CAR-T Meeting 2023 | Exploring the potential role of CD7-targeting CAR-T cells for the treatment of T-ALL
Maksim Mamonkin, PhD, Baylor College of Medicine, Houston, TX, shares some insights into the promise of CD7-targeting CAR-T therapies for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL). Dr Mamonkin explains methods used to develop these products, and further highlights the promising activity that has been observed in ongoing clinical trials. 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)
So CD7 is an excellent target in T-cell ALL. It’s expressed very brightly, uniformly in most of the cases. It is frequently downregulated in mature T-cell neoplasms, which is peripheral T-cell lymphoma. But for T-ALL, it’s among the best, if not the best target, and so, developing CAR-T cell approaches for this disease obviously makes a lot of sense. Now, unlike CD5 that are automatically fratricide resistant, for CD7 CAR-T cells, we have to do something else...
So CD7 is an excellent target in T-cell ALL. It’s expressed very brightly, uniformly in most of the cases. It is frequently downregulated in mature T-cell neoplasms, which is peripheral T-cell lymphoma. But for T-ALL, it’s among the best, if not the best target, and so, developing CAR-T cell approaches for this disease obviously makes a lot of sense. Now, unlike CD5 that are automatically fratricide resistant, for CD7 CAR-T cells, we have to do something else. We have to either CRISPR it out, or we can use protein expression blocker to remove surface expression, or the approach that we have recently developed is not to do any of those and instead just expand them in the presence of pharmacologic inhibitors of tyrosine kinases that block that signaling. And so, as a result we can generate the T-cell products that are quite functional.
And there have been several clinical trials so far of CD7 CAR-T cells using different cell sources, autologous, donor-derived, off-the-shelf, allogeneic cells, using different strategies to prevent fratricide, again, CRISPR-ing them out, sort of blocking with an additional construct that anchors inside the cell. And both of these lead to very functional T-cell products, and there have been a few studies primarily coming out from our colleagues in China that show very good activity in patients with refractory and relapsed T-cell ALL, as a bridge to hematopoietic stem cell transplant most of the time. And our own clinical experience shows that cells that are unmanipulated, unedited and expanded with tyrosine kinase inhibitors also produce very good responses, at least on dose level two, we continue escalating that. Also the important aspect of that is aplasia of normal T-cells is limited because of the normal subsets that are naturally CD7 negative, they repopulate the host, they expand, and we tend to think that they mediate protection against systemic infections. So the safety profile is pretty good for that.
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