Potent anti-multiple myeloma (MM) responses have been observed in early-stage clinical trials with virally-transduced chimeric antigen receptor (CAR) T-cells redirected to B-cell maturation antigen (BCMA), a membrane protein with extremely high sensitivity and specificity for MM and plasma cells. Despite significant potency, CAR T-cells engineered by virally-mediated gene transfer present a poor risk profile. Permanent modification enhances CAR persistence but also increases the risk of severe cytokine release syndrome (CRS), neurotoxicity, and prolonged plasma cell aplasia due to uncontrolled in vivo expansion and long-term persistence of the permanently-modified CAR T-cells. In an effort to address these shortcomings while preserving efficacy, we have developed CD8+ anti-BCMA CAR T-cells modified transiently by mRNA transfection (Descartes-08). Descartes-08 manufactured at clinical scale showed high (>90%) purity, post-cryopreservation viability, and transfection efficiency. Descartes-08 demonstrated robust dose- and time- dependent killing of BCMA+ MM cell lines, including those with acquired resistance to immunomodulatory drugs (IMiDs), as well as primary MM cells co-cultured with autologous bone marrow stromal cells. Compared with transfected pan- (CD3+) anti-BCMA CAR T-cells, Descartes-08 (CD8+) demonstrated enhanced transfection and killing but reduced secretion of IFN-g, an inflammatory cytokine highly correlated with CRS. Descartes-08 also demonstrated robust dose-dependent efficacy in a disseminated human MM model (i.v. MM1SLuc cells in NSG mice), and could be safely administered repetitively to deepen responses. These results advocate for rapid clinical translation of Descartes-08, which may improve the benefit: risk profile of CAR T-cells in MM and enable their use in patients with earlier-stage disease.
Kurtoglu: 2Cartesian Therapeutics, Inc: Employment, Equity Ownership. Holderness: Cartesian Therapeutics, Inc: Employment, Equity Ownership. Kalayoglu: Cartesian Therapeutics, Inc: Employment, Equity Ownership. Richardson: Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees. Anderson: Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; MedImmune: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Oncopep: Other: scientific founder; C4 Therapeutics: Other: scientific founder.
Asterisk with author names denotes non-ASH members.