Anti-human CD117 CAR T-cells efficiently eliminate healthy and malignant CD117-expressing hematopoietic cells

Myburgh, Renier; Kiefer, Jonathan D.; Russkamp, Norman F.; Magnani, Chiara F.; Núñez, Nicolás Gonzalo; Simonis, Alexander; Pfister, Surema; Wilk, C. Matthias; McHugh, Donal; Friemel, Juliane; Müller, Antonia; Becher, Burkhard; Münz, Christian; Broek, Maries van den; Neri, Dario; Manz, Markus G.

doi:10.1038/s41375-020-0818-9

Cited by 66 publications

(93 citation statements)

References 51 publications

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“…Activation of neutrophil growth factor receptor signaling pathway induces proliferation and early stages of HSC differentiation. Activation of CD117 receptor by neutrophil growth factor potentiates a number of cytokine-dependent signaling pathways, thereby promoting proliferation and differentiation of HSC [3,12]. The CD117 molecule is involved in the maintenance of HSC population in the blood and bone marrow.…”

Section: Resultsmentioning

confidence: 99%

Thymalin: Activation of Differentiation of Human Hematopoietic Stem Cells

et al. 2020

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Thymalin is a polypeptide complex isolated from the thymus and regulating the functions of the immune system. Thymalin is effective in therapy of acute respiratory syndrome, chronic obstructive bronchitis, and other immunopathology. Thymalin increases functional activity of T lymphocytes, but the targeted molecular mechanism of its biological activity requires further study. We studied the influence of thymalin on differentiation of human hematopoietic stem cells (HSC) and expression of CD28 molecule involved in the implementation of antiviral immunity in COVID-19 infection. It was found that thymalin reduced the expression of CD44 (stem cell marker) and CD117 (molecule of the intermediate stage of HSC differentiation) by 2-3 times and increased the expression of CD28 (marker of mature T lymphocytes) by 6.8 times. This indirectly indicates that thymalin stimulated differentiation of CD117 + cells into mature CD28 + T lymphocytes. It is known that in patients with severe COVID-19, the number of CD28 + , CD4 + , CD8 + T lymphocytes in the blood decreased, which attested to a pronounced suppression of immunity. It is possible that the antiviral effect of thymalin consists in compensatory stimulation of HSC differentiation into CD28 + T lymphocytes at the stage of immunity suppression in unfavorable course of viral infection. Thymalin can be considered as an immunoprotective peptide drug for the prevention of COVID-19.

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Section: Resultsmentioning

confidence: 99%

Thymalin: Activation of Differentiation of Human Hematopoietic Stem Cells

et al. 2020

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“…In addition to hematopoietic stem cells and mast cells, interstitial cells of Cajal (ICCs) and melanocytes, epithelial cells, and certain cells in the reproductive organs are highly positive for CD117 [66−68]. In a recent publication, we used immunohistochemistry to compare CD117 expression patterns in several vital organs of humans and mice [69]. In summary, we found that low-level CD117 expression is more common than generally acknowledged and is, for example, present in tubular epithelial cells of the kidney or ovarian follicular cells.…”

Section: Expression Patterns In Mice and Humansmentioning

confidence: 99%

Anti-CD117 immunotherapy to eliminate hematopoietic and leukemia stem cells

Russkamp

Myburgh

Kiefer

et al. 2021

Experimental Hematology

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Precise replacement of diseased or dysfunctional organs is the goal of regenerative medicine and has appeared to be a distant goal for a long time. In the field of hematopoietic stem cell transplantation, this goal is now becoming tangible as gene-editing technologies and novel conditioning agents are entering the clinical arena. Targeted immunologic depletion of hematopoietic stem cells (HSCs), which are at the very root of the hematopoietic system, will enable more selective and potentially more effective hematopoietic stem cell transplantation in patients with hematological diseases. In contrast to current conditioning regimes based on ionizing radiation and chemotherapy, immunologic conditioning will spare mature hematopoietic cells and cause substantially less inflammation and unspecific collateral damage to other organs. Biological agents that target the stem cell antigen CD117 are the frontrunners for this purpose and have exhibited preclinical activity in depletion of healthy HSCs. The value of anti-CD117 antibodies as conditioning agents is currently being evaluated in early clinical trials. Whereas mild, antibody-based immunologic conditioning concepts might be appropriate for benign hematological disorders in which incomplete replacement of diseased cells is sufficient, higher efficacy will be required for treatment and elimination of hematologic stem cell malignancies such as acute myeloid leukemia and myelodysplastic syndrome. Antibody−drug conjugates, bispecific T-cell engaging and activating antibodies (TEAs), or chimeric antigen receptor (CAR) T cells might offer increased efficacy compared with naked antibodies and yet higher tolerability and safety compared with current genotoxic conditioning approaches. Here, we summarize the current state regarding immunologic conditioning concepts for the treatment of HSC disorders and outline potential future developments.

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“…CD123 CAR-T cells are also in clinical development. CD117 CAR-T cells were recently reported to efficiently eliminate AML blasts as well as CD117 + healthy HSCs in the AML model [81]. CD117, a receptor tyrosine kinase to which stem cell factor binds, is expressed on hematopoietic precursors; however, it may remain overexpressed following malignant transformation in HSCs [82,83].…”

Section: Immunotherapy For Amlmentioning

confidence: 99%

Immunotherapy in Hematologic Malignancies: Emerging Therapies and Novel Approaches

Noh

Seo

Lee

et al. 2020

IJMS

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Immunotherapy is extensively investigated for almost all types of hematologic tumors, from preleukemic to relapse/refractory malignancies. Due to the emergence of technologies for target cell characterization, antibody design and manufacturing, as well as genome editing, immunotherapies including gene and cell therapies are becoming increasingly elaborate and diversified. Understanding the tumor immune microenvironment of the target disease is critical, as is reducing toxicity. Although there have been many successes and newly FDA-approved immunotherapies for hematologic malignancies, we have learned that insufficient efficacy due to disease relapse following treatment is one of the key obstacles for developing successful therapeutic regimens. Thus, combination therapies are also being explored. In this review, immunotherapies for each type of hematologic malignancy will be introduced, and novel targets that are under investigation will be described.

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Anti-human CD117 CAR T-cells efficiently eliminate healthy and malignant CD117-expressing hematopoietic cells

Cited by 66 publications

References 51 publications

Thymalin: Activation of Differentiation of Human Hematopoietic Stem Cells

Thymalin: Activation of Differentiation of Human Hematopoietic Stem Cells

Anti-CD117 immunotherapy to eliminate hematopoietic and leukemia stem cells

Immunotherapy in Hematologic Malignancies: Emerging Therapies and Novel Approaches

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