Multi-parametric single cell evaluation defines distinct drug responses in healthy hematologic cells that are retained in corresponding malignant cell types

Majumder, Muntasir Mamun; Leppä, Aino-Maija; Hellesøy, Monica; Dowling, Paul; Malyutina, Alina; Kopperud, Reidun Kristin; Bazou, Despina; Andersson, Emma; Parsons, Alun; Tang, Jing; Kallioniemi, Olli; Mustjoki, Satu; O’Gorman, Peter; Wennerberg, Krister; Porkka, Kimmo; Gjertsen, Bjørn Tore; Heckman, Caroline A.

doi:10.3324/haematol.2019.217414

Cited by 19 publications

(17 citation statements)

References 44 publications

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“… 33 , 73 The effect of FLT3 inhibitors on B cells is modest, with only midostaurin showing an in vitro negative effect on the viability of B cells. 74 Although proliferation and IgG production in healthy B cells are decreased by idelalisib in vitro, this is not seen upon idelalisib treatment in vivo. 45 …”

Section: Impact Of the Main Tkis On The Immune Responsementioning

confidence: 99%

Kinase inhibitors developed for treatment of hematologic malignancies: implications for immune modulation in COVID-19

Jacobs

Eldering²,

Kater

2021

Blood Advances

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Tyrosine kinase inhibitors (TKIs) are used to target dysregulated signaling pathways in virtually all hematologic malignancies. Many of the targeted signaling pathways are also essential in nonmalignant immune cells. The current coronavirus severe acute respiratory syndrome coronavirus 2 pandemic catalyzed clinical exploration of TKIs in the treatment of the various stages of COVID-19, which are characterized by distinct immune-related complications. Most of the reported effects of TKIs on immune regulation have been explored in vitro, with different class-specific drugs having nonoverlapping target affinities. Moreover, many of the reported in vivo effects are based on artificial animal models or on observations made in symptomatic patients with a hematologic malignancy who often already suffer from disturbed immune regulation. Based on in vitro and clinical observations, we attempt to decipher the impact of the main TKIs approved or in late-stage development for the treatment of hematological malignancies, including inhibitors of Bruton’s tyrosine kinase, spleen tyrosine kinase, BCR-Abl, phosphatidylinositol 3-kinase/ mammalian target of rapamycin, JAK/STAT, and FMS-like tyrosine kinase 3, to provide a rationale for how such inhibitors could modify clinical courses of diseases, such as COVID-19.

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Section: Impact Of the Main Tkis On The Immune Responsementioning

confidence: 99%

Kinase inhibitors developed for treatment of hematologic malignancies: implications for immune modulation in COVID-19

Jacobs

Eldering²,

Kater

2021

Blood Advances

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“…In both healthy and malignant patient samples (acute myeloid leukemia and multiple myeloma), in vitro assays have shown that CD19 1 B cells are most sensitive to venetoclax (50% inhibitory concentration [IC 50 ] 0.4-12 nM), with CD4 1 T cells, NK cells, and NK T cells sensitive at higher doses (IC 50 100 nM to 1 mM), whereas monocytes and granulocytes are relatively resistant (IC 50 10 mM). 48 Monocyte subclone resistance to venetoclax has been shown in patients undergoing therapy for acute myeloid leukemia. 49 This differing cell lineage sensitivity may lead to a positive selective pressure on monocyte populations with long-term treatment.…”

Section: Discussionmentioning

confidence: 99%

Immune recovery in patients with mantle cell lymphoma receiving long-term ibrutinib and venetoclax combination therapy

et al. 2020

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Combination venetoclax plus ibrutinib for the treatment of mantle cell lymphoma (MCL) has demonstrated efficacy in the relapsed or refractory setting; however, the long-term impact on patient immunology is unknown. In this study, changes in immune subsets of MCL patients treated with combination venetoclax and ibrutinib were assessed over a 4-year period. Multiparameter flow cytometry of peripheral blood mononuclear cells showed that ≥12 months of treatment resulted in alterations in the proportions of multiple immune subsets, most notably CD4+ and CD8+ effector and central memory T cells and natural killer cells, and normalization of T-cell cytokine production in response to T-cell receptor stimulation. Gene expression analysis identified upregulation of multiple myeloid genes (including S100 and cathepsin family members) and inflammatory pathways over 12 months. Four patients with deep responses stopped study drugs, resulting in restoration of normal immune subsets for all study parameters except myeloid gene/pathway expression, suggesting long-term combination venetoclax and ibrutinib irreversibly affects this population. Our findings demonstrate that long-term combination therapy is associated with immune recovery in MCL, which may allow responses to subsequent immunotherapies and suggests that this targeted therapy results in beneficial impacts on immunological recovery. This trial was registered at www.clinicaltrials.gov as #NCT02471391.

