Exploiting the CD200-CD200R immune checkpoint axis in multiple myeloma to enhance CAR T-cell therapy

Abstract

Multiple Myeloma (MM) patients treated with B-cell maturation antigen (BCMA)-specific CAR-T cells usually relapse with BCMA+ disease, indicative of CAR-T cell supression. CD200 is an immune checkpoint that is overexpressed on aberrant plasma cells (aPCs) in MM and is an independent negative prognostic factor for survival. However, CD200 is not present on MM cell lines, a potential limitation of current preclinical models. We engineered MM cell lines to express CD200 at levels equivalent to those found on aPCs in MM, and show these are sufficient to suppress clinical-stage CAR-T cells targeting BCMA or the Tn glycoform of mucin 1 (TnMUC1), costimulated by 4-1BB and CD2 respectively. To prevent CD200-mediated suppression of CAR-T cells we compared CRISRP-Cas9-mediated knockout of the CD200 receptor (CD200RKO), to coexpression of versions of the CD200 receptor that were non-signaling i.e., dominant negative (CD200RDN), or that leveraged the CD200 signal to provide CD28 costimulation (CD200R-CD28 switch). We found that the CD200R-CD28 switch potently enhanced the polyfunctionality of CAR-T cells, and improved cytotoxicity, proliferative capacity, CAR-T cell metabolism, and performance in a chronic antigen exposure assay. CD200RDN provided modest benefits, but surprisingly the CD200RKO was detrimental to CAR-T cell activity, adversely affecting CAR-T cell metabolism. These patterns held in murine xenograft models of plasmacytoma, and disseminated bone marrow predominant disease. Our findings underscore the importance of CD200-mediated immune suppression in CAR-T therapy of MM and highlight a promising approach to enhance such therapies by leveraging CD200 expression on aPCs to provide costimulation via a CD200R-CD28 switch.

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“…But to some extent, single administration of PD-1 DNR CAR-T cells provided much more convenience than repeated antibody administrations and might reduce the incidence of immune-related adverse events (IRAEs). Additionally, a recent study reported that a CD200R-CD28 switch optimally outperformed in enhancing CAR-T function in CD200 + multiple myeloma (MM) models than the approach of CD200R-dominant negative [ 6 ]. And surprisingly, the CD200RKO unexpectedly reduced cytotoxicity conversely.…”