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EBMT 2021 | Virus-specific T-cells targeting SARS-CoV-2 after BMT

Catherine Bollard, MBChB, MD, FRACP, FRCPA, Children’s National Health System, Washington, DC, shares an overview of her talk at EBMT on virus-specific T-cell therapy after bone marrow transplant (BMT), highlighting it’s application in the treatment of SARS-CoV-2 infection. Prof. Bollard explains how virus-specific T-cell therapy has been extended beyond the treatment of Epstein-Barr virus (EBV) and cytomegalovirus (CMV), and outlines the impact of novel expansion techniques on these therapies. Novel virus-specific T-cell therapies target viruses including Zika virus, norovirus and human papillomavirus (HPV). More recently, SARS-CoV-2 directed T-cells, which target membrane, spike and nucleocapsid, have been developed. Prof. Bollard describes research and outlines existing data on the use of virus-specific T-cell therapy targeting SARS-CoV-2. This interview took place during the 47th Annual Meeting of the European Group for Blood and Marrow Transplantation (EBMT) 2021.

Transcript (edited for clarity)

At the EBMT meeting, I talked about virus-specific T-cell therapy, and how the approach using virus-specific T-cells was developed primarily at the beginning for patients after bone marrow transplant to prevent and treat devastating viral diseases such as CMV and EBV. I then walked through the history of that VST approaches, which really started in the early nineties out of Seattle and St Jude’s...

At the EBMT meeting, I talked about virus-specific T-cell therapy, and how the approach using virus-specific T-cells was developed primarily at the beginning for patients after bone marrow transplant to prevent and treat devastating viral diseases such as CMV and EBV. I then walked through the history of that VST approaches, which really started in the early nineties out of Seattle and St Jude’s.

And these days we’ve really been able to broaden the applicability of these virus-specific T-cells, because we’ve been able to do rapid manufacturing approaches using very little manipulation in the laboratory. And there is a new, what I like to call “GMP in a Box” technology. One example of that is the Miltenyi Prodigy System, which really allows us to rapidly expand virus-specific T-cells when the donor is seropositive for the virus of interest.

So, I walked through that history and showed how, if you give donor-derived virus-specific T-cells to patients after bone marrow transplant as a preventative strategy, it’s over 90% effective. If you give it to those patients who are already infected or have reactivated the virus, the efficacy ranges in the 70 to 90+ range. So, pretty impressive for even against viruses where we lack conventional therapies.

So, right now, the argument is, can we expand to any virus? Currently at Children’s National, we are exploring a six-virus product targeting CMV, EBV, adenovirus, parainfluenza virus, HHV-6 and BK virus, but we and others have expanded to multiple other viruses, including HPV, Zika virus, HIV and norovirus. We currently have a trial that’s just about to start.

So, obviously with the start of this pandemic, those of us in the virus-specific T-cell field felt we had the tools in place to develop a SARS-CoV-2 specific T-cell therapy. So, I walked us through the steps that we took, starting back in March 2020. Mike Keller and his team here developed T-cells from convalescent donors. Most of them had had relatively mild disease. And we expanded the T-cells against membrane, spike, nuclear capsid, and envelope.

And what we showed was in these convalescent donors, you could reliably expand SARS-CoV-2 specific T-cells, predominantly targeting spike and membrane, and to a lesser extent nuclear capsid, but really the dominant response was to a hotspot in membrane. And this is important because obviously the current vaccines are predominantly targeting spike, and so it does raise some interest that if the natural immunity is really targeted to a conserved region of membrane, and spike is the target for the vaccines, and we know that spike is vulnerable to mutations, whereas membrane, it seems to be less vulnerable, then it does pose the question when we’re developing these approaches, preventative and treatment approaches, that involving membrane targeting may be prudent.

So right now, we’re about to submit our clinical trial to the FDA using T-cells targeting spike membrane and nuclear capsid that we’re going to generate from healthy bone marrow transplant donors, and give these to patients after bone marrow transplant as a preventative strategy or as a treatment approach.

So finally, I do want to highlight the importance of developing this sort of T-cell therapy targeting SARS-CoV-2 as a treatment. We know that with the recent mutations that are currently spreading globally, in particular, the so-called UK strain and the South African strain which appear more virulent. We know that certainly in the UK variant, that this variant developed in an immunosuppressed patient who was unable to clear the virus. And it does appear that prolonged shedding of the virus in individuals who are unable to clear the virus because they lack robust T-cell immunity to clear the virus, is contributing to the development of these mutant strains. So, by developing a T-cell therapy to treat these immunosuppressed patients to prevent this prolonged shedding may actually have an impact globally to prevent the occurrence of ongoing, more virulent mutant strains.

The broadening applicability of T-cell therapy for SARS-CoV-2 is going to need industry interest. We know that we can give virus-specific T-cells as an off-the-shelf therapeutic so this would lend itself nicely to a commercialization model. So, I could see that there is potential to develop a SARS-CoV-2 T-cell therapy that would have more of a global impact than just treating at a few boutique centers.

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