dc.contributor.author |
Velasco-Hernández, Talia |
dc.contributor.author |
Zanetti, S. R. |
dc.contributor.author |
Roca Ho, Heleia |
dc.contributor.author |
Gutiérrez-Agüera, Francisco |
dc.contributor.author |
Petazzi, Paolo |
dc.contributor.author |
Sánchez-Martínez, D. |
dc.contributor.author |
Molina, Oscar |
dc.contributor.author |
Baroni, Matteo Libero |
dc.contributor.author |
Fuster, José Luis |
dc.contributor.author |
Ballerini, Paola |
dc.contributor.author |
Bueno, Clara |
dc.contributor.author |
Fernández-Fuentes, Narcís |
dc.contributor.author |
Engel, P. |
dc.contributor.author |
Menéndez Bujan, Pablo |
dc.contributor.author |
Universitat Autònoma de Barcelona |
dc.date |
2020 |
dc.identifier |
https://ddd.uab.cat/record/236713 |
dc.identifier |
urn:10.1136/jitc-2020-000896 |
dc.identifier |
urn:oai:ddd.uab.cat:236713 |
dc.identifier |
urn:scopus_id:85089618040 |
dc.identifier |
urn:articleid:20511426v8n2e000896 |
dc.identifier |
urn:pmid:32788237 |
dc.identifier |
urn:pmc-uid:7422657 |
dc.identifier |
urn:pmcid:PMC7422657 |
dc.identifier |
urn:oai:pubmedcentral.nih.gov:7422657 |
dc.format |
application/pdf |
dc.language |
eng |
dc.publisher |
|
dc.relation |
European Commission 646903 |
dc.relation |
Ministerio de Economía y Competitividad SAF2016-80481-R |
dc.relation |
Instituto de Salud Carlos III PI17-01028 |
dc.relation |
Journal for immunotherapy of cancer ; Vol. 8 Núm. 2 (november 2020), p. e000896 |
dc.rights |
open access |
dc.rights |
Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. |
dc.rights |
https://creativecommons.org/licenses/by-nc/4.0/ |
dc.subject |
T-lymphocytes |
dc.subject |
Cell engineering |
dc.subject |
Hematologic neoplasms |
dc.subject |
Immunotherapy |
dc.subject |
Receptors |
dc.subject |
Chimeric antigen |
dc.title |
Efficient elimination of primary B-ALL cells in vitro and in vivo using a novel 4-1BB-based CAR targeting a membrane-distal CD22 epitope |
dc.type |
Article |
dc.description.abstract |
Altres ajuts: Funding This work was supported by the Obra Social La Caixa (LCF/PR/HR19/52160011), the Spanish Cancer Association and Leo Messi Foundation to PM. |
dc.description.abstract |
Background There are few therapeutic options available for patients with B-cell acute lymphoblastic leukemia (B-ALL) relapsing as CD19 - either after chemotherapy or CD19-targeted immunotherapies. CD22-chimeric antigen receptor (CAR) T cells represent an attractive addition to CD19-CAR T cell therapy because they will target both CD22 + CD19 - B-ALL relapses and CD19 - preleukemic cells. However, the immune escape mechanisms from CD22-CAR T cells, and the potential contribution of the epitope binding of the anti-CD22 single-chain variable fragment (scFv) remain understudied. Methods Here, we have developed and comprehensively characterized a novel CD22-CAR (clone hCD22.7) targeting a membrane-distal CD22 epitope and tested its cytotoxic effects against B-ALL cells both in in vitro and in vivo assays. Results Conformational epitope mapping, cross-blocking, and molecular docking assays revealed that the hCD22.7 scFv is a high-affinity binding antibody which specifically binds to the ESTKDGKVP sequence, located in the Ig-like V-type domain, the most distal domain of CD22. We observed efficient killing of B-ALL cells in vitro, although the kinetics were dependent on the level of CD22 expression. Importantly, we show an efficient in vivo control of patients with B-ALL derived xenografts with diverse aggressiveness, coupled to long-term hCD22.7-CAR T cell persistence. Remaining leukemic cells at sacrifice maintained full expression of CD22, ruling out CAR pressure-mediated antigen loss. Finally, the immunogenicity capacity of this hCD22.7-scFv was very similar to that of other CD22 scFv previously used in adoptive T cell therapy. Conclusions We report a novel, high-affinity hCD22.7 scFv which targets a membrane-distal epitope of CD22. 4-1BB-based hCD22.7-CAR T cells efficiently eliminate clinically relevant B- CD22 high and CD22 low ALL primary samples in vitro and in vivo. Our study supports the clinical translation of this hCD22.7-CAR as either single or tandem CD22-CD19-CAR for both naive and anti-CD19-resistant patients with B-ALL. |