic Stem ◽  
Acute Myeloid

The modest successes of targeted therapies along with the curative effects of allogeneic hematopoietic stem cell transplantation (alloHSCT) in acute myeloid leukemia (AML) stimulate the development of new immunotherapies. One of the promising methods of immunotherapy is the activation of immune response by the targeting of negative control checkpoints. The two best-known inhibitory immune checkpoints are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed cell death protein 1 receptor (PD-1). In AML, PD-1 expression is observed in T-cell subpopulations, including T regulatory lymphocytes. Increased PD-1 expression on CD8+ T lymphocytes may be one of the factors leading to dysfunction of cytotoxic T cells and inhibition of the immune response during the progressive course of AML. Upregulation of checkpoint molecules was observed after alloHSCT and therapy with hypomethylating agents, pointing to a potential clinical application in these settings. Encouraging results from recent clinical trials (a response rate above 50% in a relapsed setting) justify further clinical use. The most common clinical trials employ two PD-1 inhibitors (nivolumab and pembrolizumab) and two anti-PD-L1 (programmed death-ligand 1) monoclonal antibodies (atezolizumab and durvalumab). Several other inhibitors are under development or in early phases of clinical trials. The results of these clinical trials are awaited with great interest in, as they may allow for the established use of checkpoint inhibitors in the treatment of AML.

scholarly journals Post-transplantation cyclophosphamide reduces the incidence of acute graft-versus-host disease in patients with acute myeloid leukemia/myelodysplastic syndromes who receive immune checkpoint inhibitors after allogeneic hematopoietic stem cell transplantation

2021 ◽  
Vol 9 (2) ◽  
pp. e001818 ◽  
Author(s):  
Chantal Saberian ◽  
Noha Abdel-Wahab ◽  
Ala Abudayyeh ◽  
Hind Rafei ◽  
Jacinth Joseph ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Checkpoint Inhibitors ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Acute Myeloid

BackgroundImmune checkpoint inhibitors (ICIs) are being used after allogeneic hematopoietic stem cell transplantation (alloHCT) to reverse immune dysfunction. However, a major concern for the use of ICIs after alloHCT is the increased risk of graft-versus-host disease (GVHD). We analyzed the association between GVHD prophylaxis and frequency of GVHD in patients who had received ICI therapy after alloHCT.MethodsA retrospective study was performed in 21 patients with acute myeloid leukemia (n=16) or myelodysplastic syndromes (n=5) who were treated with antiprogrammed cell death protein 1 (16 patients) or anticytotoxic T lymphocyte-associated antigen 4 (5 patients) therapy for disease relapse after alloHCT. Associations between the type of GVHD prophylaxis and incidence of GVHD were analyzed.ResultsFour patients (19%) developed acute GVHD. The incidence of acute GVHD was associated only with the type of post-transplantation GVHD prophylaxis; none of the other variables included (stem cell source, donor type, age at alloHCT, conditioning regimen and prior history of GVHD) were associated with the frequency of acute GVHD. Twelve patients received post-transplantation cyclophosphamide (PTCy) for GVHD prophylaxis. Patients who received PTCy had a significantly shorter median time to initiation of ICI therapy after alloHCT compared with patients who did not receive PTCy (median 5.1 months compared with 26.6 months). Despite early ICI therapy initiation, patients who received PTCy had a lower observed cumulative incidence of grades 2–4 acute GVHD compared with patients who did not receive PTCy (16% compared with 22%; p=0.7). After controlling for comorbidities and time from alloHCT to ICI therapy initiation, the analysis showed that PTCy was associated with a 90% reduced risk of acute GVHD (HR 0.1, 95% CI 0.02 to 0.6, p=0.01).ConclusionsICI therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of acute GVHD in this cohort of patients.

scholarly journals Immunoistochemical expression of PD-1 and PD-L1 in bone marrow biopsies of patients with acute myeloid leukemia

