Impact of minimal residual disease detection by next-generation flow cytometry in multiple myeloma patients with sustained complete remission after frontline therapy

Minimal residual disease (MRD) was monitored in 52 patients with sustained CR (≥2 years) after frontline therapy using next-generation flow (NGF) cytometry. 25% of patients initially MRD- reversed to MRD+. 56% of patients in sustained CR were MRD+; 45% at the level of 10−5; 17% at 10−6. All patients who relapsed during follow-up were MRD+ at the latest MRD assessment, including those with ultra-low tumor burden. MRD persistence was associated with specific phenotypic profiles: higher erythroblasts’ and tumor-associated monocytes/macrophages’ predominance in the bone marrow niche. NGF emerges as a suitable method for periodic, reproducible, highly-sensitive MRD-detection at the level of 10−6

Recovery of Innate Immune Cells and Persisting Alterations in Adaptive Immunity in the Peripheral Blood of Convalescent Plasma Donors at Eight Months Post SARS-CoV-2 Infection

Persisting alterations and unique immune signatures have been previously detected in the peripheral blood of convalescent plasma (CP) donors at approximately two months after initial SARS-CoV-2 infection. This article presents the results on the sequential analysis of 47 CP donors at a median time of eight months (range 7.5–8.5 months) post infection, as assessed by flow cytometry. Interestingly, our results show a significant variation of the relevant immune subset composition among CP donors. Regarding innate immunity, both non-classical monocytes, and CD11b-granulocytes had fully recovered at eight months post COVID-19 infection. Intermediate monocytes and natural killer (NK) cells had already been restored at the two-month evaluation and remained stable. Regarding adaptive immunity, the COVID-19-related skewed Th1 and Th2 cell polarization remained at the same levels as in two months. However, low levels of total B cells were detected even after eight months from infection. A persisting reduction of CD8+ Tregs and changes in the NKT cell compartment were also remarkable. CP donors present with a unique immune landscape at eight months post COVID-19 infection, which is characterized by the notable restoration of the components of innate immunity along with a persisting imprint of SARS-CoV-2 in cells of the adaptive immunity. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Characterization of a PERK kinase inhibitor with anti-myeloma activity

Due to increased immunoglobulin production and uncontrolled proliferation, multiple myeloma (MM) plasma cells develop a phenotype of deregulated unfolded protein response (UPR). The eIF2‐alpha kinase 3 [EIF2αK3, protein kinase R (PKR)‐like ER kinase (PERK)], the third known sensor of endoplasmic reticulum (ER) stress, is a serine‐threonine kinase and, like the other two UPR‐related proteins, i.e., IRE1 and ATF6, it is bound to the ER membrane. MM, like other tumors showing uncontrolled protein secretion, is highly dependent to UPR for survival; thus, inhibition of PERK can be an effective strategy to suppress growth of malignant plasma cells. Here, we have used GSK2606414, an ATP‐competitive potent PERK inhibitor, and found significant anti‐proliferative and apoptotic effects in a panel of MM cell lines. These effects were accompanied by the downregulation of key components of the PERK pathway as well as of other UPR elements. Consistently, PERK gene expression silencing significantly increased cell death in MM cells, highlighting the importance of PERK signaling in MM biology. Moreover, GSK2606414, in combination with the proteasome inhibitor bortezomib, exerted an additive toxic effect in MM cells. Overall, our data suggest that PERK inhibition could represent a novel combinatorial therapeutic approach in MM. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Recovery of Innate Immune Cells and Persisting Alterations in Adaptive Immunity in the Peripheral Blood of Convalescent Plasma Donors at Eight Months Post SARS-CoV-2 Infection

Persisting alterations and unique immune signatures have been previously detected in the peripheral blood of convalescent plasma (CP) donors at approximately two months after initial SARS-CoV-2 infection. This article presents the results on the sequential analysis of 47 CP donors at a median time of eight months (range 7.5–8.5 months) post infection, as assessed by flow cytometry. Interestingly, our results show a significant variation of the relevant immune subset composition among CP donors. Regarding innate immunity, both non-classical monocytes, and CD11b- granulocytes had fully recovered at eight months post COVID-19 infection. Intermediate monocytes and natural killer (NK) cells had already been restored at the two-month evaluation and remained stable. Regarding adaptive immunity, the COVID-19-related skewed Th1 and Th2 cell polarization remained at the same levels as in two months. However, low levels of total B cells were detected even after eight months from infection. A persisting reduction of CD8+ Tregs and changes in the NKT cell compartment were also remarkable. CP donors present with a unique immune landscape at eight months post COVID-19 infection, which is characterized by the notable restoration of the components of innate immunity along with a persisting imprint of SARS-CoV-2 in cells of the adaptive immunity

Recovery of Innate Immune Cells and Persisting Alterations in Adaptive Immunity in the Peripheral Blood of Convalescent Plasma Donors at Eight Months Post SARS-CoV-2 Infection

Persisting alterations and unique immune signatures have been previously detected in the peripheral blood of convalescent plasma (CP) donors at approximately two months after initial SARS-CoV-2 infection. This article presents the results on the sequential analysis of 47 CP donors at a median time of eight months (range 7.5–8.5 months) post infection, as assessed by flow cytometry. Interestingly, our results show a significant variation of the relevant immune subset composition among CP donors. Regarding innate immunity, both non-classical monocytes, and CD11b- granulocytes had fully recovered at eight months post COVID-19 infection. Intermediate monocytes and natural killer (NK) cells had already been restored at the two-month evaluation and remained stable. Regarding adaptive immunity, the COVID-19-related skewed Th1 and Th2 cell polarization remained at the same levels as in two months. However, low levels of total B cells were detected even after eight months from infection. A persisting reduction of CD8+ Tregs and changes in the NKT cell compartment were also remarkable. CP donors present with a unique immune landscape at eight months post COVID-19 infection, which is characterized by the notable restoration of the components of innate immunity along with a persisting imprint of SARS-CoV-2 in cells of the adaptive immunity

Impact of minimal residual disease detection by next-generation flow cytometry in multiple myeloma patients with sustained complete remission after frontline therapy

Minimal residual disease (MRD) was monitored in 52 patients with sustained CR (≥2 years) after frontline therapy using next-generation flow (NGF) cytometry. 25% of patients initially MRD- reversed to MRD+. 56% of patients in sustained CR were MRD+; 45% at the level of 10−5; 17% at 10−6. All patients who relapsed during follow-up were MRD+ at the latest MRD assessment, including those with ultra-low tumor burden. MRD persistence was associated with specific phenotypic profiles: higher erythroblasts’ and tumor-associated monocytes/macrophages’ predominance in the bone marrow niche. NGF emerges as a suitable method for periodic, reproducible, highly-sensitive MRD-detection at the level of 10−6