Targeting MDM2 enhances antileukemia immunity after allogeneic transplantation via MHC-II and TRAIL-R1/2 upregulation

Ho, Jenny Giang; Schmidt, Dominik; Lowinus, Theresa; Ryoo, Jeongmin; Dopfer, Elaine-Pashupati; Núñez, Nicolás Gonzalo; Costa-Pereira, Sara; Toffalori, Cristina; Punta, Marco; Fetsch, Viktor; Wertheimer, Tobias; Rittmann, Marie-Claire; Braun, Lukas; Follo, Marie; Briere, Christelle; Vinnakota, Janaki Manoja; Langenbach, Marlene; Koppers, Felicitas; Shoumariyeh, Khalid; Engel, Helena; Rückert, Tamina; Märklin, Melanie; Holzmayer, Samuel; Illert, Anna Lena; Magon, Federica; Andrieux, Geoffroy; Duquesne, Sandra; Pfeifer, Dietmar; Staniek, Julian; Rizzi, Marta; Miething, Cornelius; Stickel, Natalie; Duyster, Justus; Menssen, Hans D.; Boerries, Melanie; Buescher, Joerg M.; Cabezas-Wallscheid, Nina; Blazar, Bruce R.; Apostolova, Petya; Vago, Luca; Pearce, Erika L.; Zeiser, Robert

doi:10.1182/blood.2022016082

Cited by 32 publications

(23 citation statements)

References 46 publications

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“…As for MHC II, it is found MHC II mediated the T-cell response to acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation. The p53 deletion caused the downregulation of MHC II and tumor necrosis factor related apoptosis-inducing ligand receptor one and receptor 2 (TRAIL-R1/2) which induced immune evasion of AML ( Chitlur, 2022 ; Ho et al, 2022 ).…”

Section: The P53 Mutation Regulates the Mhc Molecules And Reduces Imm...mentioning

confidence: 99%

p53 mutation and deletion contribute to tumor immune evasion

Liu

Liu²,

Jiang³

et al. 2023

Front. Genet.

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TP53 (or p53) is widely accepted to be a tumor suppressor. Upon various cellular stresses, p53 mediates cell cycle arrest and apoptosis to maintain genomic stability. p53 is also discovered to suppress tumor growth through regulating metabolism and ferroptosis. However, p53 is always lost or mutated in human and the loss or mutation of p53 is related to a high risk of tumors. Although the link between p53 and cancer has been well established, how the different p53 status of tumor cells help themselves evade immune response remains largely elusive. Understanding the molecular mechanisms of different status of p53 and tumor immune evasion can help optimize the currently used therapies. In this context, we discussed the how the antigen presentation and tumor antigen expression mode altered and described how the tumor cells shape a suppressive tumor immune microenvironment to facilitate its proliferation and metastasis.

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Section: The P53 Mutation Regulates the Mhc Molecules And Reduces Imm...mentioning

confidence: 99%

p53 mutation and deletion contribute to tumor immune evasion

Liu

Liu²,

Jiang³

et al. 2023

Front. Genet.

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“…MDM2 inhibits c-Cbl's binding to STAT5, reducing STAT5 degradation and stabilizing STAT5 expression in tumor-infiltrating CD8+ T cells ( Zhou et al, 2021a ). Moreover, MDM2 inhibition has been observed to induce tumor necrosis factor α and interferon γ production in T cells ( Ho et al, 2022 ), whereas it leads to the induction of interleukin-15 and major histocompatibility complex class II (MHC-II) molecules in melanoma cells ( Langenbach et al, 2023 ). This diversity in responses highlights the intricate and cell type–specific actions of MDM2 in the immune landscape of cancers, presenting a complex yet promising avenue for therapeutic intervention.…”

Section: The Rationale For Targeting Mdm2 For Molecular Targeted Therapymentioning

confidence: 99%

MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future

Wang,

Albadari,

et al. 2024

Pharmacol Rev

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Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are several current clinical trials of promising agents that may overcome the past failures, including agents granted FDA orphan drug or fast-track status. We herein summarize the research efforts to discover and develop MDM2 inhibitors, focusing on those that induce MDM2 degradation and exert anticancer activity, regardless of the p53 status of the cancer. We also describe how preclinical and clinical investigations have moved toward combining MDM2 inhibitors with other agents, including immune checkpoint inhibitors. Finally, we discuss the current challenges and future directions to accelerate the clinical application of MDM2 inhibitors. In conclusion, targeting MDM2 remains a promising treatment approach, and targeting MDM2 for protein degradation represents a novel strategy to downregulate MDM2 without the side effects of the existing agents blocking p53-MDM2 binding. Additional preclinical and clinical investigations are needed to finally realize the full potential of MDM2 inhibition in treating cancer and other chronic diseases where MDM2 has been implicated. Significance Statement Overexpression/amplification of the MDM2 oncogene has been detected in various human cancers and is associated with disease progression, treatment resistance, and poor patient outcomes. This article reviews the previous, current, and emerging MDM2-targeted therapies and summarizes the preclinical and clinical studies combining MDM2 inhibitors with chemotherapy and immunotherapy regimens. The findings of these contemporary studies may lead to safer and more effective treatments for patients with cancers overexpressing MDM2.

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“…MDM2 inhibition can contrast AML post-HCT immunological escape through the restoration of TRAIL-R1/2 and class 2 MHC production ( 127 ). MDM2 inhibition enhances cytotoxic effects against leukemic cells, leading to an increase in p53-dependent tumor necrosis factor-related apoptosis-inducing ligand receptor-1/2 (TRAIL 1/2) and MHC-class II on blast cells and higher levels of T cells with cytotoxic features ( 128 ). NCT05447663 – is a Phase Ib/II, single arm, open label, multi-center study of siremadlin, as monotherapy and in combination with DLI, in adult participants with high-risk AML in CR after allogeneic HCT.…”

Section: Novel Moleculesmentioning

confidence: 99%

The prevention of disease relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia

et al. 2022

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Disease relapse represents by far the most frequent cause of hematopoietic cell transplantation (HCT) failure. Patients with acute leukemia suffering relapse after HCT have limited conventional treatment options with little possibility of cure and represent, de facto, suitable candidates for the evaluation of novel cellular and biological-based therapies. Donor lymphocyte infusions (DLI) has been one of the first cellular therapies adopted to treat post HCT relapse of acute leukemia patients and still now, it is widely adopted in preemptive and prophylactic settings, with renewed interest for manipulated cellular products such as NK-DLI. The acquisition of novel biological insights into pathobiology of leukemia relapse are translating into the clinic, with novel combinations of target therapies and novel agents, helping delineate new therapeutical landscapes. Hypomethylating agents alone or in combination with novel drugs demonstrated their efficacy in pre-clinical models and controlled trials. FLT3 inhibitors represent an essential therapeutical instrument incorporated in post-transplant maintenance strategies. The Holy grail of allogeneic transplantation lies in the separation of graft-vs.-host disease from graft vs. tumor effects and after more than five decades, is still the most ambitious goal to reach and many ways to accomplish are on their way.

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Targeting MDM2 enhances antileukemia immunity after allogeneic transplantation via MHC-II and TRAIL-R1/2 upregulation

Cited by 32 publications

References 46 publications

p53 mutation and deletion contribute to tumor immune evasion

p53 mutation and deletion contribute to tumor immune evasion

MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future

The prevention of disease relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia

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