ASH 2021 | Overcoming resistance to CAR-T: target upregulation, microenvironment modulation, and novel targets
Hermann Einsele, MD, FRCP, University of Würzburg, Würzburg, Germany, shares an overview of current strategies under investigation to overcome resistance to CAR T-cell therapy. Several factors thought to impact on the success of CAR-T therapy are being targeted. Firstly, BCMA expression levels are thought to play a role and thus, investigators are looking to upregulate BCMA expression on myeloma cells using gamma secretase inhibitors. Based on observations of microenvironment changes in patients who respond well to CAR-T, ways to mimic these changes are being investigated. These included adding immunomodulatory agents to CAR-T therapy to create a more pro-inflammatory environment and modulating anti-apoptotic gene regulation. Finally, Prof. Einsele mentions studies of new targets for CAR-T therapies to overcome irreversible BCMA loss. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.
Transcript (edited for clarity)
There are probably several factors that have an impact on the success of a CAR T-cell therapy. First of all, it’s the BCMA expression, and there are studies and there is a presentation at the ASH meeting where they use a gamma secretase inhibitor, which increases the express of BCMA on the myeloma cells by a median of 15-times. And this seems to actually increase the efficacy of the BCMA-directed CAR T-cells...
There are probably several factors that have an impact on the success of a CAR T-cell therapy. First of all, it’s the BCMA expression, and there are studies and there is a presentation at the ASH meeting where they use a gamma secretase inhibitor, which increases the express of BCMA on the myeloma cells by a median of 15-times. And this seems to actually increase the efficacy of the BCMA-directed CAR T-cells. And in addition, maybe, therefore having the same or even better efficacy, but lower toxicity. So this is a very interesting strategy that has been developed from this finding of variable BCMA expression. The second one is that, potentially, also, the microenvironment plays a major role in the response to a CAR T-cell product. There were several presentations actually looking at the microenvironment, but they found that in patients responding, that there is an increase in CD4 and CD8 T cells in the microenvironment, that there is a reduction in the monocytes, and that there is an upregulation of pro-inflammatory cytokines and also anti-apoptotic genes.
And from these findings, there are two, maybe, conclusions. One is to add, actually, IMiDs to CAR T-cells and thereby change the microenvironment, make it even more proinflammatory, thereby increasing the efficacy of CAR T-cells. And the other one is to kind of try to modulate the regulation of anti-apoptotic genes, and thereby making myeloma cells more susceptible to CAR T-cells. A third strategy is, and that’s something a lot of presentations are addressing at this meeting, is that there is, in some myeloma patients, an irreversible BCMA loss. So the target antigen is completely lost. And this seems to be associated with a biallelic deletion of a part of the chromosome 16p which encodes for BCMA. And there was a nice publication really looking at mechanisms of the loss of BCMA. And actually to address this problem,, there are several presentations now showing CAR T-cells targeting surface antigens apart from BCMA, like GPRC5D, or we are doing a study where we generate a CAR T-cell product targeting SLAMF7. So all mechanisms to overcome these resistance mechanisms in myeloma cells.
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