Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS

Zeidner, Joshua F.; Knaus, Hanna A.; Zeidan, Amer M.; Blackford, Amanda L.; Montiel-Esparza, Raúl; Hackl, Hubert; Prince, Gabrielle T.; Gondek, Lukasz P.; Ghiaur, Gabriel; Showel, Margaret M.; DeZern, Amy E.; Pratz, Keith W.; Smith, B. Douglas; Levis, Mark J.; Gore, Steven D.; Coombs, Catherine C.; Foster, Matthew C.; Streicher, Howard; Karp, Judith E.; Luznik, Leo; Gojo, Ivana

doi:10.1038/s41375-019-0693-4

Cited by 18 publications

(12 citation statements)

References 47 publications

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“…Previous studies have found that the leukemia BM microenvironment possesses several immune suppressive factors that may protect malignant hematopoietic stem cells from immunological surveillance. We and others have also reported that PD-1 increased in BM CD8 + T cells from DN AML patients, which may promote immune evasion for leukemia cells in the BM (36,37,39,40). In this study, we further compared the expression of PD-1 and TIGIT in paired PB and BM from DN, CR, and R/R patients.…”

Section: Higher Pd-1 and Tigit Expression Detected In The Bm Of Dn And R/r Aml Patientsmentioning

confidence: 81%

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: Higher Pd-1 and Tigit Expression Detected In The Bm Of Dn And R/r Aml Patientsmentioning

confidence: 81%

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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“…Finally, combination of these HMAs with anti-tumor immunomodulatory inhibitors ( 150 – 153 ) including small molecule immunomodulatory drugs ( i.e. thalidomide, lenalidomide and pomalidomide) shown to confer antileukemic T cell immunity in AML and MDS ( 154 – 156 ) represent exemplary avenues for further explorations to achieve and maintain a robust antileukemic milieu in this complex group of blood malignancies.…”

Section: Discussionmentioning

confidence: 99%

Hypomethylating Agents and Immunotherapy: Therapeutic Synergism in Acute Myeloid Leukemia and Myelodysplastic Syndromes

2021

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Decitabine and guadecitabine are hypomethylating agents (HMAs) that exert inhibitory effects against cancer cells. This includes stimulation of anti-tumor immunity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients. Treatment of AML and MDS patients with the HMAs confers upregulation of cancer/testis antigens (CTAs) expression including the highly immunogenic CTA NY-ESO-1. This leads to activation of CD4+ and CD8+ T cells for elimination of cancer cells, and it establishes the feasibility to combine cancer vaccine with HMAs to enhance vaccine immunogenicity. Moreover, decitabine and guadecitabine induce the expression of immune checkpoint molecules in AML cells. In this review, the accumulating knowledge on the immunopotentiating properties of decitabine and guadecitabine in AML and MDS patients are presented and discussed. In summary, combination of decitabine or guadecitabine with NY-ESO-1 vaccine enhances vaccine immunogenicity in AML patients. T cells from AML patients stimulated with dendritic cell (DC)/AML fusion vaccine and guadecitabine display increased capacity to lyse AML cells. Moreover, decitabine enhances NK cell-mediated cytotoxicity or CD123-specific chimeric antigen receptor-engineered T cells antileukemic activities against AML. Furthermore, combination of either HMAs with immune checkpoint blockade (ICB) therapy may circumvent their resistance. Finally, clinical trials of either HMAs combined with cancer vaccines, NK cell infusion or ICB therapy in relapsed/refractory AML and high-risk MDS patients are currently underway, highlighting the promising efficacy of HMAs and immunotherapy synergy against these malignancies.

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“…Among them, the relatively well-studied diseases are MM and MDS. These drugs lead to selective ubiquitination and proteasomal degradation of Ikaros and Aiolos through recruiting TFs to the CRL4 CRBN E3 ubiquitin ligase, representing an original mechanism of therapy through altering the substrate specificity ( Lu et al, 2014 ; Sievers et al, 2018 ; Zeidner et al, 2020 ). Different IMiDs target the degradation of distinct sets of TFs.…”

Section: Targeted Therapy For Ikarosmentioning

confidence: 99%

Ikaros Proteins in Tumor: Current Perspectives and New Developments

Xia

Yuan

Han

et al. 2021

Front. Mol. Biosci.

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Ikaros is a zinc finger transcription factor (TF) of the Krüppel family member, which significantly regulates normal lymphopoiesis and tumorigenesis. Ikaros can directly initiate or suppress tumor suppressors or oncogenes, consequently regulating the survival and proliferation of cancer cells. Over recent decades, a series of studies have been devoted to exploring and clarifying the relationship between Ikaros and associated tumors. Therapeutic strategies targeting Ikaros have shown promising therapeutic effects in both pre-clinical and clinical trials. Nevertheless, the increasingly prominent problem of drug resistance targeted to Ikaros and its analog is gradually appearing in our field of vision. This article reviews the role of Ikaros in tumorigenesis, the mechanism of drug resistance, the progress of targeting Ikaros in both pre-clinical and clinical trials, and the potential use of associated therapy in cancer therapy.

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Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS

Cited by 18 publications

References 47 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

Hypomethylating Agents and Immunotherapy: Therapeutic Synergism in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Ikaros Proteins in Tumor: Current Perspectives and New Developments

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