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EBMT 2022 Annual Meeting - Presidential Symposium Abstract Presentation - Engineering T-Cells to prevent GvHD and Leukemia Relapse following Allogeneic SCT

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GS2 Presidential Symposium - Monday, March 21, 14:15 - 15:45 CET, Congress Hall / Virtual Hall 1

GS2-10 ENGINEERING T-CELLS TO PREVENT GRAFT-VERSUS-HOST DISEASE AND LEUKEMIA RELAPSE FOLLOWING ALLOGENEIC STEM CELL TRANSPLANTATION

Author team: Feiyan Mo, Baylor College of Medicine, Houston, Texas, USA and colleagues.

Q: Congratulations on your inclusion in the President’s Symposium Feiyan. Tell us about you.

A: I’m a graduate student at Baylor College of Medicine (Houston, Texas, USA).

Q: Why did you decide to do this study?

Acute graft-versus-host disease (GvHD) commonly arises in patients following allogeneic haematopoietic stem cell transplantation (alloHSCT) and contributes to the overall morbidity and mortality. Prophylaxis and treatment of acute GvHD involve general immunosuppression that may weaken protective T-cell responses and thus increase the risk of tumour relapse or viral reactivation.

Therefore, strategies to selectively ablate GvHD-causing T-cells while preserving beneficial T-cell immunity would improve outcomes in patients post-transplant. Engineered T-cells have been very successful in tackling various haematologic malignancies but their application beyond direct tumor targeting has been much less explored.

In this study, we sought to harness the potency of engineered T-cells and redirect them against pathogenic T-cells that mediate GvHD. In my previous work in the lab, I showed that human T-cells can be engineered to specifically target alloreactive T-cells that cause immune rejection (Mo et al., Nature Biotechnology, 2021). I subsequently became interested in extending this approach to selectively ablate pathogenic T-cells that mediate acute GvHD. Furthermore, I hypothesized that targeting these pathogenic T-cells can be combined with eliminating residual leukemia in a single donor-derived T-cell product that would suppress GvHD and potentiate the graft-versus-leukemia (GvL) effect.

Q: What were the main findings?

First, we had to understand how best to target alloreactive T-cells without producing extensive damage to beneficial T-cell responses. We identified a T cell activation marker OX40 that was upregulated on activated human alloreactive T-cells, primarily on the CD4+ subset.

We then engineered a cytotoxic OX40-specific alloimmune defense receptor (OX40.ADR) that redirected T cells to eliminate activated CD4+ T cells and effectively suppress alloimmune responses in vitro. At the same time, OX40.ADR T-cells spared the majority of activated CD8+ T cells, including EBV-, CMV- and adenovirus-specific T cells, and had no discernible activity against resting lymphocytes.

In a murine xenogeneic GvHD model, a single infusion of human OX40.ADR T cells fully protected animals from fatal GvHD driven by autologous human PBMC. To enable simultaneous activity of engineered T cells against acute GvHD and leukemia relapse, we further armed OX40.ADR T cells with a CD19-directed CAR (CD19.CAR). In a mouse model of residual leukemia post-alloHSCT, administration of T cells co-expressing OX40.ADR and CD19.CAR mediated dual protection against tumour relapse and acute GvHD.

Q: What are the implications for the findings, and will you be following up the study?

These results highlight the importance of OX40+ T-cells in driving acute GvHD pathogenesis. They also support the feasibility of a bi-functional engineered T cell product derived from the stem cell donor to suppress both disease relapse and acute GvHD following allogeneic stem cell transplantation, without substantially increasing the risk of infectious complications. We hope to eventually evaluate this approach in the clinic.

Q: What other projects are you involved in at the moment?

At the moment, I am finishing up my PhD (I have my thesis defense scheduled in June 2022) and leading the optimization of T-cell targeting receptors for clinical translation.

Thanks Feiyan and enjoy EBMT 2022!

AM22 Presidential Symposium Feiyan Mo
Feiyan Mo and Principal Investigator Maksim Mamonkin 
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