Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias, and an elevated risk of transforming into acute myeloid leukemia (AML). Conventional treatment approaches, such as supportive care, hypomethylating agents, and hematopoietic stem cell transplantation, have exhibited varying degrees of success but often come with limited efficacy and significant toxicities.

In recent years, the evolving landscape of cancer therapeutics has included the emergence of immunotherapy as a transformative strategy for various malignancies. 

In the realm of MDS, the novel immunotherapeutic interventions have shown promise in harnessing the immune system’s potent capabilities to target malignant cells selectively. This article provides a comprehensive overview of the current role of immunotherapy in MDS, outlining different treatment approaches, reviewing recent advancements, and exploring potential implications for the future of MDS management. 

Immune Checkpoint Inhibitors

Among the notable advancements in cancer immunotherapy is the use of immune checkpoint inhibitors, which have demonstrated considerable clinical relevance. By targeting inhibitory receptors that regulate immune cell activity, such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), these inhibitors unleash the suppressed immune response, facilitating enhanced recognition and elimination of MDS cells. 

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Preclinical studies and early-phase clinical trials have shown encouraging results, indicating improved overall responses and survival rates in subsets of patients with MDS. As ongoing research and clinical investigations unravel the complexities of immune checkpoint inhibitor therapy, its integration into MDS treatment paradigms could revolutionize the landscape of therapeutic options. 

PD-1/PD-L1 Inhibitors

Multiple abnormal epigenetic alterations and aberrant immune signaling pathways, including the PD-1/PD-L1 pathway, have been implicated in the risk of progression to AML, which is approximately 30% in MDS. PD-1/PD-L1 are immune checkpoint molecules that have critical functions in the disease process.1 

PD-1 is a receptor expressed on activated T cells, regulatory T cells (Tregs), and B cells that plays a crucial role in preventing immune overactivation. Understanding the complex interactions between PD-1 and its ligands PD-L1 and PD-L2 provides insights into potential strategies for cancer treatment interventions.1

In essence, when PD-1 interacts with PD-L1 and PD-L2 (primarily found on macrophages and dendritic cells) it undergoes intracellular phosphorylation, which disrupts downstream signaling pathways that ultimately lead to apoptosis of effector T cells and suppression of their proliferation and cytokine secretion.1 

In MDS, tumors may exploit this protective mechanism of PD-1/PD-L1 signaling to establish an immunosuppressive tumor microenvironment, promoting cancer cell proliferation. The binding of PD-1 to PD-L1 results in various mechanisms that favor tumor evasion, including inhibiting effector T cell function, inducing proliferation in Tregs, protecting tumor cells from apoptosis and T cell-mediated killing, and promoting tumor growth through reverse signaling that enhances glycolytic metabolism via the Akt/mTOR pathway in PD-L1+ tumor cells.1 

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A phase 1b clinical trial using the PD-1 inhibitor pembrolizumab in 28 patients with International Prognostic Scoring System (IPSS) scores ranging from intermediate 1 to high was conducted to determine the safety and objective response rate to treatment with this agent. Results were positive but somewhat underwhelming, with a partial response observed in 1 patient (3%), complete marrow response in 3 patients (11%), and stable disease in 14 patients (52%). Disease progression occurred in 9 patients (33%) and no patients underwent complete remission.2 

Researchers speculate that better results may be achievable in combination with other MDS therapies, particularly hypomethylating agents (HMAs) such as azacitidine. Currently, a phase 2 trial is being conducted at the MD Anderson Cancer Center in Houston, Texas, to assess the safety and clinical activity of azacitidine and pembrolizumab in 40 patients with higher-risk MDS. It is expected to be completed in November 2023.3 

Optimism about combination therapy with another agent is not purely speculative, as clinical trials combining checkpoint inhibitors with or without an HMA have been conducted. For instance, nivolumab, an anti-PD-1 monoclonal antibody, has been studied in MDS as monotherapy and in combination with ipilimumab or azacitidine in a phase 2 trial. Results demonstrated no response with nivolumab alone and a 30% response rate with ipilimumab alone. When nivolumab was combined with azacitidine, response rates increased to 80%​—suggesting that the drugs likely work synergistically.4  

There is a call for more research to be done in larger cohorts to thoroughly investigate the feasibility and efficacy of such immunotherapeutic strategies. 

