Towards clinical application of BCMA-CAR T cells empowered with optimized killing (OK) technology

We developed a technology, coined optimized killing (OK) technology, that boosts tumor cell killing by CAR T cells, thereby bypassing resistance mechanisms in tumor cells. We previously found that BCMA CAR T cells equipped with a granzyme B-NOXA fusion construct improves MM cell killing in vitro and in a mouse xenograft model. Here, the granzyme B sequence allows localization of pro-apoptotic NOXA into granzyme B-positive cytotoxic granules. After tumor cell recognition granzyme B, together with NOXA, is secreted into the synapse between the CAR T cell and tumor cell. NOXA enters tumor cells through perforin pores and specifically binds and inhibits MCL-1, resulting in apoptosis of the MM cell. In this proposal we aim to advance our technology and make it suitable for clinical application. Specifically, we aim to A) generate an integrated and clinically applicable NOXA-BCMA CAR vector, B) assess superiority compared to conventional BCMA CAR T cells and C) examine possible toxicity of our approach using 3D co-cultures with primary human cells and humanized mouse models.

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Corine Pleijte