CAR-T Meeting 2024 | The role of lymphodepletion in CAR T-cell therapy: current knowledge & the need for personalization
In this video, Ulrich Jäger, MD, Medical University of Vienna, Vienna, Austria, discusses the role of lymphodepletion in CAR T-cell therapy. Lymphodepletion is integral to the CAR-T process as it prepares the immune system, microenvironment, and tumor to improve the expansion of the infused CAR T-cells. However, a high degree of heterogeneity has been identified between lymphodepletion regimens, which must be addressed. Higher doses of lymphodepleting agents are associated with greater efficacy and toxicity, meaning that efforts are being made to determine an optimal lymphodepletion protocol that will maximize efficacy while decreasing the rate and severity of toxicity. Prof. Jäger highlights that many questions regarding optimal lymphodepletion remain and that personalization of the regimen to each patient will be necessary to improve outcomes. This interview took place at the EBMT-EHA 6th European CAR T-cell Meeting in Valencia, Spain.
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Transcript (edited for clarity)
Lymphodepletion is an essential part of the CAR T-cell cycle.
It prepares the body, the immune system, the microenvironment, and the tumor for the infusion of the CAR T-cells and prepares these systems to make the CAR T-cells expand better. It has initially been designed as analogous to allogeneic transplant. So the substances are pretty much the same- it’s chemotherapy, particularly fludarabine, cyclophosphamide, and similar substances...
Lymphodepletion is an essential part of the CAR T-cell cycle.
It prepares the body, the immune system, the microenvironment, and the tumor for the infusion of the CAR T-cells and prepares these systems to make the CAR T-cells expand better. It has initially been designed as analogous to allogeneic transplant. So the substances are pretty much the same- it’s chemotherapy, particularly fludarabine, cyclophosphamide, and similar substances.
And, we have studied the problem within a work package, work package six within the EU consortium, which is called T2Evolve. And what we realized is that, in reality, there is very little data on what the best regimens are and the treatment regimens differ -we identified 26 different regimens with no real scientific background on why we use what.
So, that’s the basic situation.
In the meantime, we’ve learned a few things, so there were some improvements in order to personalize things. Because what we realized is that lymphodepletion has two major effects on the tumor and the patient, which is the efficacy is increased when the lymphodepletion doses are increased, but that, at the same time, will also increase the toxicity. So, the efforts are directed towards improving the efficacy by, for instance, personalizing the dose, and towards reducing the toxicity.
And there are some attempts by our colleagues from the Sloan Kettering, for instance, who have devised an index where we can calculate, based on population and pharmacokinetic [data], how much fludarabine we should give and an optimal dose has been defined. This sounds very good; however, there are some problems because the levels that we measure in these patients regarding fludarabine (the blood levels) are not always consistent with what we predict. That’s been shown by our Spanish colleagues and so on. So we’ve made some minor progress in terms of the dosage, but we’ve defined the problems now, and I think we can move forward.
And then the other thing is that we have introduced some new substances, particularly for the lymphomas.
And what I forgot to say is that lymphodepletion is different with, for instance, the source of cells -allogeneic versus autologous cells. It will be different when we move into the solid tumor field because they will use substances which have more activity against solid tumors, etc.
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