Clinical, molecular, and immunological responses to pembrolizumab treatment of synchronous melanoma and acute myeloid leukemia

Kubasch, Anne Sophie; Wehner, Rebekka; Bazzurri, Serena; Tunger, Antje; Stasik, Sebastian; Garzarolli, Marlene; Meinel, Jörn; Baretton, Gustavo; Meier, Friedegund; Thiede, Christian; Schmitz, Marc; Platzbecker, Uwe

doi:10.1182/bloodadvances.2017014811

Cited by 8 publications

(6 citation statements)

References 20 publications

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“…89,92,96 Nonetheless, single-agent therapy might display disease-modifying activity in selected patients, including elderly patients with AML. 97 Recent studies have also indicated the potential of targeting the innate immune checkpoint CD47-SIRPa in cancer, including hematologic cancers. 98,99 So far, blocking the interaction between the "don't-eat me" signal CD47 and the phagocyte inhibitory immunoreceptor SIRPa has shown low activity in a small AML/MDS cohort (1/10), but initial results from the combination therapy with 5-Aza are promising.…”

Section: Clinical Experience With Immune Interventionsmentioning

confidence: 99%

Integrating the “Immunome” in the Stratification of Myelodysplastic Syndromes and Future Clinical Trial Design

Winter

Shoaie

Kordasti

et al. 2020

JCO

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Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and often include a dysregulation and dysfunction of the immune system. In the context of population aging, MDS incidence is set to increase substantially, with exponential increases in health care costs, given the limited and expensive treatment options for these patients. Treatment selection is mainly based on calculated risk categories according to a Revised International Prognostic Scoring System (IPSS-R). However, although IPSS-R is an excellent predictor of disease progression, it is an ineffective predictor of response to disease-modifying therapies. Redressing these unmet needs, the “immunome” is a key, multifaceted component in the initiation and overall response against malignant cells in MDS, and the current omission of immune status monitoring may in part explain the insufficiencies of current prognostic stratification methods. Nevertheless, integrating these and other recent molecular advances into clinical practice proves difficult. This review highlights the complexity of immune dysregulation in MDS pathophysiology and the fine balance between smoldering inflammation, adaptive immunity, and somatic mutations in promoting or suppressing malignant clones. We review the existing knowledge and discuss how state-of-the-art immune monitoring strategies could potentially permit novel patient substratification, thereby empowering practical predictions of response to treatment in MDS. We propose novel multicenter studies, which are needed to achieve this goal.

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Section: Clinical Experience With Immune Interventionsmentioning

confidence: 99%

Integrating the “Immunome” in the Stratification of Myelodysplastic Syndromes and Future Clinical Trial Design

Winter

Shoaie

Kordasti

et al. 2020

JCO

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“…46 First-line pembrolizumab therapy, however, was shown to induce a clinical and molecular response in a patient with secondary AML receiving the drug for melanoma. 47 Similar to pembrolizumab, no responses were seen in advanced MDS patients treated with the PD-1 inhibitor nivolumab after HMA failure. 45 Interestingly, in MDS and secondary AML, PD-L1 expression levels are higher in hematopoietic cells than in those of healthy volunteers and resistance to the HMA azacitidine and decitabine is additionally associated with up-regulation of PD-1 and PD-L1 on leukemic cells, representing an immune evasion mechanism against HMA.…”

Section: Strategies For High-risk Mdsmentioning

confidence: 99%

Old Dogs, New Tricks: Revisiting Immune Modulatory Approaches for Myelodysplastic Syndromes

Götze

Platzbecker

2018

HemaSphere

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Profound immune dysregulation is an increasingly recognized feature of myelodysplastic syndromes (MDS), contributing to ineffective hematopoiesis and driving disease progression. Immune dysregulation in MDS is highly complex and composed of many interdependent factors, including clonal hematopoietic cells with somatic mutations providing faulty signals to the immune system and altered cells of the bone marrow microenvironment contributing to inflammation and immunosuppression. Cellular components of disturbed immune regulation include T and natural killer cells, myeloid-derived suppressor cells as well as MSC. In this perspective, we highlight the role of the various players contributing to immune dysregulation in MDS and discuss novel therapeutic approaches currently being designed to improve treatment options.

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“…Findings from small subgroups of responders ( n = 3) versus non-responders ( n = 3) documented an increased diversity of TCR Vβ repertoires in CD8 + T cells from responders. A recent case report documented disease-modifying activity of pembrolizumab in an AML patient with synchronous cutaneous melanoma [108]. It is presently unknown whether selecting tumors for PD-L1 expression is the best way to optimize PD-L1 blockade in hematological malignancies.…”

Section: Immune Checkpoint Blockade and Novel Immunotherapies For mentioning

confidence: 99%

Dissecting the Immune Landscape of Acute Myeloid Leukemia

et al. 2018

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Acute myeloid leukemia (AML) is a molecularly heterogeneous hematological malignancy with variable response to treatment. Recurring cytogenetic abnormalities and molecular lesions identify AML patient subgroups with different survival probabilities; however, 50–70% of AML cases harbor either normal or risk-indeterminate karyotypes. The discovery of better biomarkers of clinical success and failure is therefore necessary to inform tailored therapeutic decisions. Harnessing the immune system against cancer with programmed death-1 (PD-1)-directed immune checkpoint blockade (ICB) and other immunotherapy agents is an effective therapeutic option for several advanced malignancies. However, durable responses have been observed in only a minority of patients, highlighting the need to gain insights into the molecular features that predict response and to also develop more effective and rational combination therapies that address mechanisms of immune evasion and resistance. We will review the state of knowledge of the immune landscape of AML and identify the broad opportunity to further explore this incompletely characterized space. Multiplexed, spatially-resolved immunohistochemistry, flow cytometry/mass cytometry, proteomic and transcriptomic approaches are advancing our understanding of the complexity of AML-immune interactions and are expected to support the design and expedite the delivery of personalized immunotherapy clinical trials.

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Clinical, molecular, and immunological responses to pembrolizumab treatment of synchronous melanoma and acute myeloid leukemia

Abstract: Key Points Pembrolizumab treatment of melanoma and concomitant sAML resulted in a significant platelet response and clearance of IDH1 mutation. Pembrolizumab therapy and response was associated with an increased PD-L1 expression on acute myeloid leukemia blasts and T cells.

Cited by 8 publications

References 20 publications

Integrating the “Immunome” in the Stratification of Myelodysplastic Syndromes and Future Clinical Trial Design

Integrating the “Immunome” in the Stratification of Myelodysplastic Syndromes and Future Clinical Trial Design

Old Dogs, New Tricks: Revisiting Immune Modulatory Approaches for Myelodysplastic Syndromes

Dissecting the Immune Landscape of Acute Myeloid Leukemia

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