CTLA-4 Inhibitors

The significance of immune tolerance and evasion by malignant cells in disease progression, including in MDS, has been well-established. Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) appears to be implicated and plays a major role in regulating T cell activation during the initial stages of the immune response.5 

In patients with higher-risk MDS, their prognosis becomes grim upon HMA treatment failure, with a median overall survival of fewer than 6 months. Researchers have postulated that CTLA-4 blockade in these patients, through the administration of the anti-CTLA-4 antibody ipilimumab, may result in clinically meaningful responses.5 

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In a phase 1b study, 11 patients who developed HMA resistance were enrolled to receive either 3 mg/kg or 10 mg/kg of ipilimumab. Their ages ranged from 50 to 79 years, with a median age of 63 years. Among them, 5 patients had received 2 prior lines of HMA therapy while 6 had received only 1 HMA. The median number of HMA cycles administered was 5, with a range of 4 to 18 cycles.5 

No patients in this study achieved objective responses; however, disease stabilization was observed in 3 patients (27.3%) for more than 6 months. One participant had prolonged stable disease after an immune-related adverse event and one experienced ongoing stable disease for over 16 months. Three patients who achieved stable disease underwent allogeneic hematopoietic stem cell transplantation (alloSCT) without any additional toxicities and achieved complete remission at 2, 12, and 18 months post-alloSCT, respectively. The median and mean overall survival for the entire cohort (censoring at the time of alloSCT) were 368 and 352 days, respectively.5  

These findings suggest ipilimumab could potentially stabilize MDS and prolong overall survival. It may also be a reasonable agent to administer prior to alloSCT.5 

Small studies using a dual checkpoint inhibitor strategy with nivolumab and ipilimumab have shown promise and prompted larger investigations using this strategy that are currently underway.4,6 


MBG453 is a novel high-affinity humanized T-cell immunoglobulin domain and mucin domain-3 (TIM-3) IgG4 antibody under investigation for its potential in managing MDS, AML, and other malignancies. The intricate regulatory function of TIM-3 in both adaptive and innate immune responses, along with its preferential expression on leukemic stem and progenitor cells, establishes it as a promising target in the context of MDS and AML.7 

Encouragingly, in vitro studies have demonstrated that MBG453 effectively augments immune cell-mediated eradication of AML cells. Given the documented evidence of HMAs increasing immune checkpoint expression in MDS and AML, there is a compelling rationale to explore the synergistic potential of combining HMAs and MBG453.7 

In a phase 1b study, concurrent administration of MBG453 and the HMA decitabine was found to be safe and well-tolerated by the patients, demonstrating an apparent manifestation of antileukemic activity. Notably, promising preliminary response rates were observed, occurring at a median of 2 cycles, and exhibited sustained efficacy in both high-risk MDS and AML.7 

These findings support the rationale that TIM-3 checkpoint inhibitors in combination with HMAs may be a viable treatment strategy; more investigation should be done to validate this hypothesis.7

Anti-CD47 Monoclonal Antibodies

CD47, functioning as an integrin-associated protein, exhibits widespread expression on the cellular membrane and plays a crucial role in orchestrating immune evasion through interactions with signal regulatory protein alpha (SIRPα) expressed in macrophages and dendritic cells. Upregulated expression of CD47, compared to normal cells, has been substantiated in numerous solid and hematological malignancies, including breast, small-cell lung, colon, ovarian, AML, and acute lymphocytic leukemia malignancies.8 

It is postulated that by employing monoclonal antibodies that target CD47/SIRPα, the interaction between cancer cells and macrophages could be disrupted, compromising a tumor cell’s ability to evade the immune system. This would exert antitumor effects by facilitating phagocytic uptake of tumor cells by macrophages, promoting adaptive immunity, inducing apoptosis, and mediating antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity by natural killer (NK) cells.8 