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“…These multicellular models can recapitulate certain elements of the tumor microenvironment and can facilitate studying the impact of perturbations on the tumor microenvironment and on the tumor cells (Neal et al 2018). These findings have been mirrored in some of the hematopoietic primary culture systems, where nontumor cells such as macrophages and T cells have been shown to play an important influencing role in drug responses and have facilitated the ex vivo analysis of additional classes of agents, such as those that act on immune cells (Carey et al 2017;Edwards et al 2018Edwards et al , 2019Kuusanmaki et al 2020;Majumder et al 2019). A related approach leveraged microarray technology to create a matrix of pairwise combinations of recombinant extracellular matrix proteins with soluble growth factors and cytokines (Smith et al 2019) and showed some of these factors could influence breast cancer cell response to tyrosine kinase inhibitors in a disease-subset-specific way (Watson et al 2018).…”

Section: Three-dimensional Semisolid Culturesmentioning

confidence: 98%

“…In recent years, new instrumentation and biological tools have facilitated dramatic updates to ex vivo readouts. These include the incorporation of high-throughput flow cytometry (Kuusanmaki et al 2020, Majumder et al 2019, Teh et al 2020) and imaging analysis ( Jacob et al 2016), both of which enable quantification of specific phenotypes on a single-cell level. These new techniques can then be combined with the multitude of highquality antibodies that are now available to organize cells into discrete biological populations as well as antibodies that can accurately distinguish between specific cell states (proliferation, death, activation) or measure drug impact on specific pathways (signaling, apoptosis, etc.).…”

Section: Evolving Readoutsmentioning

confidence: 99%

Ex Vivo Analysis of Primary Tumor Specimens for Evaluation of Cancer Therapeutics

Tognon

Sears

Mills

et al. 2021

Annu. Rev. Cancer Biol.

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The use of ex vivo drug sensitivity testing to predict drug activity in individual patients has been actively explored for almost 50 years without delivering a generally useful predictive capability. However, extended failure should not be an indicator of futility. This is especially true in cancer research, where ultimate success is often preceded by less successful attempts. For example, both immune- and genetic-based targeted therapies for cancer underwent numerous failed attempts before biological understanding, improved targets, and optimized drug development matured to facilitate an arsenal of transformational drugs. Similarly, directly assessing drug sensitivity of primary tumor biopsies—and the use of this information to help direct therapeutic approaches—has a long history with a definitive learning curve. In this review, we survey the history of ex vivo testing and the current state of the art for this field. We present an update on methodologies and approaches, describe the use of these technologies to test cutting-edge drug classes, and describe an increasingly nuanced understanding of tumor types and models for which this strategy is most likely to succeed. We consider the relative strengths and weaknesses of predicting drug activity across the broad biological context of cancer patients and tumor types. This includes an analysis of the potential for ex vivo drug sensitivity testing to accurately predict drug activity within each of the biological hallmarks of cancer pathogenesis. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Multi-parametric single cell evaluation defines distinct drug responses in healthy hematologic cells that are retained in corresponding malignant cell types

Abstract: parametric single cell evaluation defines distinct drug responses in healthy hematological cells that are retained in corresponding malignant cell types.

Cited by 19 publications

References 44 publications

Kinase inhibitors developed for treatment of hematologic malignancies: implications for immune modulation in COVID-19

Kinase inhibitors developed for treatment of hematologic malignancies: implications for immune modulation in COVID-19

Immune recovery in patients with mantle cell lymphoma receiving long-term ibrutinib and venetoclax combination therapy

Ex Vivo Analysis of Primary Tumor Specimens for Evaluation of Cancer Therapeutics

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