Defining an optimal dual-targeted CAR T-cell therapy approach simultaneously targeting BCMA and GPRC5D to prevent BCMA escape– Driven relapse in multiple myeloma Journal Article

   

Authors:	de Larrea, C. F.; Staehr, M.; Lopez, A. V.; Ng, K. Y.; Chen, Y.; Godfrey, W. D.; Purdon, T. J.; Ponomarev, V.; Wendel, H. G.; Brentjens, R. J.; Smith, E. L.
Article Title:	Defining an optimal dual-targeted CAR T-cell therapy approach simultaneously targeting BCMA and GPRC5D to prevent BCMA escape– Driven relapse in multiple myeloma
Abstract:	Chimeric antigen receptor (CAR) T-cell therapy for multiple myeloma targeting B-cell maturation antigen (TNFRSF17; BCMA) induces high overall response rates; however, relapse occurs commonly. A reservoir of multiple myeloma cells lacking sufficient BCMA surface expression (antigen escape) may be implicated in relapse. We demonstrate that simultaneous targeting of an additional antigen—here, G protein-coupled receptor class-C group-5 member-D (GPRC5D)—can prevent BCMA escape–mediated relapse in a model of multiple myeloma. To identify an optimal approach, we compare subtherapeutic doses of different forms of dual-targeted cellular therapy. These include; (i) parallel-produced and pooled mono-targeted CAR T cells, (ii) bicistronic constructs expressing distinct CARs from a single vector, and (iii) a dual-scFv “single-stalk” CAR design. When targeting BCMA-negative disease, bicistronic and pooled approaches had the highest efficacy, whereas for dual-antigen–expressing disease, the bicistronic approach was more efficacious than the pooled approach. Mechanistically, expressing two CARs on a single cell enhanced the strength of CAR T-cell/target cell interactions. ©2020 American Association for Cancer Research.
Keywords:	genetics; multiple myeloma; neoplasm recurrence, local; tumor recurrence; receptors, g-protein-coupled; g protein coupled receptor; adoptive immunotherapy; immunotherapy, adoptive; humans; human; b cell maturation antigen; b-cell maturation antigen; gprc5d protein, human
Journal Title:	Blood Cancer Discovery
Volume:	1
Issue:	2
ISSN:	2643-3230
Publisher:	American Association for Cancer Research
Date Published:	2020-09-01
Start Page:	146
End Page:	154
Language:	English
DOI:	10.1158/2643-3230.Bcd-20-0020
PUBMED:	33089218
PROVIDER:	scopus
PMCID:	PMC7575057
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85096869876&doi=10.1158%2f2643-3230.BCD-20-0020&partnerID=40&md5=0cbd45df14afdbb479e9b68820188be3
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/224471