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Adult and cord blood-derived high affinity gB-CAR-T cells effectively react against human cytomegalovirus infections.

著者 Olbrich H , Theobald SJ , Slabik C , Gerasch L , Schneider A , Mach M , Shum T , Mamonkin M , Stripecke R
Hum Gene Ther.2020 Mar 11 ; ():.
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Human cytomegalovirus (HCMV) reactivations are associated with lower overall survival after transplantations. Adoptive transfer of HCMV-reactive expanded or selected T cells can be applied as a compassionate use, but requires that the human leukocyte antigens (HLA)-matched donor provides memory cells against HCMV. In order to overcome this, we developed engineered T cells expressing chimeric antigen receptors (CARs) targeted against the HCMV glycoprotein B (gB) expressed upon viral reactivation. Single-chain variable fragments derived from a human high-affinity gB-specific neutralizing monoclonal antibody (SM5-1) were fused to CARs with 4-1BB (BBL) or CD28 (28S) co-stimulatory domains and subcloned into retroviral vectors. CD4<sup>+</sup> and CD8<sup>+</sup> T cells obtained from HCMV-seronegative adult blood or cord blood transduced with the vectors efficiently expressed the gB-CARs. The specificity and potency of gB-CAR-T cells were demonstrated and compared in vitro using: 293T cells expressing gB, and with mesenchymal stem cells infected with a HCMV TB40 strain expressing Gaussia luciferase (HCMV/Gluc). BBL-gB-CAR-T cells generated with adult or cord blood demonstrated significantly higher in vitro activation and cytotoxicity performance than 28-gB-CAR-T cells. Nod.Rag.Gamma (huNRG) mice transplanted with human cord blood CD34<sup>+</sup> cells with long-term human immune reconstitution were used to model HCMV/GLuc infection in vivo by optical imaging analyses. One week after administration, response to BBL-gB-CAR-T cell therapy was observed for 5/8 mice, defined by significant reduction of the bioluminescent signal in relation to untreated controls. Response to therapy was sporadically associated with CAR detection in spleen. Thus, exploring a scFv derived from the high affinity gB-antibody SM5-1 and the 4-1BB signaling domain for CAR design enabled an in vitro high on-target effect and cytotoxicity and encouraging results in vivo. Therefore, gB-CAR-T cells can be a future clinical option for treatment of HCMV reactivations, particularly when memory T cells from the donors are not available.
PMID: 32159399 [PubMed - as supplied by publisher]
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