| Autor: |
Worel, Nina, Grabmeier-Pfistershammer, Katharina, Kratzer, Bernhard, Schlager, Martina, Tanzmann, Andreas, Rottal, Arno, Körmöczi, Ulrike, Porpaczy, Edit, Staber, Philipp B., Skrabs, Cathrin, Herkner, Harald, Gudipati, Venugopal, Huppa, Johannes B., Salzer, Benjamin, Lehner, Manfred, Saxenhuber, Nora, Friedberg, Eleonora, Wohlfarth, Philipp, Hopfinger, Georg, Rabitsch, Werner |
| Předmět: |
|
| Zdroj: |
Frontiers in Immunology; 1/9/2023, Vol. 13, p1-17, 17p |
| Abstrakt: |
Background: Chimeric antigen receptor T (CART) cell therapy targeting the B cell specific differentiation antigen CD19 has shown clinical efficacy in a subset of relapsed/refractory (r/r) diffuse large B cell lymphoma (DLBCL) patients. Despite this heterogeneous response, blood pre-infusion biomarkers predicting responsiveness to CART cell therapy are currently understudied. Methods: Blood cell and serum markers, along with clinical data of DLBCL patients who were scheduled for CART cell therapy were evaluated to search for biomarkers predicting CART cell responsiveness. Findings: Compared to healthy controls (n=24), DLBCL patients (n=33) showed significant lymphopenia, due to low CD3+CD4+ T helper and CD3-CD56+ NK cell counts, while cytotoxic CD3+CD8+ T cell counts were similar. Although lymphopenic, DLBCL patients had significantly more activated HLA-DR+ (P=0.005) blood T cells and a higher frequency of differentiated CD3+CD27-CD28-(28.7 ± 19.0% versus 6.6 ± 5.8%; P<0.001) T cells. Twenty-six patients were infusedwithCART cells (median 81 days after leukapheresis) andwere analyzed for the overall response (OR) 3 months later. Univariate and multivariate regression analyses showed that low levels of differentiated CD3+CD27-CD28-T cells (23.3 ± 19.3% versus 35.1 ± 18.0%) were independently associated with OR. This association was even more pronounced when patients were stratified for complete remission (CR versus non-CR: 13.7 ± 11.7% versus 37.7 ± 17.4%, P=0.001). A cut-off value of ≤ 18% of CD3+CD27-CD28-T cells predicted CR at 12 months with high accuracy (P<0.001). In vitro, CD3+CD8+CD27-CD28-compared to CD3+CD8+CD27+CD28+ CART cells displayed similar CD19+ target cell-specific cytotoxicity, but were hypoproliferative and produced less cytotoxic cytokines (IFN-g and TNF-a). CD3+CD8+ T cells outperformed CD3+CD4+ T cells 3-to 6-fold in terms of their ability to kill CD19+ target cells. Interpretation: Low frequency of differentiated CD3+CD27-CD28-T cells at leukapheresis represents a novel pre-infusion blood biomarker predicting a favorable response to CART cell treatment in r/r DLBCL patients. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