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Francesco Romano ◽  
Antonino Giulio Giannone ◽  
Sergio Siragusa ◽  
Rossana Porcasi ◽  
Ada Maria Florena
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Immune Escape ◽  
Medical Community ◽  
Immune Checkpoints ◽  
Bone Marrow Biopsies ◽  
Underlying Mechanisms ◽  
Acute Myeloid

tumor immunotherapy is a rapidly evolving field. The discovery of the ability of neoplasms to evade the immune response has shifted the attention of the medical community to the underlying mechanisms of the immune response to tumors, highlighting the importance of so-called immune check points, including CTLA4, TIM-3 and PD-1.  an immune escape mechanism is the activation of the immune checkpoint pathway that contributes to the creation of an immunosuppressive microenvironment and therefore to tumor proliferation.although immune checkpoints have been extensively investigated in solid tumors, the same is not true for hematologic neoplasms, particularly for myeloid malignancies. our study is based on the evaluation of the activation of the PD-1 and PD-L1 pathway in the context of the bone marrow tumor microenvironment of patients with acute myeloid leukemia. To do so we evaluated  34 bone marrow biopsies of patients with acute myeloid leukemia comparing them to 10 controls using immunohistochemical methods.

scholarly journals Immune-Based Therapeutic Strategies for Acute Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 105
Author(s):  
Matthias Böhme ◽  
Sabine Kayser
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Solid Cancer ◽  
Drug Conjugates ◽  
Car T ◽  
Immunotherapeutic Strategy ◽  
Acute Myeloid

The development and design of immune-based strategies have become an increasingly important topic during the last few years in acute myeloid leukemia (AML), based on successful immunotherapies in solid cancer. The spectrum ranges from antibody drug conjugates, immune checkpoint inhibitors blocking programmed cell death protein 1 (PD1), cytotoxic T lymphocyte antigen 4 (CTLA4) or T cell immunoglobulin and mucin domain containing-3 (TIM3), to T-cell based monoclonal and bispecific T-cell engager antibodies, chimeric antigen receptor-T-cell (CAR-T) approaches and leukemia vaccines. Currently, there are many substances in development and multiple phase I/II studies are ongoing. These trials will help us to deepen our understanding of the pathogenesis of AML and facilitate the best immunotherapeutic strategy in AML. We discuss here the mode of action of immune-based therapies and provide an overview of the available data.

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

2021 ◽  
Vol 14 (4) ◽  
pp. 288
Author(s):  
Laura Jimbu ◽  
Oana Mesaros ◽  
Cristian Popescu ◽  
Alexandra Neaga ◽  
Iulia Berceanu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Tumor Burden ◽  
Hematopoietic Stem ◽  
Classic Hodgkin Lymphoma ◽  
Acute Myeloid

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.

scholarly journals Immunotherapy as a Turning Point in the Treatment of Acute Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6246
Author(s):  
Anna Aureli ◽  
Beatrice Marziani ◽  
Tommaso Sconocchia ◽  
Maria Ilaria Del Principe ◽  
Elisa Buzzatti ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Malignant Disease ◽  
Turning Point ◽  
Checkpoint Inhibitors ◽  
Hematopoietic Stem ◽  
Car T ◽  
Related Mortality ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a malignant disease of hematopoietic precursors at the earliest stage of maturation, resulting in a clonalproliferation of myoblasts replacing normal hematopoiesis. AML represents one of the most common types of leukemia, mostly affecting elderly patients. To date, standard chemotherapy protocols are only effective in patients at low risk of relapse and therapy-related mortality. The average 5-year overall survival (OS) is approximately 28%. Allogeneic hematopoietic stem cell transplantation (HSCT) improves prognosis but is limited by donor availability, a relatively young age of patients, and absence of significant comorbidities. Moreover, it is associated with significant morbidity and mortality. However, increasing understanding of AML immunobiology is leading to the development of innovative therapeutic strategies. Immunotherapy is considered an attractive strategy for controlling and eliminating the disease. It can be a real breakthrough in the treatment of leukemia, especially in patients who are not eligible forintensive chemotherapy. In this review, we focused on the progress of immunotherapy in the field of AML by discussing monoclonal antibodies (mAbs), immune checkpoint inhibitors, chimeric antigen receptor T cells (CAR-T cells), and vaccine therapeutic choices.

scholarly journals Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives

2018 ◽  
Vol 19 (11) ◽  
pp. 3492 ◽  
Author(s):  
Fabio Forghieri ◽  
Patrizia Comoli ◽  
Roberto Marasca ◽  
Leonardo Potenza ◽  
Mario Luppi
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Working Party ◽  
Prognostic Indicators ◽  
Prognostic Impact ◽  
Hematopoietic Stem ◽  
Measurable Residual Disease ◽  
Acute Myeloid

