Abstract 2820: Innate immune system in a bag: A novel immunotherapy comprising NK cells, Vδ1 and Vδ2 T-cells
Authors: Simoes André , Patel Mihil , Lane Amy , Illingworth Sam , Edwards Sarah , Kovacs Istvan , Koslowski Michael , Nussbaumer Oliver 
Published: June 2022

The recent successes of chimeric antigen receptor (CAR) T cells in the treatment of hematological malignancies have led to an explosion of adoptive cell therapies for cancer. Currently approved therapies are still limited to patient-autologous αβ T cells. Although successful in some settings, this approach comes with challenges including associated toxicities, high production costs and the requirement to gene edit cells to avoid graft vs host disease in an allogeneic setting. In contrast to αβ T cells, innate immune cells such as Natural Killer (NK) cells and gamma delta (γδ) T cells offer opportunities to develop MHC unrestricted, fully allogeneic, off-the-shelf immunotherapies without the need for gene editing. Whilst NK cells offer great cytotoxic potential, control of MHC dysregulation and stress sensing receptors, γδ T cells on the other hand combine the power of a TCR with a variety of natural cytotoxicity receptors and the capability to orchestrate adaptive immune responses even in an HLA-mismatched context. Lately, Vδ1 T-cells have gained significant attention in the field of cancer immunotherapy based on their evolutionary conserved role in cancer immunosurveillance. Multiple groups are developing protocols to grow clinical grade innate immune cells at scale for the treatment of cancer. Each protocol is designed to grow one specific effector cell type of adequate quality. Despite their unique potential, each cell type faces its own challenges for clinical use. A treatment combining a variety of innate cells could be desirable to mitigate for these limitations. We have developed a first in class, scalable expansion process to simultaneously grow NK cells, Vδ1 and Vδ2 T-cells from a healthy donor leukapheresis in a single culture vessel. This 12-day process induces proliferation of all three cell types, resulting in a viable and cryo-preservable drug product where all cells express markers associated with great cytotoxicity, such as CD56 and NKp30. Named after the high expression of CD56, GDX056 shows great efficacy against haematological and solid tumor cells in-vitro. Integrating a viral transduction step into the expansion process allows us to generate a CAR modified tri-cellular product which shows unprecedented cytotoxicity against target cells at E:T ratios as low as 1:100. In an in vivo NALM-6 leukemia model all cell types show engraftment but different body distribution and persistence over time. Whilst efficacious, GDX056 also serves as a great research tool to study each cell type side-by-side. In summary, we have developed an easily manufacturable, first of its kind cellular product combining all major MHC unrestricted cell types. Whilst Vδ1 T cells and NK cells demonstrate anti-cancer activities, Vδ2 T cells are strong mediators of anti-bacterial biology, hence GDX056 potentially offers a unique combinatorial immunotherapy to be considered in scenarios where patients are prone to infections.

Citation Format: André Simoes, Mihil Patel, Amy Lane, Sam Illingworth, Sarah Edwards, Istvan Kovacs, Michael Koslowski, Oliver Nussbaumer. Innate immune system in a bag: A novel immunotherapy comprising NK cells, Vδ1 and Vδ2 T-cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2820.