A compound chimeric antigen receptor strategy for targeting multiple myeloma

Abstract

Current clinical outcomes using chimeric-antigen receptors (CARs) against multiple myeloma show promise in the eradication of bulk disease. However, these anti-BCMA (CD269) CARs observe relapse as a common phenomenon after treatment due to the reemergence of either antigen-positive or -negative cells. Hence, the development of improvements in CAR design to target antigen loss and increase effector cell persistency represents a critical need. Here, we report on the anti-tumor activity of a CAR T-cell possessing two complete and independent CAR receptors against the multiple myeloma antigens BCMA and CS1. We determined that the resulting compound CAR (cCAR) T-cell possesses consistent, potent and directed cytotoxicity against each target antigen population. Using multiple mouse models of myeloma and mixed cell populations, we are further able to show superior in vivo survival by directed cytotoxicity against multiple populations compared to a single-expressing CAR T-cell. These findings indicate that compound targeting of BCMA and CS1 on myeloma cells can potentially be an effective strategy for augmenting the response against myeloma bulk disease and for initiation of broader coverage CAR therapy.

Anti-CD19 chimeric antigen receptor targeting of CD19 + acute myeloid leukemia

“…Donor T-cells were taken from residual samples following the protocol approved by the Institutional Review Board. The CD19bCAR construct was subcloned into a CAR lentiviral vector containing the same backbone described previously [6] , [7] , [8] . Lentiviral generation and co-culture killing assays were as described previously [6] , [7] , [8] .…”

Chimeric Antigen Receptor T Cells: Extending Translation from Liquid to Solid Tumors

“…Here, the authors used a single lentiviral construct to express two entire secondgeneration CARs: one against BCMA and the second against CS1, each containing a CD8 hinge and transmembrane domain, the 4-1BB costimulatory domain, and a CD3f signaling domain. 90 The strong SFFV promoter was used for dual CAR expression, and the self-cleaving P2A peptide was incorporated between the two CAR sequences to allow expression of each CAR on the T cells. Compound CAR T cells exhibited superior in vitro and in vivo anti-myeloma activity compared to CAR T cells that targeted a single antigen.…”

Paving the Way toward Successful Multiple Myeloma Treatment: Chimeric Antigen Receptor T-Cell Therapy

“…One possible solution is to use compound CAR T cells. These are T cells that express two (or more) different CARs [126]. The goal is to simultaneously target many antigens to overcome the limitation of the loss of one particular antigen [127].…”

“…The goal is to simultaneously target many antigens to overcome the limitation of the loss of one particular antigen [127]. For example, compound CAR T cells expressing both anti-BCMA and anti-SLAMF7 CAR have been developed, and it was shown that these cells efficiently reduced the number of BCMAs and SLAMF7-positive cells, in contrast to anti-BCMA CAR T cells alone [126].…”