A recent study using the synthesized monoclonal antibody 2C8 substantiated the concept that CD47 blockade results in anticancer effects in xenografts transfected with human B-cell lymphoma cell lines. The researchers reported that 2C8 significantly induces macrophage-mediated killing of tumor cells in vitro.8 

However, trials in humans with CD47 inhibitors have not yielded positive results to date.9,10 Perhaps the right combination of interventions is yet to be discovered. Researchers are still marching forward, testing new potential regimens and combinations using novel CD47 inhibitors.11

An Evolving Landscape

The journey to find effective treatments for MDS has been challenging. However, the landscape of cancer therapeutics has undergone a paradigm shift with the advent of immunotherapy, which has emerged as a transformative strategy in various malignancies. 

As the field of immunotherapeutics for MDS continues to evolve, it is evident that the promise of these innovative treatments offers hope for patients and practitioners alike. By leveraging the immune system’s potent capabilities, immunotherapeutic interventions have the potential to revolutionize the landscape of MDS management, providing new avenues for improved responses, prolonged survival, and enhanced quality of life for MDS patients. As ongoing research and clinical investigations progress, the future holds the promise of more effective and personalized immunotherapeutic approaches. 


1. Yang X, Ma L, Zhang X, Huang L, Wei J. Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia. Exp Hematol Oncol. 2022;11:11. doi:10.1186/s40164-022-00263-4

2. Garcia-Manero G, Tallman MS, Martinelli G, et al. Pembrolizumab, a PD-1 inhibitor, in patients with myelodysplastic syndrome (MDS) after failure of hypomethylating agent treatment. Blood. 2016;128(22):345. doi:10.1182/blood.V128.22.345.345

3. MD Anderson Cancer Center. A phase II study of the combination of azacitidine and pembrolizumab for patients with MDS. March 29, 2017. Updated March 21, 2023. Accessed July 24, 2023. 

4. Garcia-Manero G, Daver NG, Montalban-Bravo G, et al. A phase II study evaluating the combination of nivolumab (Nivo) or ipilimumab (Ipi) with azacitidine in pts with previously treated or untreated myelodysplastic syndromes (MDS). Blood. 2016;128(22):344. doi:10.1182/blood.V128.22.344.344

5. Zeidan AM, Zeidner JF, Duffield A, et al. Stabilization of myelodysplastic syndromes (MDS) following hypomethylating agent (HMAs) failure using the immune checkpoint inhibitor ipilimumab: a phase I trial. Blood. 2015;126(23):1666. doi:10.1182/blood.V126.23.1666.1666

6. MD Anderson Cancer Center. Combination of nivolumab and ipilimumab with 5-azacitidine in patients with myelodysplastic syndromes (MDS). August 21, 2015. Updated August 28, 2023. Accessed July 24, 2023. 

7. Borate U, Esteve J, Porkka K, et al. Phase Ib study of the anti-TIM-3 antibody MBG453 in combination with decitabine in patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Blood. 2019;134(Supplement 1):570. doi:10.1182/blood-2019-128178

8. Lin F, Xiong M, Hao W, et al. A novel blockade CD47 antibody with therapeutic potential for cancer. Front Oncol. 2021;10. doi:10.3389/fonc.2020.615534

9. Zeidan AM, DeAngelo DJ, Palmer J, et al. Phase 1 study of anti-CD47 monoclonal antibody CC-90002 in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndrome. Ann Hematol. 2022;101(3):557-569. doi:10.1007/s00277-021-04734-2

10. Gilead to discontinue phase 3 ENHANCE study of magrolimab plus azacitidine in higher-risk MDS. News release. Gilead; July 21, 2023. 

11. A phase 1b/2 trial of Hu5F9-G4 in combination with rituximab or rituximab + chemotherapy in patients with relapsed/refractory B-cell non-Hodgkin’s lymphoma. November 2, 2016. Updated August 1, 2023. Accessed July 26, 2023.