Background Kit-M, the combination of response-modifiers GM-CSF+ Prostaglandine (PGE)1, converts myeloid blasts into dendritic cells(DC) of leukemic origin (DCleu), that activate immune-cells against leukemia. Kit M treatment may be an attractive tool for immunotherapy in myeloid leukemia.
Materials and methods EX-VIVO: Culture of leukemic whole-blood (WB) with Kit-M, followed by ‘mixed lymphocyte culture’ (MLC) with patients’ T-cells and (functional) assays (flowcytometry, degranulation-, intracellular cytokine- and cytotoxicity assays. Correlation-analyses.
IN VIVO: treatment of leukemically diseased rats or therapy-refractory patient with Kit M, followed by immune-, hematological and clinical monitoring
Results 1. ex vivo : Treatment of 65 leukemic WB-samples with KIT-M increases frequencies of mature DC/DCleu, reduces tolerogenic DC. Kit-M treated WB increases frequencies of (leukemia-specific) cells of the adaptive and innate immunesystem (incl. (TCRγδ,Tβ7), memory cells (Tcm,Tβ7cm)- , NKβ7,CIKβ7cells), decreases immune-suppressive T-cells (Treg4/8) and improves blast lysis after MLC. Blast-lysis correlates with frequencies of DC and leukemia-specific cells, but not with patients’ age/sex/ELN-risk/response to chemotherapy
2. In vivo - rats: Kit-M treatment of 3 leukemically diseased (vs control) rats (followed by sacrification after treatment) leads to reduced blasts and Tregs in blood and spleen and increased DCleu and memory-like T cells.
3.In vivo - human: Kit-M salvage treatment of a 72 yo refractory AML-patient was well tolerated and the patient improved clinically (PB-blasts were below detection threshold, Neutrophils increased from 10% to 50%, thrombocytes normalized). Immune-monitoring showed a continuous activation of adaptive and innate (IFNγ producing) cells increase (incl. iNKT- , TH1/17-, Bmem-cells and DC) in PB. The patient was discharged in good clinical after the 4-weeks-therapy, however relapsed 2 weeks later.
Conclusions Kit-MTreatment of leukemic WB ex-vivo or of leukemically diseased rats or a patient in-vivo leads to (leukemia specific) activation of the adaptive and innate immune reactive cells (and downregulated suppressive mechanisms) via a DC/DCleu triggered mechanism - resulting in significantly improved blast-lysis compared to controls (independent of patients‘ characteristics). In-vivo treatment was well tolerated, led to an increase of platelets and granulocytes and stable (low) blast counts in PB - probably mediated by a (leukemia specifically) DC/DCleu activated immune system. A dose defining clinical trial in carefully selected patients to confirm clinical safety and efficacy is being prepared.
Disclosure Information H.M. Schmetzer: E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; Modiblast Pharma GmbH. D. Amberger: None. L. Klauer: None. E. Rackl: None. M. Atzler: None. S. Ugur: None. C. Plett: None. A. Rabe: None. C. Kugler: None. A. Rank: None. T. Baudrexler: None. M. Inngjerdingen: None. B. Eiz-Vesper: None. C. Schmid: None.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.