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EBMT 2021 | TGFb-resistant NK cells for hematological malignancies

Catherine Bollard, MBChB, MD, FRACP, FRCPA, Children’s National Health System, Washington, DC, outlines her talk at EBMT 2021 on TGF-beta (TGFb)-resistant natural killer (NK) cell therapy for hematological malignancies. Prof. Bollard outlines research investigating TGFb-resistant T-cells for the treatment of Hodgkin lymphoma after bone marrow transplant and describes how this has progressed into NK cells. TGFb-resistant NK cells have been evaluated in a murine model of neuroblastoma, where they demonstrated efficacy. This interview took place during the 47th Annual Meeting of the European Group for Blood and Marrow Transplantation (EBMT) 2021.

Transcript (edited for clarity)

My other talk was focused on the development of TGF-beta resistant NK cells for solid tumors, as well as hematologic malignancies. This is really born out of the work I originally did when I was working with Cliona Rooney at Baylor College of Medicine, developing TGF-beta resistant T-cells for patients with Hodgkin lymphoma after bone marrow transplant.

We showed in that setting that T-cells that were targeting the EBV proteins expressed by these Hodgkin lymphoma Reed-Sternberg cells did have, it appears, enhanced potency in vivo when they were rendered resistant to TGF-beta, which typically is very rich in the Hodgkin lymphoma tumor environment and has devastating effects on T-cell function and proliferation...

My other talk was focused on the development of TGF-beta resistant NK cells for solid tumors, as well as hematologic malignancies. This is really born out of the work I originally did when I was working with Cliona Rooney at Baylor College of Medicine, developing TGF-beta resistant T-cells for patients with Hodgkin lymphoma after bone marrow transplant.

We showed in that setting that T-cells that were targeting the EBV proteins expressed by these Hodgkin lymphoma Reed-Sternberg cells did have, it appears, enhanced potency in vivo when they were rendered resistant to TGF-beta, which typically is very rich in the Hodgkin lymphoma tumor environment and has devastating effects on T-cell function and proliferation.

So similarly, TGF-beta has devastating effects on other immune cells, including NK cells, natural killer cells, which in particular TGF-beta effects their cytolytic activity. The attraction of NK cells, however, is that they can be given as an off-the-shelf strategy. So, that’s why we then pivoted from a T cell platform to an NK cell platform. And we showed a recent paper we published in clinical cancer research, where we had genetically engineered these NK cells, not only to be resistant to TGF-beta, but also to turn the negative signal of TGF-beta into a positive signal for the NK cell, making it more activated on binding of TGF-beta.

So, we evaluated this novel therapeutic in a murine model of neuroblastoma, which is a tumor that we know can be susceptible to NK cell-mediated killing, but is also a tumor that has a high secretion of TGF-beta in the tumor microenvironment. And so, we showed in these mice that the mice that survived the longest with a lack of progression-free, disease progression was the mice that received the NK cells that were gene engineered to express this activating receptor, where we, as I said, turned the negative signal of TGF-beta into a positive signal for the NK cell.

So we now have pharma interest to move this into clinical trials. And we’re hoping to also expand this therapy to other cancers, such as CNS tumors and other adult solid tumors.

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