CAR-T Meeting 2023 | Mechanisms of resistance to CAR-T therapy in lymphoma & potential strategies to overcome these
Marco Ruella, MD, University of Pennsylvania, Philadelphia, PA, shares some insights into mechanisms of resistance to CAR-T cell therapy in patients with lymphoma. Dr Ruella highlights three major causes of resistance, including T-cell dysfunction, the role of the tumor microenvironment, and tumor intrinsic mechanisms, and concludes by discussing novel strategies being explored to overcome these. This interview took place at the EBMT-EHA 5th European CAR T-cell Meeting held in Rotterdam, The Netherlands.
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Transcript (edited for clarity)
I presented again on the mechanism of resistance to CAR-T cells, in particular focusing on lymphoma. And so, we are very excited about the clinical results of CAR- T cells in lymphoma. However, we need to recognize the majority of patients actually do not respond or eventually relapse to CAR- T cell therapy. And so, we really need to understand what are the mechanisms of resistance in order to develop better products...
I presented again on the mechanism of resistance to CAR-T cells, in particular focusing on lymphoma. And so, we are very excited about the clinical results of CAR- T cells in lymphoma. However, we need to recognize the majority of patients actually do not respond or eventually relapse to CAR- T cell therapy. And so, we really need to understand what are the mechanisms of resistance in order to develop better products.
And so, what I was presenting earlier today in my presentation is, that we have three main categories of relapse after CAR- T cell therapy. One is related to the CAR-T cell dysfunction, so the T-cell can be exhausted to start with, can become exhausted over time or dysfunctional, and that can be a cause of relapse. The second one is the role of the tumor microenvironment and the host factors, there are a lot of immunosuppressive cells in the tumor microenvironment that might inhibit CAR-T cell function.
And the last one is about the tumor intrinsic mechanism. And that’s where I really focused my presentation on two main stories. One is the antigen loss. So, this is when the lymphoma cell loses expression of CD-19. And in our cohort of patients, we saw that in about 30 to 40% of patients by doing immunochemistry at relapse. And I went on discussing potential strategies to overcome antigen escape. And I described targeting CD-79 as a new target in combination with CD-19 and we did some preclinical work on that.
And then I moved to the apoptosis. Another intrinsic mechanism, tumor intrinsic mechanism is the fact that the tumor cells can be resistant to apoptosis and thereby not being killed by the CAR- T cells. And so in that regard, we studied BCL-2. BCL-2 is an important target because it’s a target of venetoclax, which is an FDA approved inhibitor of BCL-2. And we show that you can combine BCL-2 inhibitor with CAR-T cells in-vitro. But if you do in-vivo, you will see that the combination is toxic to the CAR- T cell. And so, we developed a strategy to make the CAR-T cell resistant to venetoclax, so that now you can combine them efficiently with venetoclax. And so, this was basically the summary of the challenges and what I presented during my talk.
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