Metabolically Labeled CAR-T Cells Against Cancer

The Problem

In recent years, adoptive T cell therapies like CAR-T cell therapy – in which T cells are obtained from a patient, genetically enhanced ex vivo, and infused back into the same patient – have shown spectacular success in the treatment of blood cancers, including leukemias, lymphomas, and more lately multiple myelomas. However, not all patients with a given blood cancer benefit equally from this approach and, importantly, adoptive T cell therapies have not been successfully used to eradicate solid tumors. This is because engineered T cells do not always have the same high functionality, and because they do not easily penetrate solid tumor masses and persist long enough in them in order to exhibit their tumor cell-destroying potential.

Our Solution

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Wyss scientists have invented a novel metabolic labeling technology that enables the “tagging” the surface of T cells with immune-enhancing cytokine molecules. In a mouse melanoma model, this approach dramatically increases the persistence of T cells in solid tumors, their tumor-directed functions, as well as their ability to stimulate the host’s immune system following adoptive transfer. This cytokine-tethering approach has the potential to boost the efficacy not only of T cell therapies, but also of other cellular therapies, while largely avoiding the toxicity observed when cytokines are delivered systemically.

The basic metabolic labeling approach was originally conceived as a tool to track the activity of immune cells in vivo, but then further adapted to cytokine-labeling of therapeutic T cells in vitro. With the evolved technology, modified sugar molecules carrying a reactive “azido group” are delivered via nanoparticles to isolated and cultured T cells, whose sugar metabolism attaches the sugar to proteins as they travel to the cell-surface (surface glycoproteins). At the surface, the azido groups provide high density synthetic targets for click-chemistry reactions in which cytokine molecules modified with a compatible chemical group can be directly “clicked” into the exposed azide-sugar molecules. As a result, T cells’ anti-tumor action and cytokines’ immune-enhancing ability become linked together.

The metabolic labeling technology can be readily integrated into the current T cell manufacturing process, since both the engineered sugar molecules and the cytokine molecules are simply added to the culture media. The team, together with collaborators at the Dana-Farber Cancer Institute, demonstrated in mouse models that the technology enhances T cell functions and their stimulation of the animals’ immune system without producing unwanted systemic side-effects. It significantly inhibited the growth of solid melanoma tumors and, as an add-on to CAR-T cell therapy, helped to completely eliminate lymphoma tumors at doses at which unenhanced CAR-T cells were unable to cure the animals.

Impact

The metabolic labeling concept was first developed in an NIH-funded project, and T cell-specific applications later explored with support from the Northpond Director’s Innovation Fund as part of the Wyss Institute-Northpond Labs research and innovation alliance. Results from those studies encouraged the Wyss Institute to fund the project as a 2022 Validation Project. Since the publication of their first T cell results, the team has further increased the efficiency of metabolic T cell labeling by over 100-fold, and continues to assess the technology’s evolving efficacy in the treatment of solid and difficult blood tumors in vivo. In parallel, they are further simplifying and scaling the approach, and lowering its costs. Metabolic T cell labeling has the potential to be expanded into a platform technology with customizable delivery, sugar, and cytokine components, and applicability to various adoptive T cell and other immune cell therapeutic approaches, whose market was valued at $4.9 billion in 2022 and is expected to annually grow over 20% for the next seven years.