TY  - JOUR
A1  - Salzmann-Manrique, Emilia
A1  - Bremm, Melanie
A1  - Huenecke, Sabine
A1  - Stech, Milena
A1  - Orth, Andreas
A1  - Eyrich, Matthias
A1  - Schulz, Ansgar
A1  - Esser, Ruth
A1  - Klingebiel, Thomas
A1  - Bader, Peter
A1  - Herrmann, Eva
A1  - Koehl, Ulrike
T1  - Joint Modeling of Immune Reconstitution Post Haploidentical Stem Cell Transplantation in Pediatric Patients With Acute Leukemia Comparing CD34(+)-Selected to CD3/CD19-Depleted Grafts in a Retrospective Multicenter Study
JF  - frontiers in Immunology
N2  - Rapid immune reconstitution (IR) following stem cell transplantation (SCT) is essential for a favorable outcome. The optimization of graft composition should not only enable a sufficient IR but also improve graft vs. leukemia/tumor effects, overcome infectious complications and, finally, improve patient survival. Especially in haploidentical SCT, the optimization of graft composition is controversial. Therefore, we analyzed the influence of graft manipulation on IR in 40 patients with acute leukemia in remission. We examined the cell recovery post haploidentical SCT in patients receiving a CD34(+)-selected or CD3/CD19-depleted graft, considering the applied conditioning regimen. We used joint model analysis for overall survival (OS) and analyzed the dynamics of age-adjusted leukocytes; lymphocytes; monocytes; CD3(+), CD3(+) CD4(+), and CD3(+) CD8(+) T cells; natural killer (NK) cells; and B cells over the course of time after SCT. Lymphocytes, NK cells, and B cells expanded more rapidly after SCT with CD34(+)-selected grafts (P = 0.036, P = 0.002, and P < 0.001, respectively). Contrarily, CD3(+) CD4(+) helper T cells recovered delayer in the CD34 selected group (P = 0.026). Furthermore, reduced intensity conditioning facilitated faster immune recovery of lymphocytes and T cells and their subsets (P < 0.001). However, the immune recovery for NK cells and B cells was comparable for patients who received reduced-intensity or full preparative regimens. Dynamics of all cell types had a significant influence on OS, which did not differ between patients receiving CD34(+)-selected and those receiving CD3/CD19-depleted grafts. In conclusion, cell reconstitution dynamics showed complex diversity with regard to the graft manufacturing procedure and conditioning regimen.
KW  - immune reconstitution
KW  - allogeneic stem cell transplantation
KW  - CD34 selection
KW  - CD3/19 depletion
KW  - children
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227302
VL  - 9
ER  - 
TY  - JOUR
A1  - Feigl, Frederik Fabian
A1  - Stahringer, Anika
A1  - Peindl, Matthias
A1  - Dandekar, Gudrun
A1  - Koehl, Ulrike
A1  - Fricke, Stephan
A1  - Schmiedel, Dominik
T1  - Efficient redirection of NK cells by genetic modification with chemokine receptors CCR4 and CCR2B
JF  - International Journal of Molecular Sciences
N2  - Natural killer (NK) cells are a subset of lymphocytes that offer great potential for cancer immunotherapy due to their natural anti-tumor activity and the possibility to safely transplant cells from healthy donors to patients in a clinical setting. However, the efficacy of cell-based immunotherapies using both T and NK cells is often limited by a poor infiltration of immune cells into solid tumors. Importantly, regulatory immune cell subsets are frequently recruited to tumor sites. In this study, we overexpressed two chemokine receptors, CCR4 and CCR2B, that are naturally found on T regulatory cells and tumor-resident monocytes, respectively, on NK cells. Using the NK cell line NK-92 as well as primary NK cells from peripheral blood, we show that genetically engineered NK cells can be efficiently redirected using chemokine receptors from different immune cell lineages and migrate towards chemokines such as CCL22 or CCL2, without impairing the natural effector functions. This approach has the potential to enhance the therapeutic effect of immunotherapies in solid tumors by directing genetically engineered donor NK cells to tumor sites. As a future therapeutic option, the natural anti-tumor activity of NK cells at the tumor sites can be increased by co-expression of chemokine receptors with chimeric antigen receptors (CAR) or T cell receptors (TCR) on NK cells can be performed in the future.
KW  - chemokine receptor
KW  - migration
KW  - immune cell infiltration
KW  - trafficking
KW  - NK cells
KW  - immunotherapy
KW  - CCR2
KW  - CCR4
KW  - genetic engineering
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304049
SN  - 1422-0067
VL  - 24
IS  - 4
ER  -