Acute myeloid leukemia (AML) with NPM1 gene mutations is currently recognized as a distinct entity, due to its unique biological and clinical features. We summarize here the results of published studies investigating the clinical application of minimal/measurable residual disease (MRD) in patients with NPM1-mutated AML, receiving either intensive chemotherapy or hematopoietic stem cell transplantation. Several clinical trials have so far demonstrated a significant independent prognostic impact of molecular MRD monitoring in NPM1-mutated AML and, accordingly, the Consensus Document from the European Leukemia Net MRD Working Party has recently recommended that NPM1-mutated AML patients have MRD assessment at informative clinical timepoints during treatment and follow-up. However, several controversies remain, mainly with regard to the most clinically significant timepoints and the MRD thresholds to be considered, but also with respect to the optimal source to be analyzed, namely bone marrow or peripheral blood samples, and the correlation of MRD with other known prognostic indicators. Moreover, we discuss potential advantages, as well as drawbacks, of newer molecular technologies such as digital droplet PCR and next-generation sequencing in comparison to conventional RQ-PCR to quantify NPM1-mutated MRD. In conclusion, further prospective clinical trials are warranted to standardize MRD monitoring strategies and to optimize MRD-guided therapeutic interventions in NPM1-mutated AML patients.

scholarly journals Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia

2021 ◽  
Vol 22 (17) ◽  
pp. 9159
Author(s):  
Fabio Forghieri ◽  
Giovanni Riva ◽  
Ivana Lagreca ◽  
Patrizia Barozzi ◽  
Francesca Bettelli ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Checkpoint Inhibitors ◽  
Specific Antigen ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Promising Therapeutic Approach ◽  
Acute Myeloid

The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicating persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients.

scholarly journals Emerging Immunotherapy for Acute Myeloid Leukemia

2021 ◽  
Vol 22 (4) ◽  
pp. 1944
Author(s):  
Rikako Tabata ◽  
SungGi Chi ◽  
Junichiro Yuda ◽  
Yosuke Minami
Keyword(s):  
Acute Myeloid Leukemia ◽  
Immune Checkpoint ◽  
Myeloid Leukemia ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Leukemic Cells ◽  
Conventional Chemotherapy ◽  
Relevant Evidence ◽  
Acute Myeloid ◽  
Refractory Aml

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed complete remission (CR) or marked reduction of marrow blasts in a few enrolled patients. Bi-/tri-specific antibodies (e.g., bispecific T-cell engager (BiTE) and dual-affinity retargeting (DART)) exhibited 11–67% CR rates with 13–78% risk of cytokine-releasing syndrome (CRS). Conventional chemotherapy in combination with anti-PD-1/anti-CTLA4 antibody for relapsed/refractory AML showed 10–36% CR rates with 7–24 month-long median survival. The current advantages of IO therapy in the field of AML are summarized herein. However, although cancer vaccination should be included in the concept of IO therapy, it is not mentioned in this review because of the paucity of relevant evidence.

scholarly journals Novel therapy in Acute myeloid leukemia (AML): moving toward targeted approaches

2019 ◽  
Vol 10 ◽  
pp. 204062071986064 ◽  
Author(s):  
Eric S. Winer ◽  
Richard M. Stone
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Complex Disease ◽  
Cellular Proliferation ◽  
Checkpoint Inhibitors ◽  
Alternative Pathway ◽  
Cell Cycle Checkpoint ◽  
Novel Therapy ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a heterogenous and complex disease characterized by rapid cellular proliferation, an aggressive clinical course, and generally high mortality. While progress has been made in the understanding of the genetic and molecular biology of the disease, the standard of care for patients had only changed minimally over the past 40 years. Recently, rapid movement of potentially useful agents from bench to bedside has translated into new therapies either recently approved or in clinical trials. These therapies include improved chemotherapies, mutationally targeted inhibitors, pro-apoptotic agents, microenvironment targeting molecules, cell cycle checkpoint inhibitors, and epigenetic regulators. Furthermore, advances in immunotherapy employ monoclonal and bispecific antibodies, chimeric antigen receptor (CAR) T cells, checkpoint inhibitors, and vaccines provide an alternative pathway for AML treatment. In this review, we discuss the recent results of completed or ongoing clinical trials with these novel therapeutic agents in AML.

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