Dr. Maria Themeli, Group Leader at the Hematology Department of Amsterdam UMC (VUMC), Cancer Center Amsterdam (CCA), has extensive experience in chimeric antigen receptor-engineered T cell (CAR T) design and development. During her post-doctoral research in the lab of Dr. Michel Sadelain at Memorial Sloan Kettering Cancer Center, she reported the use of induced pluripotent stem cells (iPSC) as a broadly applicable source of therapeutic CAR T cells. Currently, her research group’s focus lies in the development of innovative, off-the-shelf CAR T cell therapeutics against hematological malignancies, especially multiple myeloma and leukemia. Their efforts mainly aim to improve safety, efficacy and persistence of the existing single-targeted CAR T-cell approaches by implementing a multiplexed strategy.

B-cell maturation antigen (BCMA) is a potential target antigen in multiple myeloma due to its highly selective expression in malignant plasma cells. BCMA targeted CAR T-cell therapy has been proven to be effective in patients with multiple myeloma. Despite that complete remission level reaching around 60-86% (Ali et al, Blood 2016; Zhao et al. J Hematol Oncol. 2018; Raje et al. NEJM 2019), a subset of patients still experience tumor relapse. One of the major suggested mechanisms for CAR T cell failure and tumor relapse in patients is significantly reduced antigen expression level, lowering the success of antigen target recognition and target tumor elimination. Other contributing factors are the lack of in vivo T-cell expansion, limited persistence and intrinsic dysfunction (exhaustion) of CAR T cells. Altogether, low antigen density on the tumor and insufficient efficiency of single-targeting BCMA CAR T-cells signify the need for a more effective approach.

Tumor escape through target antigen downregulation is one of the known mechanisms that leads to patient relapse. To counteract this effect, the researchers set out to investigate if they could increase the cell avidity of BCMA CAR T-cells against target cells expressing low levels of BCMA by co-transfecting the T-cells with a CD38 targeting CCR. Indeed, cell avidity of BCMA-CD38 CAR/CCR T-cells for the target cells, as measured using the z-Movi^® Cell Avidity Analyzer, was increased compared to the parental BCMA targeting CAR T-cells (Fig. 1a & 1b). In agreement with these results, the cells showed increased in vitro cytotoxicity against their target cells (Fig. 1c), indicating that enhancing cell avidity by co-targeting CD38 using a CCR enhances BCMA CAR T-cell functionality.